Groningen Research Institute for Asthma and COPD

Annual Report 2014

UMCG

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Content Mission statement ................................................................................................................................... 3

Introduction ............................................................................................................................................. 4

Research area .......................................................................................................................................... 7

Perspectives ............................................................................................................................................ 8

The year 2014 in review ........................................................................................................................ 11

Highlights ........................................................................................................................................... 11

Prizes/Awards .................................................................................................................................... 12

Visitors ............................................................................................................................................... 12

Special Topics ........................................................................................................................................ 13

Special Topic 1 ................................................................................................................................... 13

Special Topic 2 ................................................................................................................................... 16

Special Topic 3 ................................................................................................................................... 21

Special Topic 4 ................................................................................................................................... 25

Special Topic 5 ................................................................................................................................... 29

Departments.......................................................................................................................................... 33

Members 2014 ...................................................................................................................................... 35

International collaboration 2014 .......................................................................................................... 37

Seminar program 2014 .......................................................................................................................... 40

Research meetings 2014 - presentations .............................................................................................. 42

Genome-wide nasal gene expression in COPD ..................................................................................... 44

Brainstorm sessions 2014 ...................................................................................................................... 45

Research projects in 2014 ..................................................................................................................... 46

Publications 2014 .................................................................................................................................. 54

Dissertations ...................................................................................................................................... 54

Publications SCI journals .................................................................................................................. 55

Publications in Dutch ......................................................................................................................... 70

Books / Book chapters ....................................................................................................................... 70

Contributions to other research institutes ........................................................................................ 70

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Mission statement

The mission of GRIAC is the multidisciplinary translational study of obstructive airway and pulmonary diseases and healthy ageing

Program leaders:

Prof.dr. H.M. Boezen Prof. dr. G.H.Koppelman Visiting address: University Medical Center Groningen Hanzeplein 1 NL-9713 GZ Groningen Website: www.griac.nl Webmaster: Prof.dr. W. Timens

Secretariat: Ms. J. Blokzijl, Dept. Pediatric Pulmonology and Pediatric Allergy Beatrix Children’s Hospital University Medical Center Groningen Hanzeplein 1 P.O. Box 30.001 NL-9700 RB Groningen Phone: 31-50-361 1107 Fax: 31-50-361 1704 Email: h.m.boezen@umcg.nl and g.h.koppelman@umcg.nl

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Introduction The Groningen Research Institute for Asthma and COPD (GRIAC) is dedicated to research on obstructive and pulmonary diseases on the edge of clinical and fundamental research, arising from a clinical-scientific background. GRIAC operates within the research framework of the University Medical Center Groningen, which has a central focus on healthy ageing and the Faculty of Science of the University of Groningen, which has a focus on molecular life and health. GRIAC is part of the governmentally accredited organization GUIDE (Groningen University Institute for Drug Exploration) which is embedded in the Groningen School of Medical Sciences (GSMS). Most research is funded by external support as given by NWO, Dutch Lung Foundation, the European Community and industry. The research conducted in Groningen results from internal discussions within the scientific forum of researchers on asthma and COPD in Groningen and from consortia with researchers from collaborating institutes inside the Netherlands and abroad. Participating departments The multidisciplinary and translational research of GRIAC is the result of an intensive collaboration between the researchers of GRIAC, consisting of our members from different disciplines. The disciplines involved are allergology, experimental pulmonology and inflammation research, epidemiology, general practice, molecular pharmacology, pathology, paediatric pulmonology and paediatric allergology, pulmonology and respiratory insufficiency. GRIAC recently added new members from the department of Clinical Pharmacy and from ERIBA, the European Research Institute for the Biology of Aging. Collaboration is based on freedom, equivalence and consensus. Extensive collaboration exists with Departments of Dermatology, Gastroenterology, Genetics, Haematology, Medical oncology and Transplantation. Furthermore, collaboration exists with the Department of Analytical Biochemistry (University Center for Pharmacy).

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How we collaborate Every two weeks GRIAC organises research meetings for the whole institute in which both internal and external speakers are invited to venture new ideas and to challenge the audience. This constitutes also the forum in which different types of research are being presented to all members of GRIAC. Members of GRIAC participate in very different aspects of asthma and COPD research, ranging from epidemiology, clinical allergology, pulmonology, pharmacology, and general practice to basic research in genetics, proteomics, tissue studies, cell cultures and animal models. Lively discussions always take place. To enhance collaboration and stimulate new areas of research, GRIAC organises twice yearly a research retreat and monthly “brainstorm sessions” on a specific topic. These brainstorm sessions are used to stimulate novel ideas for multidisciplinary research, and to discuss publication ideas for high impact journals. During the GRIAC retreat the members of the Board of directors, scientific staff and post-docs of GRIAC discuss future perspectives and new developments in research and explore potential new collaborations within their research, based on international developments in the field. During and after the research meeting investigators can discuss their grant proposals with the staff members, who are expert in a particular field. Every five years GRIAC organises an internationally well-received symposium aimed at understanding the differences and similarities between asthma and COPD. In 2014 “Bronchitis IX” has been organized from 23-25th of June in Groningen with again an excellent international faculty. The theme of Bronchitis IX was “Lungs, on the edge of health and ageing” (www.bronchitis9.nl). At every occasion of the defence of a PhD thesis care is taken to also invite a top-researcher of a particular research field. He or she is asked to judge the thesis and participate in the PhD defence on site, and, in addition, to give a presentation. When these external visitors are present, workshops for exchange of ideas are organised for both senior and junior researchers. Finally, there are weekly meetings for junior researchers and staff members. At these meetings there is ample time for discussion on choosing the appropriate study design, the set-up of research protocols, analyses and interpretation of results of research, and for preparation and improvements in concepts of abstracts, and oral and poster presentations at international meetings. Introductory lectures are provided in lung function measurements, laboratory techniques, genetic research and so on. We aim to make our PhD students familiar with these research techniques. These weekly GRIAC meetings aim to teach the understanding of different aspects of the approach towards research on asthma and COPD in the various disciplines involved in GRIAC in order to improve the level of interdisciplinary research. PhD courses in epidemiology, statistics and genetic data analyses are being organised for members of GRIAC and others interested as well. Organisation Two program leaders lead the Institute. They have the following tasks:

Representatives in GSMS and GUIDE

Contacts with the UMCG

Contacts with the University of Groningen

Policy preparation for KNAW, FMW, UMCG and University of Groningen

Preparing propositions for research development The coordinators are advised extensively by the Board of GRIAC, consisting of senior members of the participating departments, who all have their own specific expertise. This board advises in all aspects of research. The board meets once monthly to exchange ideas and prepare policies.

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Research program GRIAC defines ‘obstructive airway and pulmonary disease’ in relation to healthy ageing, as its main topic, which is reflected in our mission statement. Research projects have to fit within this research topic, describing the projects in their mutual cohesion. The tuning of projects and development into a program is the responsibility of the program leaders of GRIAC, in exchange with the Scientific Board of the Institute. Program description Our research is aimed to stretch from bench to bedside and back with feedback loops. Central to the research is the goal to translate fundamental findings into the clinical situation and vice versa, i.e. translational medicine (see figure below).

Clinical research is conducted in different patient groups in comparison with normal control volunteers in order to unravel underlying mechanisms of the diseases (genetics, aetiology, pathogenesis, pathophysiology). Furthermore responses to intervention (mediated by either medical therapy, behavioural counselling, rehabilitation or other treatment modalities) as well as parameters of progression of disease are being assessed in relation to the underlying mechanisms of the disease.

Questions that are generated, but unanswered by clinical research, are approached using in vitro cellular systems and in vivo animal models. The other way around, hypotheses generated from in vitro or in vivo research are translated to the general and clinical human situation. To this aim GRIAC focuses on the following main topics related to obstructive airway and pulmonary disease:

Identification of risk factors for development, progression and remission of disease

Identification of disease related genes and their functionality

Unravelling the pathophysiology of allergen-, environment- and smoke- induced disease, in both humans and animal models

Unravelling the effects of disease related inflammation on lung function, hyperresponsiveness and remodelling of large and small airways

Defining new targets for intervention and evaluation of intervention strategies

Development of non- or minor invasive tools to assess severity of disease and (side) effects of treatment.

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Research area The focus of research is on asthma and COPD, which involves the sub-programs: 1. Epidemiology: Epidemiological studies on endogenous, environmental and lifestyle

risk factors, both in general and patient-based populations, from prenatal onwards to old age.

2. Genomics: Studies on genes, epigenetics, gene expression and function, molecular mechanisms and gene-gene and gene-environment interactions in disease development, progression, remission, and severity, as well as disease intervention (pharmaco- genomics).

3. Pathophysiology and pathogenesis of allergen, smoking and other lifestyle factors, and environment-induced diseases: In vivo studies in humans and animal models using mice and unrestrained guinea pigs. Investigations include lung function techniques and studies of blood, tissues and/or cells derived from airways or lungs. Furthermore, in vitro studies assess cellular activation and interaction as well as signaling pathways in cells and tissue explants (e.g. lymphocyte subsets, epithelial cells, fibroblasts, intact airway, and smooth muscle preparations). Interactions of different cell types are studied in cells obtained by sputum induction as well as airway and lung tissue obtained by bronchoscopy, by surgical biopsy or autopsy. The Placebo controlled food provocation database provides an excellent method to investigate the allergic response to foods.

4. Assessment, modulation and intervention in disease severity, progression and remission: Disease outcome assessment is being studied with techniques such as exhaled breath analyses and small airway function. In addition, validated questionnaires on Quality of Life, drug side effects, hyperresponsiveness and symptoms are developed for diagnostic purposes as well as outcome assessment. Interventions can be at the level of cell cultures, animal models and clinical studies with targeted therapy.

The main strategies to reach our goals are discussed below: Omics Genomics/transcriptomics/exposomics The availability of genetic techniques and the collaboration with the Department of Genetics (Head: Prof. C. Wijmenga) have greatly extended the genetic sub-programs, allowing genome-wide association and methylation studies, high throughput genetic SNP detection, fine-mapping in relevant chromosomal regions and candidate gene studies. Deep sequencing techniques and analysis strategies are currently being developed. Since gene-environment interactions are important for understanding complex diseases like asthma and COPD, these have been explored in several sub-programs, in collaboration with multiple groups in the Netherlands and abroad. This has resulted in gene-environment interaction studies on atopy and asthma, and on COPD onset and progression. The GRIAC group collaborates internationally and takes the lead in some EC-funded FP7 projects (allergy and asthma: MeDALL; COPD: COPACETIC) on genetics and epigenetics of asthma and COPD, and in exploration of specific gene-environment interactions in these projects. The exposome concept refers to the totality of environmental exposures from conception onwards, and is a novel approach to studying the role of the environment in the development of lung disease in the Lifelines cohort. Furthermore, GRIAC is leading studies on gene expression profiling (transcriptomics) and collaborates internationally (University of British Columbia, Laval University) on studies linking gene expression to (epi)genetic variants (eQTL analysis).

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Proteomics/lipidomics Proteomic and lipidomic research has added important possibilities to develop disease susceptibility markers and disease progression and intervention tools. To enable clinical studies that require greater power, continuing and promoting collaboration with general hospitals in the region has expanded the recruitment population. To enhance the quality of the collaboration, local physicians in these hospitals are more involved in the research group and also propose their own studies for discussion in research meetings. Molecular Medicine GRIAC is actively engaged in studies linking clinical outcomes to (molecular) pathophysiology. Often inspired by outcomes from omics studies, the functionality of genes and proteins in disease is studied using molecular approaches in cells and tissues from patients, in cell lines and in animal models. Molecular techniques are being used more effectively and widely, and are being introduced when not present (either in our own labs or as part of local facilities; for example, the recently developed custom micro-array development and accompanying data-mining). In vivo and in vitro silencing of genes are now established techniques that are operational at the University Medical Center and Pharmacy, including the development of knock out and transgenic mouse models.This has enabled the use of RNAi and pharmacological modulation of membrane and nuclear receptors and signaling proteins in cells and tissue slices. Fundamental to this line of research is the exploration of intracellular pathways relevant for disease development.

Clinical Medicine Patient centered research is at the heart of GRIAC. Our translational research approach included clinical and intervention studies in asthma and COPD. Moreover, several cohort studies, both regional as well as national, are lead by GRIAC investigators. The LifeLines cohort study is a unique asset for large scale epidemiological research into healthy ageing. Healthy ageing “Healthy Aging” has been adopted as the main theme for research and clinical profile of the UMCG. An important long term project within this theme is “LifeLines” a planned 30-year survey on risk factors (obtained by questionnaire, objective physiological data and biological and genomic markers) for disease development, COPD being one of the leading themes. This fits very well with the research agenda of GRIAC, including co-morbidity and systemic manifestations of COPD. We are actively participating in the development and sustainment of this program within the UMCG.

Perspectives Asthma and COPD research takes place in a lively and rapidly changing field. New developments will encompass the functional genomics (including exposomics, lipidomics and proteomics) of asthma and COPD. We envisage that integration of the – omics techniques will provide novel insight into the disease networks that lead to these obstructive airway diseases. The population for genetic analyses in asthma and COPD has been greatly expanded, and will be expanded even further, allowing replication and association studies. A number of international genome-wide association studies on asthma and COPD, including analysis on gene-environment interactions are ongoing, as well as gene methylation studies. This will lead to identification of novel genes and environmental factors playing a role in disease onset and progression. We will incorporate integrative genomic approaches in follow up studies.

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Functional studies on gene variations in asthmatic and healthy individuals are ongoing, both in cells and in animal studies. Integration of longitudinal epidemiological data with genetics will provide insight into genetic variants as risk factors for the development, progression or remission of asthma and COPD. Finally, the integration of newly discovered genes with the results of gene expression in relevant tissues that are available and/or cell cultures allows further research into functional relevance and this can be integrated into systems medicine. Increasingly so, epigenetics (e.g. gene-by-environment interactions and differential (genome wide) methylation) is focus of our research. Within GRIAC, we translate the findings from these genomic approaches back to models of disease, such as animal models or cellular experiments. The molecular basis of pathophysiology including airway (hyper)responsiveness, inflammation and remodeling in asthma and COPD is increasingly on the forefront of GRIAC research. For both asthma and COPD, we will gain better insight into the intricate interplay between tissue resident celss (epithelial cells, fibroblasts, smooth muscle cells) on one hand and their interaction with the extracellular matrix and different inflammatory cell types in the lung on the other. With the recognition that most tissue resident cells are highly plastic governed by complex interactions between multiple receptor systems and environmental changes, research will remain focused on unraveling the interactive mechanisms that determine inflammation and remodeling in chronic airways disease. Newly discovered genes will be incorporated into our studies on in vitro modification of epithelial, smooth muscle and fibroblast cell cultures. . In addition, a new area of interest in this research line is tissue repair in COPD and the role of resident cells (including progenitor cells and structural cells of the alveoli) in this response. A focus on the background question of why not all smokers develop COPD will remain a priority, in association with the consequences of smoking cessation and intervention in the progression of inflammation and remodeling. This knowledge is enhanced by studies regarding the effect of smoking (also during pregnancy) on allergy development, asthma progression and susceptibility to develop COPD as well as the effects on treatment response. The former topics will be investigated in animal models and in humans. Exacerbations are sometimes life-threatening occurrences in patients with asthma and COPD, which may affect activities of daily living, increase symptoms, reduce quality of life, and affect disease outcome. Research will focus on practical and minimal interventions to prevent these exacerbations, including research on the underlying mechanisms and the associated increase in symptoms. Finally, side effects of drugs will be assessed by questionnaires, which will help to further understand the optimal approach to asthma and COPD management. Novel techniques like bronchoscopic lung volume reduction in severe COPD patients are explored and evaluated in relation to their effects on e.g. daily physical activity. Physical inactivity, obesity, and a low grade systemic inflammation are increasingly recognized as important risk factors for the induction and clinical expression of asthma and COPD. The determinants and consequences of physical inactivity in COPD are systematically investigated in relation with co-morbid disorders. A physical activity enhancement strategy has been developed in collaboration with the faculty of human movement sciences, which may be used in the primary, secondary and tertiary echelons of our health care system. Research in the rehabilitation program has been recently reinforced with respect to asthma and COPD, and is expected to increase the input to and output of the GRIAC program. This has been expanded by novel invasive techniques such as applying stents in airway walls and chronic ventilatory support in COPD. As both improve exercise capacity in emphysema this might lead to a more effective rehabilitation.

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Notwithstanding the fact that understanding of a disease is of prime importance, the management of the disease as it exists in current patients is of importance. Thus, it is of great interest that transmural management of asthma and COPD is becoming more mature. Collaborative efforts of lung function departments, general practitioners and pulmonologists in addition to nurse practitioners help to provide better health care for individuals with respiratory symptoms that affect their daily life. This ultimately may improve the quality of life of individuals with asthma and COPD. Output, visibility and (external) funding Productivity of GRIAC is at present overall very good and the whole GRIAC institute was graded “excellent”in its most recent Mid Term Review. Results in internal medicine and basic science have been published in top peer reviewed journals and patents have also been filed. GRIAC members have been urged to focus on publication strategy and brainstorm sessions have been organized to even further improve the impact of scientific output. Asthma and COPD are highly prevalent in the general population, and thus focussing on these two syndromes is appropriate and has a high societal relevance. At current the priority of the institute is ranging from cellular models to the underlying disease models to the clinic (translational research) with transdisciplinarity as a major feature. The national and international academic reputation of the senior GRIAC members can be weighted at its merits judging the invitations to address international congresses and their prominent roles in various national and international research and professional societies and working groups in addition to their role in EU collaborations. In 2014, the Expertscape Website graded GRIAC amongst the top institutes in Europe in relation to asthma and COPD. Moreover, since several of these GRIAC members are relatively young and proven to develop their high potential in their specific research field (e.g. epidemiology, pediatric and adult pulmonology, and molecular pharmacology), GRIAC can face its future with confidence. We will continue to invest in the training of young scientists in the field of obstructive airways and pulmonary disease, with a focus on multidisciplinary translational research. Given the true interdisciplinary nature of the institute, we feel confident that ongoing close collaboration of GRIAC members who share their in-depth knowledge of specific research fields in asthma and COPD will keep the institute at the internationally acknowledged level of excellence in the future, and that they will be able to generate sufficient resources to finance this research. We have shifted our focus from smaller (University Medical Centers) towards larger (inter)national and interdisciplinary research grants (Lung foundation consortium grants, NWO TOP grants, European funding) as well as personal grants (VENI, VIDI, VICI and ERC grants). Within the U4 collaboration of the Universities of Groningen, Ghent, Göttingen and Uppsala, international collaborations are ongoing for PhD students to stay at 2 or 3 of these universities for an international PhD project.

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The year 2014 in review

All contributions to the scientific work in GRIAC are important and highly appreciated. It cannot be stressed enough that all the scientific output and results obtained are only possible due to the contribution of every single person who works within our research institute. Nevertheless, without disrespect to the work of members who are not specifically mentioned, we like to highlight some topics that drew particular attention in 2014.

Highlights

The Bronchitis IX symposium entitled: Lungs: on the edge of health and aging, organized by GRIAC, was held from June 23–25 in the UMCG in Groningen. There was an outstanding program with leading researchers in the field of obstructive pulmonary diseases. The presentations were highly interesting and followed by lively discussions. The organizing committee consisted of Dr. M. van de Berge, Prof. G.H. Koppelman, Dr. J.N.G. Oude Elberink, Prof. W. Timens and C. Verver. Following the Bronchitis symposium, the COST congress entitled ‘Early origins of chronic lung disease: a Birds eye view on the ageing lung’ was organized on June 26 and 27, by Dr. R. Gosens and Dr. M.N. Hylkema. 102 registrants from 19 countries presented their work in scientific lectures or the poster session. The COST conference was preceded by the 2nd COST training school on “Molecular Mechanisms of Ageing”, also organized by Dr. R. Gosens and Dr. M.N. Hylkema. Thirteen participants originating from 6 countries registered for the summer school that consisted of workshops and scientific sessions. For some of the scientific sessions, participants benefited from the parallel Bronchitis conference. This not only ensured high quality speakers from all around the world, but also enabled close interaction with these researchers during breaks and at the poster session. In honor of the retirements of Prof. E.J. Duiverman and Prof. J.G.R. de Monchy farewell symposia were organized and in relation to the thesis defences of Dr. O.E.M. Savenije, Dr. D. Ierodiakonou, Dr. A. Oldenburger, and Dr. N.J. Goossens minisymposia were organized. Speakers at these symposia were all national and international leading researchers. Prof. H.M. Boezen organized, in collaboration with Dr. V. Schlünssen from the Aarhus University in Denmark, a hot topic symposium at the annual ERS-conference in Munich entitled: Determine personalized exposure and gene-environment interactions underlying chronic airway disease; the exposome and the epigenome. In March and April two information evenings for the general public entitled: the hereditary causes of asthma and COPD, were organized by Prof. D.S. Postma and Prof. G.H. Koppelman. These evenings were very well attended. In March, Dr. H. Oude Elberink organized a patient information day for patients with Mastocytosis. Prof. H.M. Boezen was elected chair of the ERS working group 6.4 of the ERS Epidemiology assembly ‘genes and environment’. Prof. H. Meurs and Prof. D.S. Postma were awarded as ERS honorary fellow (FERS). Prof. M. Schmidt was appointed as Teaching Director of the Groningen Research Institute of Pharmacy.

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Prizes/Awards

C.E. Boorsma, MSc won the NRS Chiesi Young Investigators award Dr. O.E.M. Savenije won the NRS Young Investigator SAB award for her thesis J. Saleh-Langenberg, MSc won an abstract award at the Food Allergy and Anaphylaxis meeting in Dublin L. Hesse, MSc won an award for the best poster presentation at the EAACI summer school E. van Dijk, MSc won the NRS Young Investigators Presentation award A.I.R. Spanjer, MSc obtained the Presentation Award of the Pharmacy Day, GRIP, 2014.

Visitors

Dr. C. Grainge, University of Southampton, Southampton, UK. January 9, 2014. Prof. Dr. M. Kabesch, University Hospital Regensburg, Regensburg, Germany. January 14, 2014. Prof. Dr. A. Bush, Imperial College, London, UK. January 14, 2014. Dr. S. Krauss-Etschmann, Helmholtz Center, Munich, Germany. February 4, 2014. Prof. Dr. S.T. Weiss, Channing lab, Harvard University, Boston, USA. March 3, 2014. Prof. Dr. J. Vestbo, University of Manchester, Manchester, UK. June 17, 2014. Prof. Dr. I. Sabroe, University of Sheffield, Sheffield, UK. September 2, 2014. Prof. Dr. T. Sigsgaard, Aarhus University, Denmark. September 23, 2014. Dr. G.A. Lockett, University of Southampton, Southampton, UK. October 7, 2014. Prof. Dr. M.C. Michel, University of Mainz, Germany. October 24, 2014. Prof. Dr. E. Klussmann, Max Delbrück Centrum für Molekulare Medizin (MDC), Berlin, Germany. October 24, 2014. Prof. Dr. W. Windisch, University of Witten/Herdecke, Köln, Germany, October 24, 2014. Prof. Dr. H. Maarsingh, Palm Beach Atlantic University, USA. October 30, 2014. Prof. Dr. L.C. Porto, Rio de Janeiro State University, Brazil. October 30, 2014. Prof. Dr. M. Peters-Golden, University of Michigan, Michigan, USA. October 30, 2014. Dr. A. Kruis, Leiden University Medical Center, Leiden, NL. November 18, 2014. Prof. Dr. D. Heederick, University of Utrecht, Utrecht, NL. December 16, 2014. Dr. J. Burgess, University of Sydney, Sydney, Australia. December 19, 2014.

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Special Topics

Special Topic 1

First results of the GENEVA study: Research on the genetics of food allergy in

children C. Dorien van Ginkel, Gerard H. Koppelman, Ewoud A. Dubois.

Departments of pediatric pulmonology and pediatric allergy. Food allergy is a potentially lethal disease and its prevalence is increasing in the Western world1. Furthermore, food allergy reduces quality of life in patients to a greater extent than diabetes2 and is strongly heritable3. One study reported a 5-fold increase for the risk of peanut allergy for a child with a peanut allergic sibling or parents4. Remarkably, only 1 in 2 children suspected to be food allergic and sensitised to food has a positive outcome of a double blind placebo-controlled food challenge (DBPCFC) and is thereby diagnosed as clinically reactive5. We hypothesize that the genetic makeup of a child influences the difference between sensitisation with and without clinical reactivity to food. Specifically, we hypothesize that genes that contribute to skin epithelial integrity are associated with clinical food allergy. To study this hypothesis we use the database of the Food Challenge Unit of the Beatrix Children’s Hospital of the UMCG which contains phenotypic information on food allergy as well as other atopic morbidities on over one thousand children who have been diagnosed by the gold standard test, the Double-Blind Placebo Controlled Food Challenge. This will be coupled to a DNA collection which will be expanded to include samples from 800 children and their parents. This will be achieved by collecting DNA from blood- and saliva samples. We will focus on candidate genes involved in epithelial integrity, and are aiming to perform a genome-wide association study in the future.

The first results of the GENEVA study examined the association between food allergy and the filaggrin gene (FLG). The FLG gene is located on chromosome 1q21 and is part of the epidermal differentiation complex. These genes play an important role in skin barrier function since the filaggrin protein helps aggregate the epidermal cytoskeleton to form a protein-lipid barrier6. An impaired barrier function may permit intact proteins to pass the barrier and to elicit an immune response. Loss of function (LOF) variants of the FLG gene result in a defective form of the filaggrin protein and have a prevalence of about 10% in Western populations7. FLG LOF variants are associated with ichtyosis vulgaris, characterized by palmar hyperlinearity, keratosis pilaris and a fine white scale on the extremities. Ichtyosis vulgaris is strongly associated with atopy8. Furthermore, the FLG LOF variants are strong risk factors for atopic dermatitis9 and are associated with allergic rhinitis and sensitization10. In children with atopic dermatitis, these variants are also associated with asthma11. Other studies suggest a role of FLG in sensitization to foods and clinical food allergy12. We showed that in high risk children suspected of being food allergic, those carrying one or more loss of function variants of the FLG gene are 1.5 times more likely to be clinically allergic as diagnosed by the DBPCFC than children carrying wild type alleles. This strong association is replicated using a family based design, confirming the robustness of this observation13. We furthermore showed that genetic markers may be useful as an addition to clinical assessment in the diagnosis of food allergy13.

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Figure 1. Prevalence of food allergy in subjects with and without FLG risk alleles.

The genetic findings of FLG being an important gene for food allergy have led to the dual-allergen exposure hypothesis for the pathogenesis of food allergy. This proposes that low-dose cutaneous exposure to food allergens triggers Th2 responses and IgE production by B cells while early oral exposure induces tolerance by stimulating regulatory T cells and Th1 cells14. This hypothesis is supported by a study showing that epicutaneous exposure to peanut protein causes Th2-type immunity with high levels of peanut specific IgE and prevents the development of oral tolerance to peanut15. A recent study showed that early life environmental exposure to peanuts, as measured by peanut in household dust, is indeed associated with peanut sensitization and allergy as confirmed by open food challenges, but only in children carrying FLG mutations16. This percutaneous priming is also proposed for the role of FLG in asthma and rhinitis10. In conclusion, we recently showed that in high risk children, loss of function variants of the filaggrin gene are associated with clinical food allergy, as diagnosed by the double blind placebo-controlled food challenges. The FLG gene is therefore likely to be important in the mechanism driving the difference between asymptomatic sensitisation and food allergy, most likely through an impaired skin barrier. Since children carrying one or more loss of function variants of the FLG gene are 1.5 times more likely to be food allergic, such genetic markers may be useful as an addition to clinical assessment in the diagnosis of food allergy. After completing the DNA collection, we hope to replicate the results of the filaggrin gene in a larger study population and study the effect and diagnostic role of the other candidate genes. Furthermore we will use the genome wide data of the LifeLines cohort in the search for new genetic variants associated with food allergy. The GENEVA study is supported by grants of the Nutricia Research Foundation and the JK de Cock stichting. References

1. Branum, A. M. & Lukacs, S. L. Food allergy among children in the United States. Pediatrics 124, 1549–55

(2009).

2. Flokstra-de Blok, B. M. J. et al. Health-related quality of life of food allergic patients: comparison with the general population and other diseases. Allergy 65, 238–44 (2010).

3. Tsai, H.-J. et al. Familial aggregation of food allergy and sensitization to food allergens: a family-based study. Clin. Exp. Allergy 39, 101–9 (2009).

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4. Hourihane, J. O., Dean, T. P. & Warner, J. O. Peanut allergy in relation to heredity, maternal diet, and other atopic diseases: results of a questionnaire survey, skin prick testing, and food challenges. BMJ 313, 518–21 (1996).

5. Van den Berg, M. E. et al. Parental eczema increases the risk of double-blind, placebo-controlled reactions to milk but not to egg, peanut or hazelnut. Int. Arch. Allergy Immunol. 158, 77–83 (2012).

6. Sandilands, A., Sutherland, C., Irvine, A. D. & McLean, W. H. I. Filaggrin in the frontline: role in skin barrier function and disease. J. Cell Sci. 122, 1285–94 (2009).

7. Van den Oord, R. a H. M. & Sheikh, a. Filaggrin gene defects and risk of developing allergic sensitisation and allergic disorders: systematic review and meta-analysis. Bmj 339, b2433–b2433 (2009).

8. Smith, F. J. D. et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat. Genet. 38, 337–42 (2006).

9. Sandilands, A. et al. Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema. Nat. Genet. 39, 650–4 (2007).

10. Weidinger, S. et al. Filaggrin mutations, atopic eczema, hay fever, and asthma in children. J. Allergy Clin. Immunol. 121, 1203–1209.e1 (2008).

11. Rodríguez, E. et al. Meta-analysis of filaggrin polymorphisms in eczema and asthma: robust risk factors in atopic disease. J. Allergy Clin. Immunol. 123, 1361–70.e7 (2009).

12. Brown, S. J. et al. Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy. J. Allergy Clin. Immunol. 127, 661–7 (2011).

13. Van Ginkel, C. D. et al. Loss-of-function variants of the filaggrin gene are associated with clinical reactivity to foods. Allergy (2015).

14. Lack, G. Update on risk factors for food allergy. J. Allergy Clin. Immunol. 129, 1187–97 (2012).

15. Strid, J., Hourihane, J., Kimber, I., Callard, R. & Strobel, S. Epicutaneous exposure to peanut protein prevents oral tolerance and enhances allergic sensitization. Clin. Exp. Allergy 35, 757–66 (2005).

16. Brough, H. a et al. Peanut allergy: Effect of environmental peanut exposure in children with filaggrin loss-of-function mutations. J. Allergy Clin. Immunol. 134, 867–875.e1 (2014).

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Special Topic 2

New avenues for Epac in inflammation and tissue remodeling in COPD

Anouk Oldenburger, Wim Timens, Herman Meurs, Harm Maarsingh, Martina Schmidt Departments of molecular pharmacology and pathology.

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease of the airways and the lung parenchyma, further characterized by airway obstruction and remodeling (1). Symptoms are treated with glucocorticosteroids, anticholinergics, β2-agonists or phosphodiesterase (PDE)-4 inhibitors (2,3). Both β2-agonists and PDE4 inhibitors elevate the second messenger cyclic AMP (cAMP), although by distinct mechanisms (4,5). The two main effectors of cAMP are protein kinase A (PKA) and the exchange protein directly activated by cAMP (Epac), which consists of the two isoforms Epac1 and Epac2.

Epac1 and Epac2: Inflammation

An important cytokine that is increased in COPD is interleukin-8 (IL-8). Our data indicate that Epac and PKA decrease cigarette smoke extract (CSE)-induced IL-8 release by airway smooth muscle (ASM) cells, via inhibition of NF-κB and ERK signalling, respectively. Importantly, we also observed reduced Epac1 expression in lung tissue from COPD patients (6,7).

To investigate the potential cause for the downregulation of Epac1, we studied microRNAs (miRNAs). MiRNAs are epigenetic regulators involved in fine-tuning of cellular activities by posttranscriptional repression of mRNA. In COPD patients, miRNA-7 is increased in serum (8). We investigated the potential interaction of Epac1 and miRNA-7. CSE induced miRNA-7 specifically in human ASM cells. In line, miRNA-7 was increased in bronchial smooth muscle of COPD stage II patients isolated by laser dissection. Importantly, Epac1 expression is reduced in miRNA-7 overexpressing human ASM cells (Figure 1). Our data implicate that upregulation of miRNA-7 by cigarette smoke correlates with the downregulation of Epac1 in COPD (8).

Both Epac1 and Epac2 seem to be implicated in the reduction of CSE-induced IL-8 release from human ASM cells. However, phospholipase Cε (PLCε), a direct effector of Epac, acts pro-inflammatory. To translate our findings on inflammation in vitro to the in vivo situation, Epac1-/-, Epac2-/- and PLCε-/- mice were exposed to cigarette smoke for 5 days. We demonstrated that compared to wild-type (WT) mice exposed to cigarette smoke, the number of total inflammatory cells, macrophages, and neutrophils as well as IL-6 release were lower in Epac2-/- mice, which was also the case for neutrophils and IL-6 in PLCε-/- mice (Figure 2, ref 9). Compared to WT mice exposed to cigarette smoke, the number of macrophages was reduced in Epac1-/- mice. Whereas, the numbers of lymphocytes, only present in low numbers in BALF of air-exposed WT mice, were increased in Epac1-/- mice. Together our data indicated that particularly Epac2 acts pro-inflammatory in vivo (9).

Aberrant epithelial repair is also regarded as a pathophysiological feature of COPD. It is of interest that the A-kinase anchoring protein (AKAP) family member AKAP9 enhanced the endothelial barrier function in concert with Epac1. AKAPs compartmentalize cellular cAMP upon generation of multiprotein complexes. We found that CSE reduced the barrier function in human bronchial epithelial cells, a process accompanied by a reduced membrane expression of E-cadherin and AKAP9 (Figure 1). Silencing of AKAP9 reduced the functional epithelial barrier and prevented the ability of st-Ht31, an inhibitor of AKAP-PKA interactions, to restore membrane localization of E-cadherin. Our data indicate that AKAP9 maintains the bronchial epithelial barrier function and may be important in the pathophysiology of COPD (10).

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Altogether, Epac1 and Epac2 seem to be involved in cigarette smoke induced inflammation, although with a clear distinction regarding their relative contribution. Compartmentalization of cAMP driven by AKAP family members, may be responsible for the distinct biological effects of cAMP.

Remodeling: Epac1 and Epac2 Figure 1: (A) In human bronchial epithelial cells, cigarette smoke extract reduces the barrier function (resistance)which is prevented by St-Ht31, a inhibitory peptide of AKAP-PKA interactions. In addition, the expression of both AKAP9 and E-cadherin is reduced by cigarette smoke extract (further details see ref 9). (B) In airway smooth muscle cells, cigarette smoke extract enhances miRNA-7 levels. Overexpression of miRNA-7 inhibits the protein expression of Epac1. In bronchial smooth muscle of COPD patients a upregulation of miRNA-7 is observed. (C) Epac: implications for structural lung cell functioning(further details see ref 6).

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Tissue remodeling is another feature of COPD and covers different characteristics of the disease such as mucus hypersecretion, airway fibrosis and emphysema. The majority of extracellular matrix (ECM) proteins, including collagens and fibronectin, are produced by fibroblasts. Alterations in the tightly controlled balance of production and degradation of ECM proteins causes structural changes in the lung such as emphysema, characterized by excessive degradation of parenchymal ECM , and (small) airway fibrosis characterized by excessive deposition of ECM proteins (1). Although a role for cAMP in the regulation of remodeling has been shown (4,5), the exact role of the cAMP effectors Epac and PKA on the different aspects of remodeling is not completely known.

Interestingly, it has been reported that cAMP-elevating drugs reduce collagen I synthesis in human lung fibroblasts. A PDE inhibitor and a cAMP analog have been shown to reduce MMP9 and TIMP1 gene expression and activity in different cell types. CSE exposure of the human bronchial epithelial cell line 16HBE14o- leads to increase of MMP9 mRNA and thereby of the MMP9/TIMP1 ratio. Induction of MMP9 mRNA was reduced by specific PKA activation. Pro-MMP9 levels induced by CSE were reduced by the fenoterol, an effect specifically mimicked by pharmacological activation of PKA. PKA inhibition may enhance the MMP9/TIMP1 ratio and thereby reduce emphysema. In contrast, activation of PKA may reduce emphysema by a decrease of the MMP9/TIMP1 ratio (further details see ref 6).

In addition, we tried to identify the role of Epac1 and Epac2 in remodeling processes in the lung by exposure of Epac1-/- and Epac2-/- mice to cigarette smoke. We demonstrated that Epac1-/- mice expressed higher levels of TGF-β1, collagen I and fibronectin. We propose that Epac1, but not Epac2, acts anti-fibrotic. Concerning mucus hypersecretion, Epac1-/- and Epac2-/- were characterized by a constitutively higher expression of MUC5AC mRNA at basal level (Figure 2). We observed that goblet cells tended to be increased in Epac2-/- and PLCε-/- mice, whereas primarily Epac1-/- mice tended to stain positive for the inducer of goblet cell differentiation SPDEF (9).

Overall, we identified distinct roles of Epac1 and Epac2 in remodeling processes. This suggest that Epac1 alone controls remodeling. In contrast, both Epac1 and Epac2 seem to control MUC5AC (9). Similar as for inflammation, compartmentalization of Epac by AKAPs will most likely define a potential role of AKAP-dependent compartmentalization of cAMP in remodeling processes.

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Figure 2: (A) In an acute mouse model of cigarette smoke exposure, Epac2, possibly via PLCε, enhances neutrophils (left panel). Epac1 bears the capacity to reduce the deposition of collagen I in lung tissue (right panel) . (B) Both Epac1 and Epac2 regulate mucus hypersecretion in mice. (C) Epac1 and Epac2: implications in inflammation and remodelling in vivo. Epac2 contributes to cigarette smoke induced-increase in macrophages and IL-1β release. Possibly via PLCε, Epac2 also enhances neutrophils and IL-6 release. Epac1 inhibits collagen I and fibronectin deposition. Both Epac1 and Epac2 play an inhibitory role in mucus hypersecretion. For further details see refs 6, 9.

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Conclusions

These studies implicate an important role for cAMP in COPD. We defined distinct roles of Epac1 and Epac2 in inflammation and remodeling. In an acute model of cigarette smoke exposure in mice, we unraveled pro-inflammatory actions of Epac2. We showed that Epac1 alone is able to reduce remodeling, whereas for the reduction of MUC5AC a concerted action with Epac2 seemed to be required. Based on our findings, the development of selective Epac1 and Epac2 activators and/or inhibitors could be of additive value to alleviate symptoms of COPD. Targeting of these selective Epac activators or inhibitors to specific areas in the lung represents a future goal. Research into compartmentalization of cAMP by AKAPs should be another subject of future research.

Acknowledgement

This work was supported by a Long Fonds (grant 3.2.09.34) and a Rosalind Franklin Fellowship from the University of Groningen to Martina Schmidt. Harm Maarsingh was supported by the Schering-Plough Research Institute (Oss, The Netherlands).

References

1. Hogg JC, Timens W: The pathology of chronic obstructive pulmonary disease. Annual Rev Pathol 2009, 4,

435-459

2. Hoonhorst SJ, Ten Hacken NH, Vonk JM, Timens W, Hiemstra PS, Lapperre TS, Sterk PJ, Postma DS:

Steroid resistance in COPD? overlap and differential anti-inflammatory effects in smokers and ex-smokers.

PloS One 2014, 9, e87443

3. Meurs H, Oenema TA, Kistemaker LE, Gosens R: A new perspective on muscarinic receptor antagonism in

obstructive airways diseases. Curr Opin Pharmacol 2013, 13, 316-323

4. Oldenburger A., Maarsingh H, Schmidt M: Multiple facets of cAMP signalling and physiological impact:

CAMP compartmentalization in the lung. Pharmaceuticals 2012, 5, 1291-1331

5. Dekkers BG, Racke K, Schmidt M: Distinct PKA and epac compartmentalization in airway function and

plasticity. Pharmacol Therap 2013, 137, 248-265

6. Oldenburger A: New avenues for Epac in inflammation and tissue remodelling in COPD. Thesis 2014,

University Groningen.

7. Oldenburger A, Roscioni SS, Jansen E, Menzen MH, Halayko AJ, Timens W, Meurs H, Maarsingh H,

Schmidt M: Potential anti-inflammatory role of the cAMP effectors Epac and PKA: implications in chronic

obstructive pulmonary disease. PLoS ONE 2012, 7, e31574

8. Oldenburger A, van Basten B, Kooistra W, Meurs H, Maarsingh H, Krenning G, Timens W, Schmidt M:

Interaction between Epac1 and miRNA-7 in airway smooth muscle cells. Naunyn Schmiedebergs Arch

Pharmacol 2014, 387, 795-7

9. Oldenburger A, Timens W, Bos S, Smit M, Smrcka AV, Laurent A, Cao J, Hylkema M, Meurs H, Maarsingh

H, Lezoualc'h F, Schmidt M: Epac1 and Epac2 are differentially involved in inflammatory and remodeling

processes induced by cigarette smoke. FASEB J 2014, 28, 4617-28

10. Oldenburger A, Poppinga WJ, Kos F, de Bruin HG, Rijks WJ, Heijink IH, Timens W, Meurs H, Maarsingh H,

Schmidt M: A-kinase anchoring proteins contribute to the loss of E-cadherin and bronchial epithelial barrier

by cigarette smoke. Am J Physiol 2014, 15, 306, C585-97

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Special Topic 3

Occupational pesticide exposure increases risk for COPD

Kim de Jong, Judith M. Vonk, Dirkje S. Postma, H. Marike Boezen

Departments of epidemiology and pulmonology

Chronic obstructive pulmonary disease (COPD) is characterized by persistent and often

progressive airflow obstruction caused by and abnormal inflammatory response to noxious

particles and gases. Tobacco smoking is considered to be the main risk factor for COPD, yet

a substantial proportion of 15–20% of all cases has been attributed to occupational

exposures (1), with proportions up to 30% in never smokers (2). Because occupational

exposures are common, yet also potentially modifiable contributors to the global burden of

COPD, it is important to determine which occupational factors drive the development of this

disease.

Within two Dutch general populations based cohorts, i.e. the LifeLines cohort study and the

Vlagtwedde-Vlaardingen study, we estimated occupational exposure to amongst others

pesticides using a job exposure matrix (JEM). The JEM classified subjects based on ISCO-

88 job codes into no, low and high exposure categories (0/1/2).

First, we showed cross-sectional associations between pesticide exposure and lower levels

of FEV1 and FEV1/FVC in 11,851 individuals from the LifeLines cohort study and 2,364

subjects included in the last survey (1989/1990) of the Vlagtwedde-Vlaardingen cohort (see

figure 1 for associations in LifeLines). Subjects with high levels of exposure to pesticides had

also an increased risk for COPD gold stage 2 and higher (OR = 1.95 (0.92 – 4.13) in

LifeLines and OR = 1.78 (1.14 – 2.79) in Vlagtwedde-Vlaardingen) (3). There were no

consistent associations between exposure to pesticides and the FEF25-75%, a marker of small

airways obstruction (4).

Figure 1. Cross-sectional associations between occupational pesticide exposure and the level of FEV1 (A) and FEV1/FVC (B), for he whole group and stratified according to smoking status (never/ever smoker) in the LifeLines cohort study. Associations with FEV1 were significantly stronger (p<0.05) for ever compared to never smokers.

Additionally within 12,772 observations from 2,527 subjects assessed between 1965 and

1990 in the Vlagtwedde-Vlaardingen cohort we found that subjects with high pesticide

exposure had an accelerated decline in FEV1 and FEV1%IVC (figure 2) (5). Especially within

smokers these implied substantial losses of lung function, for example smokers with high

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exposure to pesticides had 7 ml/year larger decline in FEV1 compared to smokers without

pesticide exposure.

Interestingly, in both the cross-sectional (FEV1) and longitudinal study (FEV1 and FEV1%IVC)

we found significantly stronger associations in ever compared to never smokers, suggesting

synergistic effects of tobacco smoke and pesticide exposure. For example for a pesticide like

Paraquat the primary mechanism for toxicity is related to its cyclic redox reactions and

consequently free radical generation resulting in oxidative damage of the lung tissue. It is

very well likely that the effect of exposure to such a pesticide is more pronounced when anti-

oxidant systems are already depleted by cigarette smoking and the lung is already damage

by free radicals from tobacco smoke.

Fig 2. Estimated course of FEV1 (A) and FEV1%IVC (B) for subjects with high exposure to VGDF only (VGDF + : Pesticides -)

and subjects with joint high exposure to VGDF and pesticides (VGDF + : Pesticides +) compared to unexposed subjects,

modeled for time (years) since first survey after the age of 30 years in the Vlagtwedde-Vlaardingen cohort (1965-1990).

Finally common genetic variation may affect individual susceptibility to exposures such as

pesticides. We therefore assessed interactions between single nucleotide polymorphisms

and pesticide exposure on the level of FEV1 in a genome-wide manner. We identified one

common genetic variant (prevalence minor allele ~25%) in NOS1 that increased

susceptibility to high levels of pesticide exposure in both the LifeLines cohort study (12,400

subjects) and the Vlagtwedde-Vlaardingen study (1,436 subjects) (figure 3) (6).

The NOS1 gene encodes for neuronal nitric oxide synthase that synthesizes endogenous

nitric oxide (NO) from arginine. In the human lung, NOS1 was found in submucosal nerves

and endothelial cells (7). Interestingly this gene has been implicated in pesticide toxicity as

well as in COPD pathogenesis. This suggests that excess release of NO may underlie

pesticide toxicity in the lungs and subsequently lead to an impaired lung function, a hallmark

of COPD.

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Figure 3. Associations of no, low and high occupational exposure to pesticides and the level of FEV1 (ml) in the LifeLines cohort

(A) and Vlagtwedde-Vlaardingen cohort (B) stratified for NOS1 rs482555 genotype.

Apart from a few small scale cross-sectional studies that found associations between specific

types of pesticides and lower levels of FEV1 and FVC in occupationally exposed farmers

from Sri-Lanka (8), South Korea (9) and Costa Rica (10), relatively few studies have focused

on the effects of pesticide exposure on lung function (11). To our knowledge no studies thus

far have shown associations between pesticide exposure and the longitudinal decline of lung

function.

Globally, the agricultural sector employs more than 1.1 billion workers worldwide (about 34%

of the global working force) (12) potentially putting a large amount of workers at risk for

pesticide exposure. Additionally, people living in agriculture-intensive regions may be at risk

for exposure due to pesticide drift (13). This may be especially relevant in a densely

populated country as the Netherlands where large numbers of people live near greenhouses

and pesticide-treated farmland. Little is known about the risks of people living in the vicinity of

these pesticide-treated areas in the Netherlands, and such risks were not taken into account

during the approval process for pesticides’ entry on the Dutch market. Growing concerns

about these risks have led to a first advisory report of a Committee of the Health Council of

the Netherlands, and consequently the initiation of an exposure study among people living in

the vicinity of greenhouses and pesticide-treated farmland that will be carried out in 2015 and

2016.

Publication of the above mentioned studies led to a reaction from the Dutch parliament, but

the approval process for pesticides’ entry of the Dutch marked will not be reconsidered

based on these findings (14) (Rijksoverheid).

References

1. Balmes J, Becklake M, Blanc P, Henneberger P, Kreiss K, Mapp C, et al. American thoracic society statement:

Occupational contribution to the burden of airway disease. American journal of respiratory and critical care

medicine. 2003;167(5):787-97.

2. Hnizdo E, Sullivan PA, Bang KM, Wagner G. Association between chronic obstructive pulmonary disease and

employment by industry and occupation in the US population: A study of data from the third national health and

nutrition examination survey. American Journal of Epidemiology. 2002 October 15;156(8):738-46.

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3. de Jong K, Boezen HM, Kromhout H, Vermeulen R, Postma DS, Vonk JM, et al. Pesticides and other

occupational exposures are associated with airway obstruction: The LifeLines cohort study. Occup Environ Med.

2014 Feb;71(2):88-96.

4. de Jong K, Boezen HM, Kromhout H, Vermeulen R, Vonk JM, Postma DS, et al. Occupational exposure to

vapors, gases, dusts, and fumes is associated with small airways obstruction. Am J Respir Crit Care Med. 2014

Feb 15;189(4):487-90.

5. de Jong K, Boezen HM, Kromhout H, Vermeulen R, Postma DS, Vonk JM. Association of occupational

pesticide exposure with accelerated longitudinal decline in lung function. Am J Epidemiol. 2014 Jun

1;179(11):1323-30.

6. de Jong K, Vonk JM, Kromhout H, Vermeulen R, Postma DS, Boezen HM, et al. NOS1: A susceptibility gene

for reduced level of FEV1 in the setting of pesticide exposure. Am J Respir Crit Care Med. 2014 Nov

15;190(10):1188-90.

7. Kobzik L, Bredt DS, Lowenstein CJ, Drazen J, Gaston B, Sugarbaker D, et al. Nitric oxide synthase in human

and rat lung: Immunocytochemical and histochemical localization. Am J Respir Cell Mol Biol. 1993 Oct;9(4):371-7.

8. Peiris-John RJ, Ruberu DK, Wickremasinghe AR, van-der-Hoek W. Low-level exposure to organophosphate

pesticides leads to restrictive lung dysfunction. Respir Med. 2005 10;99(10):1319-24.

9. Cha ES, Lee YK, Moon EK, Kim YB, Lee Y, Jeong WC, et al. Paraquat application and respiratory health

effects among south korean farmers. Occupational and Environmental Medicine. 2012 June 01;69(6):398-403.

10. Schenker M, Stoecklin M, Lee K, Lupercio R, Zeballos RJ, Enright P, et al. Pulmonary function and exercise-

associated changes with chronic low-level paraquat exposure. American journal of respiratory and critical care

medicine. 2004;170(7):773-9.

11. Hoppin JA. Pesticides and respiratory health: Where do we go from here? Occup Environ Med. 2014

Feb;71(2):80,2013-101876. Epub 2013 Nov 12.

12. International Labour Office. Global employment trends 2012. Geneva: International Labour Organization;

2012. Report No.: ISBN 978-92-2-124924-5 (print).

13. Lee SJ, Mehler L, Beckman J, Diebolt-Brown B, Prado J, Lackovic M, et al. Acute pesticide illnesses

associated with off-target pesticide drift from agricultural applications: 11 states, 1998-2006. Environ Health

Perspect. 2011 Aug;119(8):1162-9.

14. Ministerie van Economische Zaken. Reactie op artikel werkgerelateerde longziekte COPD bij boeren en

kwekers als gevolg van het gebruik van pesticiden. 3 December 2014.

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Special Topic 4

Targeted lung denervation for chronic obstructive pulmonary disease Dirk-Jan Slebos

Department of pulmonology

We recently performed the first-in-human study investigating bronchoscopic radio-frequent ablation of the parasympathetic pulmonary nerves in patients. This new bronchoscopic minor-invasive therapy called “targeted lung denervation” (TLD) is a potential future treatment option for patients with advanced COPD. The first results show that TLD in patients with COPD is feasible, safe and has clinical benefit which appears both durable and dose dependent [ref 1].

Targeted lung denervation (TLD) is a novel bronchoscopic therapy that ablates the parasympathetic innervation of the lungs and has a similar proposed mechanism of action to anticholinergic drugs. TLD therapy is delivered via a dual-cooled radiofrequency (RF) catheter (Holaira, Inc., Minneapolis, MN, USA) (figure 1) designed to target tissue heating at depth thereby producing a narrow band of ablation around the main bronchi while minimizing effects to the inner surface of the airway.

Figure 1 - dual-cooled radiofrequency catheter

As RF current passes from the electrode through the airway and surrounding tissues, these tissues are heated. Coolant continuously circulated through the electrode and balloon removes heat from the surface of the airway wall. The net effect is targeted tissue ablation at depth with minimal heating and damage of the inner surface of the airway.

This targeted tissue ablation is intended to disrupt motor axons within bronchial nerve branches running along the outside of the main bronchi, thereby blocking parasympathetic signaling to the lungs and decreasing neuronal release of acetylcholine. This decrease in acetylcholine reduces airway obstruction in the whole lung by decreasing smooth muscle tone and mucous production (figure 2).

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Figure 2- Targeted Lung Denervation is intended to block parasympathetic signaling and reduce acetylcholine release from the nerve endings.

In a first-in-human study we investigated the safety and feasibility of TLD therapy using two energy doses (20 and 15 watts) in patients with moderate to severe COPD. In a non-randomized, prospective study COPD patients were included with a post-bronchodilator FEV1 of 30-60% of predicted normal values and with a 15% or greater relative increase in FEV1 following inhalation of 80μg ipratropium bromide.

TLD-Treatment procedure Figure 3 – TLD Procedureroom

Due to the construction of this first generation device, procedures were performed via rigid bronchoscopy under general anesthesia in 2 sequential bronchoscopies (figure 3). The dual-cooled catheter was placed through the rigid bronchoscope and a flexible bronchoscope placed beside it for visualization. The electrode was placed and activated in up to 8 rotational positions per bronchus to achieve complete circumferential treatment. Total balloon inflation times were approximately 3 minutes per activation. Bronchoscopic and fluoroscopic visualization was used to guide in electrode positioning throughout treatment (figure 3).

Figure 4: Fluoroscopic view (A) and Bronchoscopic view (B) of the electrode during the procedure. The electrode is indicated by the arrow.

Results

Twelve patients were included in the 20watt cohort and an additional 10 patients were included as part of the 15watt cohort. Baseline characteristics were similar between the two cohorts. The primary safety endpoint was achieved in 100% (11/11) in the 20watt cohort and

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90% (9/10) in the 15watt cohort. The one subject that failed to meet the endpoint had a sustained decline in lung function over time.

The RF energy applied to the airway wall resulted in local asymptomatic airway blanching, which resolved at the 3 month follow-up bronchoscopy in all 10 of the 15watt patients, and in 8 of the 11- 20watt patients with long-term follow up (figure 5).

Figure 5 - Bronchoscopic confirmation of airway healing after TLD: (A) Left main bronchus pre-treatment (B) During treatment (C) Immediately post-Treatment (D) 3 month follow-up.

In the 20watt group, one patient had a superficial tissue defect at the first treatment site seen at 30 days, a second patient had a small 1.5 mm perforation through the thin tissue of the main carina also discovered at 30 days, and the third patient had a superficial tissue defect at the initial treatment site just distal to the main carina, as well as a 4 mm granuloma at the second treatment site.

Figure 6: Secondary efficacy endpoints. Data represented as mean. Error bars represent standard error of the mean. *p<0.05 compared to baseline. FEV1: Forced Expiratory Volume in 1 second. FVC: Forced Vital Capacity. Cycle Erg. Endurance: Cycle Ergometry Endurance. SGRQ: St. George’s Respiratory Questionnaire

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The procedure was feasible in all cases and technical success was 98%, with 326 of 332 expected treatment sites able to be treated. No device related adverse events occurred during the procedure. The results of FEV1 (% relative change), FVC, cycle ergometry endurance and SGRQ at each time point assessed are shown in figure 6.

Discussion

This first-in-human clinical trial evaluated the novel “targeted lung denervation” (TLD) therapy, designed to ablate the parasympathetic pulmonary nerves surrounding the main bronchi thereby decreasing bronchomotor tone in patients with COPD. This study demonstrated TLD to be feasible, safe, and potentially beneficial. The primary endpoint was met in 95% of patients and technical success was 98%. Tendency toward improvements in lung function, exercise capacity, and HRQL were observed in the 20watt cohort. These improvements tended to be larger than those seen in the 15watt cohort.

TLD has the potential to overcome many of the limitations of inhaled drugs for the treatment of COPD. First, TLD may eliminate inhaler compliance issues for the 63% of new tiotropium users who discontinue treatment after 1 year. Second, TLD would not be subject to the peak and trough variations seen with drugs. Third, TLD may eliminate variable regional drug delivery and deposition in patients with obstructive lung disease by ablating the nerves that travel throughout the bronchial tree independent of regional airflow obstruction. Fourth, by interfering with parasympathetic nerve derived acetylcholine by two different mechanisms, the combination of TLD + inhaled anticholinergic drugs, as suggested by figure 7, may have a synergistic effect that results in a reduction in airway obstruction and mucus production, as well as inhibition of local airway inflammation induced by non-neural muscarinic action.

In this paper we introduced TLD, a novel bronchoscopic treatment concept for symptomatic patients suffering from COPD. Based on the concept of ablating parasympathetic pulmonary nerves, TLD was shown to be feasible, safe, and potentially clinically effective. The beneficial effects appear durable, dose dependent and potentially additive to inhaled anticholinergics.

Further investigation and progressive product development is currently underway. A new catheter and RF system have been developped, allowing a single outpatient 45 mins procedure (figure 7). This system will be tested and used in the “AIRFLOW-1 trial” (NCT02058459): A Sequential 2-Phase Multicenter, Randomized Study to Optimize Dose Selection and Evaluate Safety After Treatment with the Holaira™ Lung Denervation System in Patients with Moderate to Severe COPD.

Figure 7. The new generation TLD system

Reference:

Slebos DJ, Klooster K, Koegelenberg CF, Theron J, Styen D, Valipour A, Mayse M, Bolliger CT. Targeted lung denervation for moderate to severe COPD: a pilot study. Thorax. 2015 Mar 4. [Epub ahead of print]

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Special Topic 5

Granted projects in 2014

In 2014 GRIAC researchers were very succesfull in obtaining grants. The summaries of the most prestigious granted proposals are outlined below. Initiation of HOme MEchanical ventilation at home in a selective group of patients with chronic hypercapnic Respiratory failUre in the Netherlands (HOMERUN) Dr. P.J. Wijkstra (UMCG), Prof. H.A.M. Kerstjens (UMCG), A. Hazenberg (UMCG) Dr. M. Gaytant ( UMCU), A.Otte ( MUMC), R. van den Biggelaar ( ErasmusMC) Granted by ZonmW Home mechanical ventilation (HMV) in the Netherlands routinely starts in a clinical setting supervised by one of the 4 HMV centers. Depending on the local organization this can be done on different wards. The proposed intervention to be studied is initiation of HMV at home as compared to in hospital initiation in different settings. Our hypothesis is that initiation of chronic ventilatory support at home is not inferior to a hospital-based initiation. Patients with chronic respiratory insufficiency due to a neuromuscular disease (NMD) or thoracic cage problem who are referred for chronic ventilator support and > 18 years of age can be included. The primary outcome parameter is the arterial carbon dioxide (PaCO2). Secondary parameters are health related quality of life questionnaires, lung function and costs. Tissue repair in COPD: WNT you get it right? Dr. R. Gosens (UMCG), Dr. J. Stolk (LUMC), Prof. M. Königshof (Helmholtz Zentrum München). Granted by Netherlands Lung Foundation COPD is a chronic lung disease caused primarily by smoking. COPD patients suffer from airflow limitation caused by airway inflammation and remodelling and tissue destruction in the lung parenchyma. The damaged lung cannot be repaired with current medical technology. Halting tissue destruction or reversing the existing damage are therefore important challenges for pulmonary research. It is now feasible to promote tissue repair using novel stem cell therapy and pharmacological approaches that specifically target the WNT pathway. The WNT pathway, which regulates lung development in utero and is required for tissue homeostasis and repair, is inadequately activated in COPD. In this project, pulmonologists, pharmacologists and (stem) cell biologists will form a consortium to for the first time target the WNT pathway to promote tissue repair in COPD using pharmacological and cell therapy approaches. We postulate that in COPD, WNT signalling that drives tissue repair is out of balance due to interference by inflammation, inappropriate TGF-β activation and ER stress. This redirects WNT signalling to other transcriptional programs, thereby preventing repair, and promoting remodelling instead. Restoring this balance will boost repair of the damaged lung. We will use functional studies and gene expression profiling in vulnerable cell populations including alveolar epithelial cells, parenchymal fibroblasts and microvascular pulmonary

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endothelial cells from COPD patients and controls. This way, we aim to understand the mechanisms that distort adequate WNT signalling in COPD. Furthermore, we will evaluate cell therapy and novel drugs that restore WNT mediated repair. We will focus on bone marrow-derived mesenchymal stromal cells (BM-MSCs) as a known source and target of WNT ligands. We are currently investigating MSCs for their therapeutic potential in COPD patients. Collectively, we will establish key mechanisms fundamental to inadequate repair in COPD and identify novel therapeutic targets to reactivate repair in COPD.

Design, synthesis and validation of potent and isozyme selective arginase inhibitors for therapeutic use in asthma Prof. A.S.S. Dömling (Drug Design, RUG), Prof. H. Meurs (Molecular Pharmacology, RUG), Prof. P.H. Elsinga (Nuclear Medicine and Molecular Imaging, RUG)

Granted by Grant Technology Foundation STW

Allergic asthma is a chronic inflammatory obstructive airway disease, characterized by

attacks of breathlessness due to periods of intermittent airflow obstruction. The prevalence

and morbidity of this disease have steadily risen worldwide during the last few decades.

Many patients with asthma are poorly controlled by current drug treatment with ß2-agonists

and corticosteroids, in particular patients with severe asthma characterized by chronic

symptoms, severe exacerbations, progressive loss of lung function and frequent

hospitalization. Therefore, new therapeutic options are highly warranted. Recent studies in

animal models and in asthma patients have revealed that the arginine metabolizing enzyme

arginase has a key role in allergic airway inflammation, obstruction, hyperresponsiveness

and remodeling, and therefore represents an attractive and entirely novel target for the

treatment of this disease. Two isoenzymes (types 1 and 2) have been identified, which are

differentially expressed in the body and may regulate different biological functions. Enhanced

expression of particularly arginase 1 appears to be involved asthma, although the exact role

of both subtypes remains to be established. Thus far, no arginase inhibitors are available for

therapeutic treatment. Aim of the present project is to develop novel potent isozyme-selective

arginase inhibitors by structure-based drug design, using unique advanced chemical

technology. Potential application of these inhibitors for the treatment of asthma will be

investigated by state-of-the art pharmacological and Positron Emission Tomography imaging

methods, using animal models of acute and chronic asthma as well as human lung tissue. It

is envisaged that these inhibitors will give more insight in the pathophysiology of the disease

and provide novel effective treatment options.

Identifying causal mechanisms of the inception of asthma through a novel experimental model for the interaction on the PCDH1 gene and environment Dr. M. Nawijn (UMCG), Prof. G.H. Koppelman (UMCG), Prof. L. Bont (UMCU), Prof. B. Lambrecht (University of Ghent) Granted by Netherlands Lung Foundation Asthma starts in early childhood. The inception of asthma occurs in a susceptible child upon exposure to environmental triggers, typically respiratory viral infections and sensitization to aero-allergens. Current treatment suppresses airway inflammation but does not cure asthma. To progress towards curative treatment, we need to understand the inception of asthma rather than the chronic inflammation characterizing established asthma. Since opportunities

31

to perform such studies in young children are limited, there is an urgent need for experimental models to understand the inception of asthma. We propose to base such models on relevant asthma susceptibility genes. This study integrates major recent discoveries by the consortium. We identified Protocadherin-1 (PCDH1) as a novel asthma and bronchial hyperresponsiveness (BHR) gene, and show its interaction with SMAD3, another asthma gene, in airway epithelium. Based on these human data we generated PCDH1 knockout mice that display spontaneous BHR as well as exaggerated house-dust mite induced BHR. In addition, we identified respiratory syncytial virus infection as an important cause of recurrent wheezing in the first three years of life. We aim to dissect the PCDH1/SMAD3 pathway during the inception of asthma by exposing PCDH1 deficient mice and controls to aeroallergens and respiratory syncytial virus-infection. We will test the critical role of the airway epithelium for asthma inception in vivo. We will translate these findings to the human disease using primary bronchial epithelial cells obtained from asthmatic children, adult asthma patients and controls. Moreover, we will evaluate human lung epithelial organoids, a novel 3D culture system, as an individualized screening platform for testing novel interventions. We have brought together a multidisciplinary consortium of excellent clinicians and scientists with an outstanding track record for productive collaboration in translational asthma research. This consortium will reveal key mechanisms in the inception of asthma, resulting in novel treatment targets.

A window of opportunity: Prevention of epigenetic programming of asthma Prof. G.H. Koppelman (UMCG), Dr. U. Gerhring (UU) , Dr. A. Wijga (RIVM), Prof. H.A. Smit (UMCU) on behalf of the PIAMA consortium Granted by the Netherlands Lung Foundation Children with asthma are at increased risk of developing a lung function deficit in adulthood. Importantly, the risk factors related to asthma and lung function impairment operate already in utero and infancy, critical periods of lung development. There is ample evidence that environmental exposures during different stages of childhood affect the risk of asthma and lung function impairment later in life. The impact of these environmental exposures may critically depend on timing. It is becoming increasingly clear that environmental exposures, e.g. air pollution and (passive) smoking, and indoor exposures like endotoxin may cause epigenetic modifications of our DNA. This impacts especially the respiratory epithelium, the cell layer that is the first line of defence against inhaled environmental stimuli. Important asthma genes are expressed in the epithelium, yet it is unknown how epigenetic programming regulates airway epithelial gene expression and if this affects asthma and lung function development. This project will investigate if environmental exposures during different stages of childhood (in utero / infancy, preschool, school and early adolescence) affect asthma risk and lung function impairment. We will do so by analyzing data from the PIAMA birth cohort followed up to age 16. We will determine if environmental factors result in changes in DNA methylation of airway epithelial cells at age 16 and subsequently link DNA methylation to DNA polymorphisms and gene expression in these nasal epithelial cells. This opens a new perspective on asthma prevention, in particular since each stage of childhood has its specific setting for prevention. Our multidisciplinary approach will integrate the environment, DNA polymorphisms, DNA methylation in respiratory epithelium, and their

32

effects on gene transcription in the same children. We ultimately will determine causal networks that are active in the airway epithelium leading to asthma and the associated lung function deficit in adulthood.

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Departments Dept. Epidemiology University Medical Center Groningen Hanzeplein 1 P.O. Box 30.001 NL-9700 RB Groningen Phone 31-50-361 0739 Fax 31-50-361 4493 Principal Investigators: Prof. Dr. H.M. Boezen, Dr. M. Kerkhof, Dr. J.M. Vonk Dept. General Practice University of Groningen, Faculty of Medical Sciences A. Deusinglaan 1 NL-9713 AV Groningen Phone 31-50-363 2963 Fax 31-50-363 2964 Principal Investigator: Prof. Dr. T. van der Molen Dept. Internal Medicine, div. Allergology University Medical Center Groningen Hanzeplein 1 P.O. Box 30.001 NL-9700 RB Groningen Phone: 31-50-361 2976 Fax: 31-50-3121576 Principal Investigators: Prof. Dr. J.G.R. de Monchy, Dr. J.N.G. Oude Elberink Dept. Pathology and Medical Biology, Div. Medical Biology, Experimental Pulmonology and Inflammation Research University Medical Center Groningen Hanzeplein 1 P.O. Box 30.001 NL-9700 RB Groningen Phone: 31-50-361 8043 Fax: 31-50-361 9911 Principal Investigators: Dr. H.I. Heijink University Centre for Pharmacy University of Groningen A. Deusinglaan 1 NL-9713 AV Groningen Phone 31-50-363 3197 Fax: 31-50-363 6908 Principal Investigators: Prof. Dr. M.A. Schmidt, Prof. Dr. H. Meurs, Dr. R. Gosens, Dr. B.N. Melgert Dept. Pathology and Medical Biology University Medical Center Groningen Hanzeplein 1 P.O. Box 30.001 NL-9700 RB Groningen Phone: 31-50-361 4684 Fax: 31-50-363 2510 Principal Investigators: Prof. Dr. W. Timens, Dr. M.N. Hylkema

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Dept. Pediatric Pulmonology and Pediatric Allergy Beatrix Children’s Hospital, University Medical Center Groningen Hanzeplein 1 P.O. Box 30.001 NL-9700 RB Groningen Phone: 31-50-361 1107 Fax: 31-50-361 1704 Principal Investigators: Prof. Dr. G.H. Koppelman, Prof. Dr. E.J. Duiverman, Prof. Dr. A.E.J. Dubois Dept. Pulmonary Diseases and Tuberculosis University Medical Center Groningen Hanzeplein 1 P.O. Box 30.001 NL-9700 RB Groningen Phone: 31-50-361 3532 Fax: 31-50-361 9320 Principal Investigators: Prof. Dr. D.S. Postma, Prof. Dr. H.A.M. Kerstjens, Dr. N.H.T. ten Hacken, Dr. M. van den Berge Working group on Respiratory Insufficiency University Medical Center Groningen Hanzeplein 1 P.O. Box 30.001 NL-9700 RB Groningen Phone: 31-50-361 3235 Fax: 31-50-361 9320 Principal Investigator: Dr. P.J. Wijkstra

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Members 2014

Other scientific staff

Berge van den M., MD, PhD Brand P.L.P., MD, PhD, Prof. (associate member) Brandsma C.A., PhD Diamant Z., PhD, Prof. Flokstra-de Blok B.M.J., PhD Guryev V., PhD Hacken ten N.H.T., MD, PhD Heide van der S., PhD Kerkhof M., MD, PhD

Kocks J.W.H., MD, PhD Melgert B.N, PhD Nawijn M.C., PhD Rottier B.L., MD, PhD Slebos D.J., MD, PhD Touw D.J., PhD, Prof. (associate member) Vrijlandt E.J.L.E., MD, PhD Wempe J.B, MD, PhD Willemse B.W., MD, PhD

Post-docs

Bidan, C. PhD Schokker S., PhD Faiz, A. PhD Sopi R., PhD Hartman J.E., PhD Tsiligianni I., MD, PhD Jong de C., PhD Velde van der J.L., MD, PhD Jong de K., PhD Wright D.B., PhD Maarsingh E.J., PhD Xu C., PhD Riemersma R.A., MD, PhD PhD students

Alma H.J., MD/PhD student Klijnsma M., MSc Altenburg W.A., MSc Klooster K. Berkhof, F., MSc Koopmans T., MSc Boorsma C.E., MSc Kumawat K., MSc Boudewijn I, MD Metting E.I., MSc Cao, J.J. MSc, Meyer, K. Msc. van Dijk E., MSc Nieuwenhuis M.A.E., MSc Dijk F.N., MD Oenema T.A., PhD Dijkstra A.E., MSc Oldenburger A., MSc Draijer C., MSc Osei E., MSc Fattahi F., MSc Poppinga W., MSc Faura Tellez G., MSc Pouwels S.D., MSc Figarska S.M., MSc Rajendran V., MSc Franciosi L., MSc Robbe P., MSc Gemert van F.A., MD Rozeveld D., MSc Ginkel van C.D., MD/PhD student Saleh-Langenberg J., MD/PhD student Goossens N.J., MD/PhD student Sattarzadeh A., MSc Grotenboer N.S., MSc Savenije O.E.M., MD Han B., MSc Spanjer A.I.R., MSc

Scientific Board

Boezen H.M., PhD, Prof Dubois A.E.J., MD, PhD, Prof Duiverman E.J., MD, PhD, Prof Gosens, R., PhD Heijink H.I., PhD Hylkema M.N., PhD Kerstjens H.A.M., MD, PhD, Prof Koppelman G.H., MD, PhD, Prof Meurs H., PhD, Prof

Molen van der T., MD, PhD, Prof Monchy de J.G.R., MD, PhD, Prof Oude Elberink J.N.G., MD, PhD Postma D.S., MD, PhD, Prof Schmidt M.A., PhD, Prof Timens W., MD, PhD, Prof Vonk J.M., PhD Wijkstra P.J., MD, PhD

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Hazenberg A. Struik F.M., MSc Hesse L., MSc Song, J., MSc Hoffmann R.F., MSc Tania N., MSc Hoonhorst S.J.M., MSc Vos B.J.P.R., MD/PhD student Ierodiakonou D., MD de Vries G.E., MSc Jong de L., MSc de Vries M., MSc Kennedy Feitosa E., MSc Vroegop J.S., MD Ketelaar M., MD/PhD student van der Wiel E., MD Kirenga B.J., MSc Zeng X., MSc Kistemaker L.E.M., MSc Zijlstra J., MD

Other research staff Augustijn S. Laan van der-Boers A. Beusekamp B. Leever M. Beverdam H.R. Leij van der J., PhD Bladder G. Lodewijk M. Bos I. S.T Medema S. Bouwman J. Menzen M. Brouwer S. Noordhoek J. Brouwer U. Oeseburg D.S. Bruin de H.G. Oomkes-Pilon A.M. Bruins Slot F.J. Oosterom H. Eems van der M.R. Platteel M. Elzinga C.R.S. Rakers J.A. Gras R. Reinders-Luinge M. Heijst van E.C.M. Rijkom van B. Heuving M.E. Smaalen van M. Homan A.A.J. Smidt-Huizinga H.D.M. Jankipersadsing S.A. Smit M. Jonge de O.R.M. Staal R. Jonker M.R. Star-Kroesen M. Kooistra W. Swierenga M. Klok P. Wedzinga A. Koops H. Zuidhof A.B Kukler J. Zwart G.

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International collaboration 2014 (As far as related to joint projects and publications in 2014)

Prof. S. Andreas Georg-August University Göttingen, Germany

Prof. J. Antó IMIM, CREAL Barcelona, Spain

Prof. E. Bateman University of Cape Town Cape Town, South Africa

Prof. R. Beasley Medical Research institute of New Zealand

Wellington, New Zealand

Dr. C. Bidan University of Grenoble Grenoble, France

Prof. E.R. Bleecker Wake Forest School of Medicine Winston Salem, USA

Dr. B. Bohle Medical University of Vienna Vienna, Austria

Dr. Y. Bossé Université de Laval Quebec, Canada

Prof. J. Bousquet INSERM Villejuif, France

Prof. G. Brusselle University Hospital of Ghent Ghent, Belgium

Dr. J.K. Burgess Woolcock Institute Sydney, Australia

Prof. A. Bush Imperial College London, UK

Prof. R.H. Casaburi Harbor-UCLA medical center Torrance, USA

Dr. M. Cho Harvard Medical School Boston, USA

Prof. R. Dahl Odense University Hospital Odense, Denmark

Prof. D. Davies University of Southampton Southampton, UK

The EAACI Food Allergy and Anaphylaxis Guidelines Group

Dr. G. Fejer University of Plymouth Plymouth, UK

Prof. J. Fonseca University of Porto Porto, Portugal

Prof. M. Gjomarkaj University of Palermo Palermo, Italy

Prof. R.S. Goldstein University of Toronto Toronto, Canada

Prof. Dr. C.M. Greene Royal College of Surgeons in Ireland Dublin, Ireland

Dr. T.L. Hackett University of British Columbia Vancouver, Canada

Prof. A.J. Halayko University of Manitoba

Winnipeg, Canada

Prof. A.J. Henderson

University of Bristol Bristol, UK

Prof. F. Herth University of Heidelberg Heidelberg, Germany

Prof. J.C. Hogg University of British Columbia Vancouver, Canada

Dr. J.W. Holloway University of Southampton Southampton, UK

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Prof. C. Janson Uppsala University Uppsala, Sweden

Prof. D. Jarvis Imperial College London London, UK

Prof. G. Joos University Hospital of Ghent Ghent, Belgium

Prof. M. Kamya Makerere University Kampala, Uganda

Prof. L. Kobzik Harvard School of Public Health Boston, USA

Prof. M. Königshoff Helmholtz Center Munich München, Germany

Dr. R. Korstanje The Jackson Laboratory Bar Harbor, USA

Dr. S. Krauss-Etschmann

Helmholtz Center Munich Munich, Germany

Dr. R. Krishnan Harvard Medical School Boston, USA

Prof. H. Kubo Tohoku University Sendai, Japan

Prof. B.N. Lambrecht University Hospital of Ghent Ghent, Belgium

Dr. M. Lenburg Boston University School of Medicine Boston, USA

Dr. S. London National Institute of Environmental Health Sciences (NIEHS)

North Carolina, USA

Dr. H. Maarsingh Palm Beach Atlantic University West Palm Beach, USA

Dr. K. Malakauskas Lithuanian University of Health Sciences

Kaunas, Luthuania

Dr. F.O. Martinez Oxford University Oxford, UK

Dr. E. Melén Karolinska Institute Stockholm, Sweden

Prof. D.A. Meyers Wake Forest School of Medicine Winston Salem, USA

Dr. M. Miravitlles Hospital Universitari Vall d’Hebron Barcelona, Spain

Prof. T. Miyazawa St. Marianna University school of Medicine

Kawasaki, Japan

Prof. L.C. de Moraes Sobrino Porto

State University of Rio de Janeiro Rio de Janeiro, Brazil

Dr. B. Oliver Woolcock Institute Sydney, Australia

Dr. E. Pace University of Palermo Palermo, Italy

Prof. P.D. Pare University of British Columbia Vancouver, Canada

Prof. M. Peters-Golden University of Michigan Medical School Michigan, USA

Prof. E. Pizzichini Universidade Federal de Santa Catarina

Florianópolis, Brasil

Dr. J. Porsasz Harbor-UCLA medical center Torrance, USA

Prof. D. Price University of Aberdeen Aberdeen, UK

Prof. N. Probst-Hensch Swiss Tropical and Public Health Institute

Basel, Switzerland

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Dr. B.A. Raby Harvard Medical School Boston, USA

Dr. H.K. Reddel University of Sydney Sydney, Australia

Prof. F. van Roy Flemish Institute of Biotechnology Ghent, Belgium

Prof. I. Sabroe University of Sheffield Sheffield, UK

Prof. S. dos Santos Valenca

Federal University of Rio de Janeiro

Rio de Janeiro, Brazil

Dr. I. Sayers

University of Nottingham Nottingham, UK

Dr. K. Schulz Klinik Bad Reichenhall Bad Reichenhall, Germany

Dr. J. Schwarze University of Edinburgh Edinburgh, UK

Prof. F. Sciurba UPMC Pittsburgh, PA, USA

Prof. T. Sigsgaard Aarhus University Aarhus, Denmark

Dr. P. Shah Royal Brompton Hospital London, UK

Prof. E. Silverman Harvard Medical School Boston, USA

Prof. D.D. Sin University of British Columbia Vancouver, Canada

Prof. L. Sorokin University of Münster Münster, Germany

Dr. A. Spira Boston University School of Medicine Boston, USA

Dr. K. Steiling Boston University School of Medicine Boston, USA

Dr. K. Tantisira Harvard Medical School Boston, USA

Prof. M. Tobin University of Leicester Leicester, UK

Prof. T. Troosters University of Leuven Leuven, Belgium

Prof. N. Tzanakis University of Crete Heraklion, Greece

Prof. M. Weatherall University of Otago Wellington, New Zealand

Prof. S.T. Weiss Harvard Medical School Boston, USA

Prof. J. Wess National Institute of Health Bethesda, USA

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Seminar program 2014

Date Speaker Title 09-01-2014 Dr. C. Grainge

University of Southampton, UK

Effect of bronchoconstriction on airway remodelling in asthma

21-01-2014 S. Hoonhorst

Pulmonology UMCG

Results of TI Pharma 1-108

04-02-2014 Dr. S. Krauss-

Etschmann Helmholtz Center Munich, Germany

Prenatal smoke exposure and postnatal phenotype

18-02-2014 B. van Anrooij

Allergology UMCG

Markers for anaphylaxia

03-03-2014 Prof. S. Weiss

Channing Lab, Harvard University Boston, USA

Does childhood asthma develop into COPD?: results from the CAMP study

01-04-2014 Prof. H. Meurs

Molecular Pharmacology, University Centre for Pharmacy, Groningen

‘Arthritic’ airway: a novel mechanism of airway hyperresponsiveness? A sabbatical report

15-04-2014 E. van der Wiel

Pulmonology UMCG

Small airway dysfunction in asthma; new tools and clinical features

06-05-2014 Dr. J.W.H. Kocks

General Practice UMCG

From cluster analysis in obstructive lung disease to GP research networks: experiences from New Zealand

03-06-2014 C. Draijer

Pharmacokinetics, Toxicology and Targeting RUG

The influence of sex hormones in the development of asthma

17-06-2014 Prof. J. Vestbo

University of Manchester UK

Biomarkers in COPD – ECLIPSE and epidemiology

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Date Speaker Title 02-09-2014

Prof. I. Sabroe University of Sheffield UK

Mechanisms of airway inflammation

23-09-2014 Prof. T. Sigsgaard

Institute of Environmental and Occupational Medicine Aarhus University, Denmark

Health, exposure and genetics in young Danish farmers: 15 years of follow up on asthma and allergy

07-10-2014 Dr. G.A. Lockett

University of Southampton UK

Genetics and epigenetics of allergy

04-11-2014 M. Nieuwenhuis

Pulmonology UMCG

Genetics of asthma and its phenotypes: hyperresponsiveness, severity and remission

18-11-2014 A. Kruis

Public Health and Primary Care LUMC

The effectiveness of integrated disease management in COPD patients

02-12-2014 Dr. P. Wijkstra & Prof.

D.S. Postma Respiratory insufficiency & Pulmonology UMCG

The link between NRS, National roadmap lung research and GRIAC

16-12-2014 Prof. D. Heederick

IRAS University of Utrecht

What are health effects from living near livestock producing industries: a Dutch experience

19-12-2014 Dr. J. Burgess

Woolcock Institute of Medical Research Sydney, Australia

Unravelling the contributions of the extracellular matrix to airway remodelling in asthma

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Research meetings 2014 - presentations

Date Speaker Title 07-01-2014 Laura Hesse

Medical Biology, Experimental Pulmonology and Inflammation Research

Vitamin D as adjuvant in a therapeutic vaccine for allergic asthma

14-01-2014 Karin Klooster

Pulmonology Lung volume reduction coil treatment in COPD patients with homogeneous emphysema reduces hyperinflation and airway resistance

21-01-2014 Gerard Koppelman

Pediatric Pulmonology GRIAC-chair

Introduction to GWAS and array analysis

28-01-2014 Jun Jun Cao

Pathology Effect of maternal smoking during pregnancy on airway epithelial differentiation in 1-day-old pups

04-02-2014 Loes Kistemaker

Molecular Pharmacology

A regulatory role for the muscarinic M3 receptor in airway inflammation and remodelling

18-02-2014 Nicole Dijk

Pediatric Pulmonology TRPA1 in asthmatic children, a replication study in PIAMA

25-02-2014 Maartje Nieuwenhuis

Pulmonology Genetic interaction between ATP2A2 and ORMDL3, a calcium handling origin of asthma

04-03-2014 Eline van Dijk

Molecular Pharmacology

WNT-5B: role in inflammation, repair and interaction with oxidative stress in pulmonary fibroblasts

11-03-2014 Vijay Rajendran

Pathology Role of microRNAs in regulating the pulmonary fibroblasts function in COPD

18-03-2014 Corry-Anke Brandsma

Pathology

Introduction to basic laboratory techniques

25-03-2014 Emmanuel Osei

Pathology & Medical Biology

Crosstalk between epithelium and fibroblasts; implications for COPD

01-04-2014 Karolin Meijer

Pathology Prenatal programming by maternal smoking during pregnancy

08-04-2014 Ilse Boudewijn

Pulmonology CT-scan identified pulmonary changes with smoking and aging in healthy smokers and never-smokers

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Date Speaker Title 15-04-2014

Grissel Faura Tellez Pediatric Pulmonology & Medical Biology, Experimental Pulmonology and Inflammation Research

Protocadherin-1: and the challenge of not getting fooled

22-04-2014 Irene Heijink

Medical Biology, Experimental Pulmonology and Inflammation Research & Reinoud Gosens Molecular Pharmacology

Pro-Con discussion: Lung repair in COPD is feasible/not feasible

27-05-2014 Anita Spanjer

Molecular Pharmacology

The role of the Frizzled-8 receptor in COPD patients with chronic mucus hypersecretion

03-06-2014 Jan Willem Kocks

General Practice How to prepare a GRIAC poster

10-06-2014 Juan Song

Pathology Epigenetic reprogramming of mucin synthesis in primary airway epithelial cells

17-06-2014 Tim Koopmans

Molecular Pharmacology

WNT-5A modulates mitochondrial calcium handling in airway smooth muscle

16-09-2014 Maaike de Vries

Medical Biology, Experimental Pulmonology and Inflammation Research

Pim1 kinase, a new therapeutic target in virus-induced asthma exacerbations

23-09-2014 Néomi Grotenboer

Pediatric Pulmonology & Medical Biology, Experimental Pulmonology and Inflammation Research

Role of asthma susceptibility gene IL1RL1 in TLR signaling

30-09-2014 Christina Draijer

Pharmacokinetics, Toxicology and Targeting

Two faces of M2 macrophages in asthma

07-10-2014 Maartje Nieuwenhuis

Pulmonology GWAS, lung eQTLs and asthma phenotypes

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Date Speaker Title 14-10-2014

Grietje de Vries Pulmonology

Heart failure and sleep apnea

21-10-2014 David Wright

Molecular Pharmacology

The role of laminins in modulating ASM phenotype

04-11-2014 Daan Pouwels

Medical Biology, Experimental Pulmonology and Inflammation Research

Increased serum levels of the RAGE-activating DAMPs LL37, HMGB1 and S100A9 during exacerbation in COPD patients

11-11-2014 Laura Hesse

Medical Biology, Experimental Pulmonology and Inflammation Research

Vitamin D as an adjuvants in a specific immunotherapy for allergic asthma

18-11-2014 Dirkje Postma

Pulmonology The Dutch hypothesis

25-11-2014 Wilfred Poppinga

Molecular Pharmacology

Cyclic AMP compartmentalization in obstructive pulmonary disease

02-12-2014 Ilse Boudewijn

Pulmonology Genome-wide nasal gene expression in COPD

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Brainstorm sessions 2014

Date Initiator Subject

28-01-2014 Dr. D. Wright Molecular Pharmacology RUG

Lung Fund project on the regulation of inflammatory cell recruitment to the lung by extracellular matrix proteins, such as laminins

11-03-2014 Prof. Dr. D.S. Postma

Pulmonology UMCG

Bronchial hyperresponsiveness (for an ERC grant application)

22-04-2014 Dr. B. Melgert

Pharmacokinetics, Toxicology and Targeting UMCG

New targets for COPD

23-09-2014 Dr. J.M. Vonk

Epidemiology UMCG

Comorbidities in COPD

28-10-2014 Dr. I. Heijink & Dr. M.

Nawijn Medical Biology, Experimental Pulmonology and Inflammation Research UMCG

Next generation epithelial cell culture: organoids and 3D cell culture models

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Research projects in 2014 Aeris Medical, USA. A randomized Controlled Multi-center Trial of the AeriSeal® System in Patients with Advanced Emphysema: ASPIRE-trial, FDA-IDE RCT, Aeris USA. 2012-2018, Dr. D.J. Slebos. Almirall educational grant: Self-reported side effects of inhaled corticosteroids in patients with COPD, an educational project focusing on feasibility and benefits. 2012-2015. Dr. C. de Jong, Prof.dr. T. van der Molen. AstraZeneca: The risk to develop pneumonia in COPD: Comparing the effects of fluticasone propionate and budesonide on airway epithelial barrier function. 2011-2014. Dr. I.H. Heijink, Dr. M. van den Berge, Dr. N.H.T. ten Hacken, Prof.dr. W. Timens, Prof.dr. A.J.M. van Oosterhout, Prof.dr. D.S. Postma AstraZeneca; Health status guided-COPD care; the MARCH study. 2008-2016. Prof.dr. T. van der Molen, Prof.dr. H.A.M. Kerstjens. Res. Fellows: Dr. J.W.H. Kocks, Dr. C. de Jong. AstraZeneca; Evaluation of unexplained exercise induced dyspnea in mild to moderate COPD. 2008-2014. Prof.dr. T. van der Molen, Prof.dr. H.A.M. Kerstjens, Dr. L.H. Steenhuis. Res. Fellow: J.S. Vroegop. AstraZeneca; CARAT; identifying cutoff values. 2014-2016. Prof.dr. T. van der Molen, Dr. BMJ Flokstra – de Blok, Dr. C. de Jong. Boehringer Ingelheim International GmbH:, Evaluation of the anti-inflammatory and anti-

remodeling effects of the novel ultralong-acting 2-agonist olodaterol, alone and in concerted action with tiotropium, in an animal model of COPD. 2012-2014. Prof.dr. H. Meurs, Dr. R. Gosens, Dr. H .Maarsingh. Junior Research Fellow: M. Smit. Boehringer Ingelheim International GmbH: The protective effects of tiotropium: role of the muscarinic M3 receptor. 2013-2015. Dr. R. Gosens. Research Fellow: L. Kistemaker Boehringer Ingelheim International GmbH. A phase II/III randomised, double blind, placebo-controlled, parallel group trial to evaluate safety and efficacy of tiotropium inhalation solution (2.5 mcg and 5 mcg) administered once daily in the afternoon via respimat inhaler for 12 weeks in patients 1 to 5 years old with persistent asthma. 2012-2015. Dr. E.J.L.E. Vrijlandt, Dr. B.W.M. Willemse, M. van Smaalen Brazil Science Without Borders: Targeting the histone acetyltransferases and histondeacetylase balance in the inflammatory lung diseases asthma and COPD. 2012-2015. Prof.dr. M. Schmidt. Sandwich PhD student: E. Kennedy Feitosa, post-doc: vacancy CAPES/NUFFIC (Edital 68/2013): Activation of nuclear factor (erythroid=derived 2)-like 2 (Nrf2) & antioxidant response element (ARE) as therapeutic target for tissue repair in chronic degenerative lung disease. 2013-2017. Prof.dr. S. dos Santos; Prof.dr. L.C. de Moraes Sobrino Porto; Prof.dr. M. Schmidt Chiesi: FAIR studie: Role of small particle steroids and LABA in COPD. 2011-2014. Dr. M. van den Berge, Dr. N.H.T. ten Hacken, Prof.dr. D.S. Postma. PhD student: E van der Wiel Chiesi: the role of small airways in asthma. Development of the SADT questionnaire. 2011-2016. Prof.dr. T. van der Molen, Prof.dr. D.S. Postma, Dr. M. van den Berge.

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Chiesi: CHF-5843, a novel long-acting anticholinergic, alone and in concerted action with CHF-6001, a PDE inhibitor, in a guinea pig model of COPD. 2013-2014. Dr. R. Gosens, Prof.dr. H. Meurs, Prof.dr. M. Schmidt. Postdoc: T.A. Oenema. CSA Medical: Prospective Study of RejuvenAir™ System Radial Spray Cryotherapy to Determine Safety and Histological Effect in the Lung. 2013-2014. Dr. DJ Slebos, K. Klooster. European Community (KP7, Innovative Medicines Initiative). PROactive. Physical Activity as a Crucial Patient Reported Outcome in COPD. 2009-2015. Prof.dr. M. Decramer, Prof.dr. T. Troosters, Prof.dr. W. MacNee, Prof.dr. C. Roussos, Prof.dr. M Polkey, Dr. P. de Boer, Prof.dr. T. van der Molen, Dr. S. Schokker, Dr. C. de Jong. European Community (FP7); European Union MeDALL-mechanisms of the Development of Allergy. 2010-2015. Prof.dr. D.S. Postma, Prof.dr. G.H. Koppelman, Prof.dr. C. Wijmenga. Postdocs: Dr. M. Kerkhof, Dr. C. Xu, technician: S.A. Jankipersadsing, B. van Rijkom. European Community (FP7); European Union MeDALL-mechanisms of the Development of Allergy. 2010-2015. Dr. M.C. Nawijn, Prof.dr. G.H. Koppelman, Prof.dr. A van Oosterhout. Technician:U. Brouwer. Faculty of Mathematics and Natural Sciences. Macrophages in the pathogenesis of pulmonary lung fibrosis and their potential as drug targets. 2011-2015. Dr. B.N. Melgert, Prof.dr. K. Poelstra. PhD student: C.E. Boorsma. European Union/COST action (European Cooperation in the field of Scientific and Technical Research): Developmental Origins of Chronic Lung Disease. 2012-2016. Dr. M.N. Hylkema, Dr. R. Gosens, Prof.dr. D.S. Postma Goedebuure / Air Liquide: Cost-effectiveness of obstRuctivE Sleep apnea Therapy (REST study): Comparison of MRA therapy versus CPAP therapy in moderate OSAS. 2011-2014. Dr. P.J. Wijkstra , Prof.dr. H.A.M. Kerstjens. PhD-student: G de Vries Groningen Graduate School of Science (Ubbo Emmius PhD-position); Key role of A-kinase anchoring proteins in the pathophysiology of asthma. 2011-2015. Prof.dr. M. Schmidt, Dr. H. Maarsingh. PhD-student: B. Han. GSK/IVAX/MSD/NAF (3.4.04.013) Stichting Astma Bestrijding; Predictive factors in children aged 1- 5 years with recurrent respiratory symptoms for the development of asthma at the age of 6-10 years. 2005-2014. Prof.dr. E.J. Duiverman, Prof.dr. T. van der Molen. Post-doc: Dr. S. Schokker. GSK/Unlock. Health economics of COPD. 2011-2015. Prof.dr. M.J. Postma, Prof.dr. T van der Molen, Dr. M. Roman (Mallorca). PhD student: J. van Boven GSMS: An old dilemma: Asthma with irreversible airway obstruction or COPD? 2009-2014. Dr. N.H.T. ten Hacken, Dr. M.N. Hylkema, Prof.dr. W. Timens and Prof.dr. D.S. Postma. PhD student: F. Fattahi. GSMS/Joint project University of Southampton: Unravelling the protective role of Pim kinases in airways diseases. 2011-2014. Dr. M.C. Nawijn Prof.dr. D.E. Davies. PhD student: M. de Vries

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GSMS/Joint project University of Southampton: Functional characterisation of PCDH1, a novel gene for asthma and bronchial hyperresponsiveness. 2011-2015. Prof.dr. G.H. Koppelman, Prof.dr. J. Holloway, Dr. M.C. Nawijn, Dr. B.M. Willemse. PhD student: G. Faura Tellez GSMS/ Shantou University Medical College, China (Abel Tasman bursaal). Effect of toxic exposures during pregnancy on fetal immune and lung development. 2012-2016. Dr. M.N. Hylkema, Prof.dr. X. Huo. PhD student: J.J. Cao GSMS/Shantou University Medical College. Genes, environment and respiratory health 2011-2015. Prof.dr. H. M. Boezen. PhD Student: X. Zeng GSMS/TianJin Medical University. Maternal smoking during pregnancy: Aberrant epigenetic regulation of genes involved in lung development, ageing and repair. 2013-2016. Dr. M.N. Hylkema, Prof.dr. M. Rots. PhD student: J. Song GSMS-UBC: Dysfunctional crosstalk between epithelial cells and fibroblasts contributes to abnormal tissue repair and remodeling processes in COPD. 2013-2017. Dr. C.A. Brandsma, Dr. I.H. Heijink, Prof.dr. W. Timens, Prof.dr. D.S. Postma, Dr. T.L. Hackett, Dr. S. Wadsworth. PhD student: E. Osei Holaira, USA: Evaluation of the Innovative Pulmonary Solutions System for Targeted Lung Denervation Therapy in patients with moderate to severe COPD, “IPS-1”. 2011-2014. Dr. D.J. Slebos. Holaira, USA: A Sequential Two Phase Multicenter, Randomized Study to Optimize Dose Selection and Evaluate Safety After Treatment with the Holaira™ Lung Denervation System in Patients with Moderate to Severe COPD, 2014-2018 The AIRFLOW-1 trial. Dr DJ Slebos, Dr J Hartman, K. Klooster. International Primary Care Respiratory Group. UNLOCK: Uncovering and Noting Long-term Outcomes in COPD to enhance Knowledge. 2010-2016. Dr. N. Chavannes, Dr. I. Tsiligianni, Prof.dr. D. Price, Prof.dr. T. van der Molen. IPCRG: The I-HARP SERVICE: international, cross-sectional evaluation of inhaler technique and associated predictors of asthma control in patients receiving fixed dose combination inhaled corticosteroid / long-acting beta2-agonist therapy in general practice. 2011-2014. Prof.dr. D. Price, Prof.dr. T. van der Molen, E.C.M. van Heijst. IPCRG: Fresh Air: prevalence and burden of COPD in a rural area of sub-Saharan Africa. 2010-2016. Prof.dr. T. van der Molen, Dr. N.H. Chavannes, Dr. C. de Jong. PhD student: F.A. van Gemert IPCRG: Fresh Air: Biomass fuel induced COPD, prevalence and pathophysiology. 2010-2016. Prof.dr. T. van der Molen, Dr. C. de Jong. PhD student: BJ. Kirenga IPCRG: Does the use of inhaled corticosteroids reduce diabetic control in patients with concomitant COPD and Diabetes: an international primary care cohort study. 2014-2016. Dr. J.W.H. Kocks, Prof.dr. T van der Molen, Prof.dr. D. Price. Longfonds/ZonMW/Boston Scientific: Unraveling Targets of Therapy in Bronchial Thermoplasty in Severe Asthma: TASMA Study, Multicenter trial (AMC/London/Heidelberg/UMCG). 2014-2016. UMCG: Dr. D.J. Slebos, Dr. N.H.T. Ten Hacken

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MD/PhD: Voedselallergie, een cross-cultureel vergelijk: kwaliteit van leven, socio-economische impact, kennisniveau van patiënten en huisartsen. 2010 - 2014. Prof.dr. A.E.J. Dubois, Prof.dr. E.J. Duiverman, Prof.dr. T. van der Molen, Dr. B.M.J. Flokstra-de Blok. MD/PhD student: N.J. Goossens. MD/PhD/ALK: Epinephrine auto-injector prescription, compliance and quality of life. 2011 – 2016. Prof.dr. A.E.J. Dubois, Dr. B.M.J. Flokstra-de Blok. MD/PhD student: J. Saleh-Langenberg MD/PhD: COPD in primary care and pulmonary rehabilitation: discovering the dynamics of the Minimal Clinically Important Difference (MCID) 2014-2018. Prof.dr. T van der Molen, Dr. C. de Jong. PhD student: H.J. Alma MD/PhD: Insensitivity to glucocorticosteroid treatment in obstructive pulmonary diseases. 2009-2014. Dr. N.H.T. ten Hacken, Prof.dr. A.J.M. van Oosterhout, Dr. I.H. Heijink. MD/PhD student: J. Zijlstra MD/PhD: Translating asthma associated genetic variation in IL33 and IL1RL1 into pathophysiology and clinical expression of asthma. 2013 – 2017. Prof.dr. G.H. Koppelman and Dr. M.C. Nawijn. MD/PhD student: M. Ketelaar MD/PhD. Genetics of food allergy. 2013-2018. Prof.dr. A.E.J. Dubois, Prof.dr. G.H. Koppelman. MD/PhD student: C.D. van Ginkel MD/PhD: Diagnosis, treatment and risk factors for therapy failure of Hymenoptera venom allergy. 2012-2016. Prof.dr. A.E.J. Dubois, Dr. J.N.G. Oude Elberink. PhD-student: B.J.P.R Vos NAF 08.014: The role of acetylcholine in chronic inflammation and remodelling in asthma and COPD. 2010-2014. Dr. R. Gosens, Prof.dr. H.A.M. Kerstjens, Prof.dr. P.S. Hiemstra. PhD student: L.E.M. Kistemaker. NAF 3.2.10.042. Wnt/Frizzled signalling in small airway remodelling in COPD. 2010-2015. Dr. R. Gosens, Dr. H.I. Heijink, Dr. W.M. Blankesteijn. PhD student: A.I.R. Spanjer. NAF 3.4.06.044: The effect of chronic non–invasive ventilation at home after treatment of acute respiratory failure in hypercapnic COPD patients. 2007-2014. Dr. P.J. Wijkstra, Prof.dr.H.A.M. Kerstjens. PhD student: F.M. Struik; research nurse: G. Bladder NAF, special grant for translational research in Pediatric Pulmonology: Asthma phenotypes. 2009-2015. Prof.dr. G.H. Koppelman, Prof.dr. J.C. de Jongste. PhD students: N.S. Grotenboer, F.N. Dijk NAF 3.2.09.055: Protocadherin-1 expression in airway epithelium: Investigations into a novel cause of bronchial hyperresponsiveness and asthma. 2009-2016. Prof.dr. G.H. Koppelman, Dr. M.C. Nawijn, Prof.dr. D.S. Postma. NAF 3.2.09.034: The novel cAMP effector Epac: new avenues in the treatment of inflammation, tissue remodelling and airway narrowing in COPD. 2009-2014. Prof.dr. M. Schmidt, Prof.dr. W. Timens, Prof.dr. H. Meurs. PhD student: A. Oldenburger. NAF 3.2.09.036: Th17 responses in asthma: Protection against atopy versus development of non-allergic asthma. 2010-2014. Dr. M.N.Hylkema, Dr. I. Wouters. PhD student: P. Robbe.

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NAF 3.2.09.031. The role of alternatively activated macrophages in the pathogenesis of asthma. 2011-2015. Dr. B.N. Melgert, Dr. M.N. Hylkema, Prof.dr. K. Poelstra. PhD student C. Draijer. NAF 3.2.11.015: A-kinase anchoring proteins as novel drug targets in the development and progression of airway obstruction in COPD. 2011-2015. Prof.dr. M. Schmidt, Dr. H. Maarsingh, Dr. H.I. Heijink. PhD-student: W. Poppinga. NAF 3.2.10.060: Vitamin D3 as adjuvant in a therapeutic vaccine for allergic asthma. 2011-2015. Prof.dr. A.J.M. van Oosterhout, Dr. J.H.N. Oude Elberink, Dr. M.C. Nawijn. PhD-student: L. Hesse. NAF 3.2.11.025: Epithelial cells alarming the immune system in COPD – at the root of COPD susceptibility? 2011-2015. Dr. M.C. Nawijn, Dr. N.H.T. ten Hacken, Prof.dr. A.J. van Oosterhout, Dr. I.H. Heijink. PhD-student: S.D. Pouwels. NAF 3.2.11.024: Abnormal tissue repair and remodeling in COPD; from genomics to biological function. 2011-2014. Dr. C.A. Brandsma, Dr. M. van den Berge, Prof.dr. W. Timens. Post-doc: C.A. Brandsma, technician: S. Brouwer NAF 3.2.12.044: The functional relevance of microRNAs in COPD; elucidating their role in regulating pulmonary fibroblast function in COPD development. 2012-2016. Dr. C.A. Brandsma, Prof.dr. W. Timens, Prof.dr. DS Postma. PhD-student: V. Rajendran, J. Ong NAF 3.2.12.083: Follistatin-like 1, a crucial factor in lung development, as a novel regulator in COPD. 2012-2017. Dr. H. Maarsingh, Dr. M. van den Hoff, Prof.dr. M. Schmidt. PhD student: N.P. Tania NAF 3.2.12.079: Laminin α4 and α5 as regulators of airway inflammation and remodelling in allergic asthma. 2013-2016. Dr. B.G.J. Dekkers, Prof.dr. L.M. Sorokin, Prof.dr. H. Meurs. Post-doc: Dr. D.B. Wright NAF 3.2.11.013: Prenatal programming by maternal smoking during pregnancy: susceptibility for development of COPD. 2012-2016. Dr. M.N. Hylkema, Prof.dr. L. Kobzik. PhD student: K. Meyer Netherlands Lung Foundation 4.1.13.007. Genes and exposures underlying COPD onset. 2013 – 2016. Nederlands Longfonds consortium project in collaboration with Erasmus Medical Center. Prof.dr. H.M. Boezen, Prof.dr. C.M. van Duijn, Dr. C.C. van Diemen, Prof.dr. D.S. Postma. Postdoc: Dr. K. de Jong. PhD students: D. van der Plaat, I. Nedeljković Netherlands Lung Foundation 1.14.001. Prevention of epigenetic programming of asthma. 2014 – 2018. Nederlands Longfonds consortium project in collaboration with University of Utrecht and RIVM. Prof. dr. G.H. Koppelman, Dr. U. Gehring, Prof. dr. H. A. Smit, Dr. A. Wijga. Netherlands Lung Foundation 5.1.14.020 Identifying causal mechanisms of the inception of asthma through a novel experimental model for the interaction on the PCDH1 gene and environment. 2014 – 2017. Nederlands Longfonds consortium project in collaboration with University of Utrecht and University of Ghent. Dr. M. Nawijn, Prof. dr. G.H. Koppelman, Prof. dr. L. Bont , Prof. dr. B. Lambrecht Netherlands Lung Foundation 6.1.14.009: Tissue repair in COPD: WNT you get it right? 2014-2018. Dr. R. Gosens, Dr. J. Stolk, Dr. M. Königshoff. Postdoc: Dr. J-P Ng-Blichfeldt (as of 01-03-2015); 1 post-doc vacancy.

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Northern CARA Foundation: Characterization of macrophage subsets in airways of patients with COPD and their controls. 2014-2015. Dr. B.N. Melgert, C.E. Boorsma Northern CARA Foundation: Characterization of macrophage subsets in airway biopsies of healthy controls. 2014-2015. Dr. B.N. Melgert, C. Draijer Novartis: Effects of (combinations of) beta-adrenoceptor agonists and muscarinic receptor antagonists on intrapulmonary airway constriction. 2012-2014. Dr. H. Maarsingh, Prof.dr. M. Schmidt. Post-doc: Dr. R. Sopi Nycomed; Development of the Clinical Short-form Inhaled Corticosteroid Questionnaire Scale. 2008-2014. Prof.dr. T. van der Molen, Prof.dr. R. Sanderman, Prof.dr. D.S. Postma. Post-doc: J.M. Foster. Pender Foundation for Pulmonary Fibrosis: Exchange of fresh human lung tissue of patients transplanted for pulmonary fibrosis between RUG/UMCG (Groningen) and Erasmus MC (Rotterdam). 2014-2018. Dr. B.N. Melgert, Dr. B. van den Blink Phadia; In vitro Diagnostiek en Eerstelijns Allergie Leidraad (IDEAL) 2009-2016. Prof.dr. A.E.J. Dubois, Prof.dr. T. van der Molen, Dr. B.M.J. Flokstra-de Blok. PneumRx, Inc. USA: Lung Volume Reduction Coil for Treatment in Patients with Emphysema (RENEW) Study, FDA-IDE RCT, PneumRx, Inc. USA. 2012-2018. Dr. D.J. Slebos, K. Klooster PneumRx, Icc: The safety and feasibility of re-treating patients with severe emphysema with the RePneu LVRC system: a pilot study (RECOIL study). 2014-2015. Dr. D.J. Slebos, K. Klooster. PulmonX Inc: A Multi-center, Prospective, Randomized, Controlled, one-way Crossover Investigation of Endobronchial Valve Therapy vs Standard of Care in Homogeneous Emphysema: IMPACT trial. 2014 – 2015. Dr D.J. Slebos, Dr N.H.T. Ten Hacken, Dr J.E. Hartman, K. Klooster.. PulmonX Inc: Study of proactive treatment of collateral ventilation in CV-positive emphysema patients before EBV treatment: “MIND THE GAP”. 2014-2016. Dr D.J. Slebos, Dr J.E. Hartman, K. Klooster. RESMED : SERVE-HF; The SERVE-HF trial is investigating the value of adaptive servo-ventilation (ASV) to improve morbidity and mortality rates in heart failure patients with predominant central sleep apnoea. 2012-2014. Dr. P.J. Wijkstra , Prof.dr. H.A.M. Kerstjens. PhD-student: G de Vries. Rosetta Inpharmatics ; LKR57970: Identification of key mechanistic drivers of lung disease. 2009-2014. Prof.dr. W. Timens, Prof.dr. D.S. Postma. (Lung eQTL Study, together with University of British Columbia, Vancouver (P. Pare) and Hospital Laval, Quebec (Y. Bosse)). SBOH: Improving COPD care by optimising inhalation technique in elderly. 2012-2014. Dr. J.W.H. Kocks, Prof.dr. T. van der Molen. Researcher: M. Dijkstra. SMF; Remission and progression of asthma: genetic and epigenetic regulation. 2012-2015. Prof.dr. D.S. Postma, Prof.dr. G.H. Koppelman, Dr. J.M. Vonk. PhD student: M.A.E. Nieuwenhuis.

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STW Improvement of Diagnostic mEthods for ALlergy assessment. Cashew allergy in children as a showcase (IDEAL/ORCA study). 2012-2016. Prof.dr. A.E.J. Dubois, Dr. B.M.J. Flokstra-de Blok. technician: A. Oomkes-Pilon STW Open Technology Programme: Design, synthesis and validation of potent and isozyme selective arginase inhibitors for therapeutic use in asthma. 2014-2020. Prof. dr. A.S.S. Dömling, Prof. dr. H. Meurs, Prof. dr. P.H. Elsinga, 2 PhD students, 1 postdoc: vacancies Top Instituut Pharma 1-108; Groningen, Utrecht; Acute and chronic inflammatory responses induced by smoking in individuals susceptible and non-susceptible for development of COPD: from complex disease phenotype toward novel tailor-made therapy. 2008-2014. Prof.dr. D.S. Postma, Prof.dr. L. Koenderman, Prof.dr. J.W.J. Lammers, Dr. N.H.T. ten Hacken, Dr. P. Zanen, Dr. R. Schweizer, Prof.dr. R.P.H. Bischoff. Technicians; J. van der Leij, M. Lodewijk, T. Bijma, S. Brouwer. PhD students: S.J.M. Hoonhorst, L. Franciosi. Research nurse. R.G.A. Hiltermann-Tilanus. Top Instituut Pharma 1-201; Groningen, Maastricht, Utrecht; Transition of systemic inflammation into multiorgan pathology. 2008-2014. Prof.dr. A.M.W.J. Schols, Prof.dr. E.F.M. Wouters, Prof.dr. W. Buurman, Prof.dr. W. Lamers, Dr. E. Blaak, Dr. R. Langen, Dr. H. Gosker, Prof.dr. L. Koenderman, Prof.dr J.W.J. Lammers, Dr. L. Ulfman, Prof.dr. D.S. Postma. PhD student: R.F. Hoffmann, Technician: S.M. Brandenburg. University of Groningen. The role of Wnt signaling in airway smooth muscle remodeling in asthma. 2010-2014. Dr. R. Gosens. PhD student: K. Kumawat University of Groningen. Macrophages in the pathogenesis of pulmonary lung fibrosis and COPD and their potential as drug targets. 2011-2015. Dr. B.N. Melgert. PhD student: C.E. Boorsma University of Groningen. Application of eHealth to improve care for asthma and COPD patients in primary care: from focus groups to data mining. 2012-2016. Prof.dr. T. van der Molen, Prof.dr. R. Sanderman. PhD student: E.I. Metting University Medical Center Groningen (Innovative research): “A structured life style intervention on enhancement of daily physical activity and physical fitness in COPD patients in the first, second, and third line. 2006-2014. Dr. N.H.T. ten Hacken, Dr. M.H. de Greef, Dr. J.B. Wempe. PhD-student: W. Altenburg. University Medical Center Groningen (doelmatigheidsonderzoek): Feasibility of an allergy service in primary care. 2013-2015. Dr. B.M. Flokstra-de Blok. Prof.dr. A.E.J. Dubois, Prof.dr. T. van der Molen, Dr. J.N.G. Oude Elberink, Dr. M.L.A. Schuttelaar, Prof.dr. P.J. Coenraads. University Medical Center Groningen / GSK NL: Phenotyping airways disease by cluster analysis in primary care. 2013-2014. Dr. J.W.H. Kocks, Prof.dr. T. van der Molen, Prof.dr. R. Beasley, Prof.dr. M. Weatherall ZonMW 016.126.307: On the origins of airway smooth muscle thickening in asthma. Vidi-award. 2012-2017. Dr. R. Gosens. PhD students: T. Koopmans, E. van Dijk. Technician: M. Menzen ZonMW 80-82305-97-11018. A randomized controlled trial to evaluate the performance of bronchoscopic lungvolume reduction for patients with severe COPD using the best responder criteria (STELVIO trial). 2010-2014. Dr. D.J. Slebos. Dr. N.H.T. ten Hacken. PhD-student: K. Klooster

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ZonMW 837002501. Initiation of HOme MEchanical ventilation at home in patients with chronic hypercapnic Respiratory failUre in the Netherlands (HOMERUN). 2014-2018. Dr. P.J. Wijkstra, Prof.dr. H.A.M. Kerstjens. PhD-student: R. van den Biggelaar Zorggroep Zwolle: Development of patient satisfaction with care questionnaire and validation of HowRu & HowRwe questionnaires. 2012-2015. Dr. J.W.H. Kocks, Prof.dr. H.J.G. Bilo, Dr. M.H. Blanker. Student researcher: J. Rutgers. Also a substantial contribution for several projects has been obtained from the Stichting Astma Bestrijding (SAB).

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Publications 2014

Dissertations

O.E.M. Savenije Origins of asthma in childhood: an approach by longitudinal wheezing phenotypes 13-01-2014 Promotores: Prof. Dr. D.S. Postma, Prof. Dr. G.H. Koppelman Copromotor: Dr. M. Kerkhof D. Ierodiakonou Genetic and environmental interplay in asthma severity and its underlying airway pathology 03-03-2014 Promotores: Prof. Dr. D.S. Postma, Prof. Dr. H.M. Boezen, Prof. Dr. G.H. Koppelman Copromotor: Dr. J.M. Vonk S.M. Figarska Genetics of healthy aging 26-05-2014 Promotor: Prof. Dr. H.M. Boezen Copromotor: Dr. J.M. Vonk A.E. Dijkstra Chronic mucus hypersecretion and airway wall structure: genes and environment 17-06-2014 Promotores: Prof. Dr. D.S. Postma, Prof. Dr. H.J.M. Groen, Prof. Dr. H.M. Boezen Copromotor: Dr. J.M. Vonk N.J. Goossens Health-related quality of life in food allergic patients - Beyond Borders. 30-06-2014 Promotores: Prof. Dr. A.E.J. Dubois, Prof. Dr. E.J. Duiverman, Prof. Dr. T. van der Molen Copromotor: Dr. B.M.J. Flokstra – de Blok K. de Jong Genes and environment underlying lung health 22-09-2014 Promotores: Prof. Dr. H.M. Boezen, Prof. Dr. D.S. Postma Copromotor: Dr. J.M. Vonk A. Oldenburger New avenues for EPAC in inflammation and tissue remodeling in COPD 31-10-2014 Promotores: Prof. Dr. M. Schmidt, Prof. Dr. W. Timens, Prof. Dr. H. Meurs, Prof. Dr. H. Maarsingh S.J.M. Hoonhorst COPD: Recognizing the susceptible smoker. 10-12-2014 Promotor: Prof. Dr. D.S. Postma Copromotor: Dr. N.T.H. ten Hacken

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Publications SCI journals

Akhabir L, Bérubé JC, Bossé Y, Laviolette M, Hao K, Nickle DC, Timens W, Sin DD, Paré PD, Postma DS, Sandford AJ. Lung expression quantitative trait loci data set identifies important functional polymorphisms in the asthma-associated IL1RL1 region. J Allergy Clin Immunol. 2014;34(3):729-731. Alkhouri H, Poppinga WJ, Tania NP, Ammit A, Schuliga M. Regulation of pulmonary inflammation by mesenchymal cells. Pulm Pharmacol Ther 2014;29:156-165. van Anrooij B, Kluin PM, Oude Elberink JN, Kluin-Nelemans JC. CD30 in systemic mastocytosis. Immunol Allergy Clin North Am. 2014;34(2):341-355. Baker KE, Bonvini SJ, Donovan C, Foong RE, Han B, Jha A, Shaifta Y, Smit M, Johnson JR, Moir LM. Novel drug targets for asthma and COPD: lessons learned from in vitro and in vivo models. Pulm Pharmacol Ther 2014;29:181-198. Berge van den M, Steiling K, Timens W, Hiemstra PS, Sterk PJ, Heijink IH, Liu G, Alekseyev YO, Lenburg ME, Spira A, Postma DS. Airway gene expression in COPD is dynamic with inhaled corticosteroid treatment and reflects biological pathways associated with disease activity. Thorax. 2014;69(1):14-23. Berkhof FF, Hesselink AM, Vaessen DL, Uil SM, Kerstjens HA, van den Berg JW. The effect of an outpatient care on-demand-system on health status and costs in patients with COPD. A randomized trial. Respir Med 2014;108:1163-1170. Berkhof FF, Metzemaekers L, Uil SM, Kerstjens HA, van den Berg JW. Health status in patients with coexistent COPD and heart failure: a validation and comparison between the Clinical COPD Questionnaire and the Minnesota Living with Heart Failure Questionnaire. Int J Chron Obstruct Pulmon Dis 2014;9:999-1008. Bertsias A, Tsiligianni IG, Duijker G, Siafakas N, Lionis C, Cretan CAP Research Group. Studying the burden of community-acquired pneumonia in adults aged >/=50 years in primary health care: an observational study in rural Crete, Greece. NPJ Prim Care Respir Med 2014;24:14017. Bidad K, Nawijn MC, van Oosterhout AJ, van der Heide S, Elberink JN. Basophil activation test in the diagnosis and monitoring of mastocytosis patients with wasp venom allergy on immunotherapy. Cytometry B Clin Cytom. 2014;86(3):183-190. Biggelaar RJ van den, Kerstjens HA, de Jong WK. Hemoptysis and hydrocephalus. Follow the lead. Am J Respir Crit Care Med 2014;189:e6. Bjermer L, Alving K, Diamant Z, Magnussen H, Pavord I, Piacentini G, Price D, Roche N, Sastre J, Thomas M, Usmani O. Current evidence and future research needs for FeNO measurement in respiratory diseases. Respir Med 2014;108:830-841. Boardman C, Chachi L, Gavrila A, Keenan CR, Perry MM, Xia YC, Meurs H, Sharma P. Mechanisms of glucocorticoid action and insensitivity in airways disease. Pulm Pharmacol Ther 2014;29:129-143.

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Boorsma CE, Dekkers BG, van Dijk EM, Kumawat K, Richardson J, Burgess JK, John AE. Beyond TGFbeta--novel ways to target airway and parenchymal fibrosis. Pulm Pharmacol Ther 2014;29:166-180. Bouma W, Klinkenberg TJ, Van De WC, Timens W, Mariani MA. Removal of a giant intrathoracic cyst from the Anterior mediastinum. J Cardiothorac Surg 2014,9:152. Boven van JF, Chavannes NH, van der Molen T, Rutten-van Molken MP, Postma MJ, Vegter S. Clinical and economic impact of non-adherence in COPD: a systematic review. Respir Med 2014;108:103-113. Boven van JF, Stuurman-Bieze AG, Hiddink EG, Postma MJ, Vegter S. Medication monitoring and optimization: a targeted pharmacist program for effective and cost-effective improvement of chronic therapy adherence. J Manag Care Pharm 2014;20:786-792. Boven van JF, Tommelein E, Boussery K, Mehuys E, Vegter S, Brusselle GG, Rutten-van Molken MP, Postma MJ. Optimizing pharmacotherapy in patients with COPD by community-pharmacists: a cost-effectiveness analysis. J Pharm Belg 2014;(3):15-16. Boven van JF, Tommelein E, Boussery K, Mehuys E, Vegter S, Brusselle GG, Rutten-van Molken MP, Postma MJ. Improving inhaler adherence in patients with chronic obstructive pulmonary disease: a cost-effectiveness analysis. Respir Res 2014;15:66. Boven van JF, van Raaij JJ, van der Galien R, Postma MJ, van der Molen T, Dekhuijzen PN, Vegter S. Impact of multiple-dose versus single-dose inhaler devices on COPD patients' persistence with long-acting beta(2)-agonists: a dispensing database analysis. NPJ Prim Care Respir Med 2014;24:14069. Brusse-Keizer M, VanderValk P, Hendrix R, Kerstjens H, van der Palen J. Necessity of amoxicillin clavulanic acid in addition to prednisolone in mild-to-moderate COPD exacerbations. BMJ Open Respir Res 2014;1:e000052. Burgess JK, Gosens R. Airway smooth muscle and fibroblast biology still a leading research focus for young investigators in the field. Pulm Pharmacol Ther 2014;29:91-92. Chen L, Ge Q, Tjin G, Alkhouri H, Deng L, Brandsma CA, Adcock I, Timens W, Postma D, Burgess JK, Black JL, Oliver BG. Effects of cigarette smoke extract on human airway smooth muscle cells in COPD. Eur Respir J. 2014;44(3):634-646. Dale PR, Cernecka H, Schmidt M, Dowling MR, Charlton SJ, Pieper MP, Michel MC. The pharmacological rationale for combining muscarinic receptor antagonists and β-adrenoceptor agonists in the treatment of airway and bladder disease. Curr Opin Pharmacol 2014;16:31-42. Davis KJ, Landis SH, Oh YM, Mannino DM, Han MK, van der Molen T, Aisanov Z, Menezes AM, Ichinose M, Muellerova H. Continuing to Confront COPD International Physician Survey: physician knowledge and application of COPD management guidelines in 12 countries. Int J Chron Obstruct Pulmon Dis 2014;10:39-55. Deslee G, Klooster K, Hetzel M, Stanzel F, Kessler R, Marquette CH, Witt C, Blaas S, Gesierich W, Herth FJ, Hetzel J, van Rikxoort EM, Slebos DJ. Lung volume reduction coil treatment for patients with severe emphysema: a European multicentre trial. Thorax. 2014;69(11):980-986.

57

van Deursen VM, Damman K, van der Meer P, Wijkstra PJ, Luijckx GJ, van Beek A, van Veldhuisen DJ, Voors AA. Co-morbidities in heart failure. Heart Fail Rev. 2014;19(2):163-172. Dhami S, Panesar SS, Roberts G, Muraro A, Worm M, Bilò MB, Cardona V, Dubois AE, DunnGalvin A, Eigenmann P, Fernandez-Rivas M, Halken S, Lack G, Niggemann B, Rueff F, Santos AF, Vlieg-Boerstra B, Zolkipli ZQ, Sheikh A; EAACI Food Allergy and Anaphylaxis Guidelines Group. Management of anaphylaxis: a systematic review. Allergy. 2014;69(2):168-175. Diamant Z, Clarke GW, Pieterse H, Gispert J. Disease models of chronic inflammatory airway disease: applications and requirements for clinical trials. Curr Opin Pulm Med 2014;20:37-45. Diamant Z, Sidharta PN, Singh D, O'Connor BJ, Zuiker R, Leaker BR, Silkey M, Dingemanse J. Setipiprant, a selective CRTH2 antagonist, reduces allergen-induced airway responses in allergic asthmatics. Clin Exp Allergy 2014;44:1044-1052. Dickhoff C, Hartemink KJ, Slebos DJ, Symersky P, Vonk-Noordegraaf A. Extrathoracic proof of intrathoracic trouble. Thorax. 2014;69(8):785. Dijkstra AE, de Jong K, Boezen HM, Kromhout H, Vermeulen R, Groen HJ, Postma DS, Vonk JM. Risk factors for chronic mucus hypersecretion in individuals with and without COPD: influence of smoking and job exposure on CMH. Occup Environ Med. 2014;71(5):346-352. Dijkstra AE, Smolonska J, van den Berge M, Wijmenga C, Zanen P, Luinge MA, Platteel M, Lammers JW, Dahlback M, Tosh K, Hiemstra PS, Sterk PJ, Spira A, Vestbo J, Nordestgaard BG, Benn M, Nielsen SF, Dahl M, Verschuren WM, Picavet HS, Smit HA, Owsijewitsch M, Kauczor HU, de Koning HJ, Nizankowska-Mogilnicka E, Mejza F, Nastalek P, van Diemen CC, Cho MH, Silverman EK, Crapo JD, Beaty TH, Lomas DA, Bakke P, Gulsvik A, Bossé Y, Obeidat MA, Loth DW, Lahousse L, Rivadeneira F, Uitterlinden AG, Hofman A, Stricker BH, Brusselle GG, van Duijn CM, Brouwer U, Koppelman GH, Vonk JM, Nawijn MC, Groen HJ, Timens W, Boezen HM, Postma DS; LifeLines Cohort study. Susceptibility to chronic mucus hypersecretion, a genome wide association study. PLoS One. 2014;9(4):e91621. Dobbels F, de Jong C, Drost E, Elberse J, Feridou C, Jacobs L, Rabinovich R, Frei A, Puhan MA, de Boer WI, van der Molen T, Williams K, Pinnock H, Troosters T, Karlsson N, Kulich K, Rudell K, PROactive consortium, PROactive consortium. The PROactive innovative conceptual framework on physical activity. Eur Respir J 2014;44:1223-1233. Eeftens M, Hoek G, Gruzieva O, Mölter A, Agius R, Beelen R, Brunekreef B, Custovic A, Cyrys J, Fuertes E, Heinrich J, Hoffmann B, de Hoogh K, Jedynska A, Keuken M, Klümper C, Kooter I, Krämer U, Korek M, Koppelman GH, Kuhlbusch TA, Simpson A, Smit HA, Tsai MY, Wang M, Wolf K, Pershagen G, Gehring U. Elemental composition of particulate matter and the association with lung function. Epidemiology. 2014;25(5):648-657. European Innovation Partnership on Active and Healthy Ageing, Action Plan B3, Mechanisms of the Development of Allergy, WP 10, Global Alliance against Chronic Respiratory Diseases, Bousquet J, Addis A, Adcock I, Agache I, Agusti A, Alonso A, Annesi-Maesano I, Anto JM, Bachert C, Baena-Cagnani CE, Bai C, Baigenzhin A, Barbara C, Barnes PJ, Bateman ED, Beck L, Bedbrook A, Bel EH, Benezet O, Bennoor KS, Benson M, Bernabeu-Wittel M, Bewick M, Bindslev-Jensen C, Blain H, Blasi F, Bonini M, Bonini S, Boulet LP, Bourdin A, Bourret R, Bousquet PJ, Brightling CE, Briggs A, Brozek J, Buhl R, Bush A, Caimmi D, Calderon M, Calverley P, Camargos PA, Camuzat T, Canonica GW,

58

Carlsen KH, Casale TB, Cazzola M, Cepeda Sarabia AM, Cesario A, Chen YZ, Chkhartishvili E, Chavannes NH, Chiron R, Chuchalin A, Chung KF, Cox L, Crooks G, Crooks MG, Cruz AA, Custovic A, Dahl R, Dahlen SE, De Blay F, Dedeu T, Deleanu D, Demoly P, Devillier P, Didier A, Dinh-Xuan AT, Djukanovic R, Dokic D, Douagui H, Dubakiene R, Eglin S, Elliot F, Emuzyte R, Fabbri L, Fink Wagner A, Fletcher M, Fokkens WJ, Fonseca J, Franco A, Frith P, Furber A, Gaga M, Garces J, Garcia-Aymerich J, Gamkrelidze A, Gonzales-Diaz S, Gouzi F, Guzman MA, Haahtela T, Harrison D, Hayot M, Heaney LG, Heinrich J, Hellings PW, Hooper J, Humbert M, Hyland M, Iaccarino G, Jakovenko D, Jardim JR, Jeandel C, Jenkins C, Johnston SL, Jonquet O, Joos G, Jung KS, Kalayci O, Karunanithi S, Keil T, Khaltaev N, Kolek V, Kowalski ML, Kull I, Kuna P, Kvedariene V, Le LT, Lodrup Carlsen KC, Louis R, MacNee W, Mair A, Majer I, Manning P, de Manuel Keenoy E, Masjedi MR, Melen E, Melo-Gomes E, Menzies-Gow A, Mercier G, Mercier J, Michel JP, Miculinic N, Mihaltan F, Milenkovic B, Molimard M, Momas I, Montilla-Santana A, Morais-Almeida M, Morgan M, N'Diaye M, Nafti S, Nekam K, Neou A, Nicod L, O'Hehir R, Ohta K, Paggiaro P, Palkonen S, Palmer S, Papadopoulos NG, Papi A, Passalacqua G, Pavord I, Pigearias B, Plavec D, Postma DS, Price D, Rabe KF, Radier Pontal F, Redon J, Rennard S, Roberts J, Robine JM, Roca J, Roche N, Rodenas F, Roggeri A, Rolland C, Rosado-Pinto J, Ryan D, Samolinski B, Sanchez-Borges M, Schunemann HJ, Sheikh A, Shields M, Siafakas N, Sibille Y, Similowski T, Small I, Sola-Morales O, Sooronbaev T, Stelmach R, Sterk PJ, Stiris T, Sud P, Tellier V, To T, Todo-Bom A, Triggiani M, Valenta R, Valero AL, Valiulis A, Valovirta E, Van Ganse E, Vandenplas O, Vasankari T, Vestbo J, Vezzani G, Viegi G, Visier L, Vogelmeier C, Vontetsianos T, Wagstaff R, Wahn U, Wallaert B, Whalley B, Wickman M, Williams DM, Wilson N, Yawn BP, Yiallouros PK, Yorgancioglu A, Yusuf OM, Zar HJ, Zhong N, Zidarn M, Zuberbier T. Integrated care pathways for airway diseases (AIRWAYS-ICPs). Eur Respir J 2014;44:304-323. Faura Tellez G, Nawijn MC, Koppelman GH. Protocadherin-1: epithelial barrier dysfunction in asthma and eczema. Eur Respir J. 2014;43(3):671-674. Foster JM, Schokker S, Sanderman R, Postma DS, van der Molen T. Development of a brief questionnaire (ICQ-S) to monitor inhaled corticosteroid side-effects in clinical practice. Allergy. 2014;69(3):372-379. Franciosi L, Postma DS, van den Berge M, Govorukhina N, Horvatovich PL, Fusetti F, Poolman B, Lodewijk ME, Timens W, Bischoff R, Ten Hacken NH. Susceptibility to COPD: Differential Proteomic Profiling after Acute Smoking. PLoS One. 2014;9(7):e102037. Fuertes E, MacIntyre E, Agius R, Beelen R, Brunekreef B, Bucci S, Cesaroni G, Cirach M, Cyrys J, Forastiere F, Gehring U, Gruzieva O, Hoffmann B, Jedynska A, Keuken M, Klümper C, Kooter I, Korek M, Krämer U, Mölter A, Nieuwenhuijsen M, Pershagen G, Porta D, Postma DS, Simpson A, Smit HA, Sugiri D, Sunyer J, Wang M, Heinrich J. Associations between particulate matter elements and early-life pneumonia in seven birth cohorts: Results from the ESCAPE and TRANSPHORM projects. Int J Hyg Environ Health. 2014;217(8):819-829. Garde van de MD, Martinez FO, Melgert BN, Hylkema MN, Jonkers RE, Hamann J. Chronic exposure to glucocorticoids shapes gene expression and modulates innate and adaptive activation pathways in macrophages with distinct changes in leukocyte attraction. J Immunol 2014;192:1196-1208. Gimeno-Santos E, Frei A, Steurer-Stey C, de Batlle J, Rabinovich RA, Raste Y, Hopkinson NS, Polkey MI, van Remoortel H, Troosters T, Kulich K, Karlsson N, Puhan MA, Garcia-Aymerich J, PROactive consortium. Determinants and outcomes of physical activity in patients with COPD: a systematic review. Thorax 2014;69:731-739.

59

Gompelmann D, Herth FJ, Slebos DJ, Valipour A, Ernst A, Criner GJ, Eberhardt R. Pneumothorax following endobronchial valve therapy and its impact on clinical outcomes in severe emphysema. Respiration 2014;87(6):485-491. Gompelmann D, Eberhardt R, Slebos DJ, Brown MS, Abtin F, Kim HJ, Holmes-Higgin D, Radhakrishnan S, Herth FJ, Goldin J. Diagnostic performance comparison of the Chartis System and high-resolution computerized tomography fissure analysis for planning endoscopic lung volume reduction. Respirology 2014;19(4):524-530. Goossens NJ, Flokstra-de Blok BM, van der Meulen GN, Arnlind MH, Asero R, Barreales L, Burney P, Cerecedo I, Clausen M, Fernandéz-Rivas M, Frewer L, de la Hoz Caballer B, Jansson SA, Jedrzejczak-Czechowicz M, Knulst AC, Kowalski ML, Papadopoulos NG, Purohit A, Rokicka E, Starosta P, Vásquez-Cortés S, Duiverman EJ, Dubois AE. Health-related quality of life in food-allergic adults from eight European countries. Ann Allergy Asthma Immunol. 2014;113(1):63-68. Guan WJ, Zheng XY, Zheng JP, Boudewijn IM, Telenga ED, van der Wiel E, van der Molen T, Schiphof L, Ten Hacken NH, S Postma D, van den Berge M. Small airway dysfunction in asymptomatic bronchial hyperresponsiveness and asthma. Allergy 2014;69:1258-1259. Hartman JE, Boezen HM, Zuidema MJ, de Greef MH, Ten Hacken NH. Physical activity recommendations in patients with chronic obstructive pulmonary disease. Respiration 2014;88(2):92-100. Hazenberg A, Kerstjens HA, Prins SC, Vermeulen KM, Wijkstra PJ. Initiation of home mechanical ventilation at home: a randomised controlled trial of efficacy, feasibility and costs. Respir Med. 2014;108(9):1387-1395. Heijink I, van Oosterhout A, Kliphuis N, Jonker M, Hoffmann R, Telenga E, Klooster K, Slebos DJ, ten Hacken N, Postma D, van den Berge M. Oxidant-induced corticosteroid unresponsiveness in human bronchial epithelial cells. Thorax 2014;69(1):5-13. Heijink IH, Noordhoek JA, Timens W, van Oosterhout AJ, Postma DS. Abnormalities in airway epithelial junction formation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2014;189(11):1439-1442. Heijink IH, Nawijn MC, Hackett TL. Airway epithelial barrier function regulates the pathogenesis of allergic asthma. Clin Exp Allergy 2014;44:620-630. Holt S, Sheahan D, Helm C, Tofield C, Corin A, Kocks JW. Little agreement in GOLD category using CAT and mMRC in 450 primary care COPD patients in New Zealand. NPJ Prim Care Respir Med 2014;24:14025. Hoonhorst SJ, Ten Hacken NH, Vonk JM, Timens W, Hiemstra PS, Lapperre TS, Sterk PJ, Postma DS. Steroid Resistance in COPD? Overlap and Differential Anti-Inflammatory Effects in Smokers and Ex-Smokers. PLoS One. 2014;9(2):e87443. Hoonhorst SJ, Ten Hacken NH, Lo Tam Loi AT, Koenderman L, Lammers JW, Telenga ED, Boezen HM, van den Berge M, Postma DS. Lower Corticosteroid Skin Blanching Response Is Associated with Severe COPD. PLoS One. 2014;9(3):e91788. Hoonhorst SJ, Lo Tam Loi AT, Hartman JE, Telenga ED, van den Berge M, Koenderman L, Lammers JW, Marike Boezen H, Postma DS, Ten Hacken NH. Advanced glycation end products in the skin are enhanced in COPD. Metabolism. 2014;63(9):1149-1156.

60

Hoonhorst S, Timens W, Koenderman L, Lo Tam Loi AT, Lammers JW, Boezen H, van Oosterhout A, Postma DS, Ten Hacken N. Increased activation of blood neutrophils after cigarette smoking in young individuals susceptible to COPD. Respir Res. 2014;15(1):121. Jones RC, Price D, Ryan D, Sims EJ, von Ziegenweidt J, Mascarenhas L, Burden A, Halpin DM, Winter R, Hill S, Kearney M, Holton K, Moger A, Freeman D, Chisholm A, Bateman ED; Respiratory Effectiveness Group. Opportunities to diagnose chronic obstructive pulmonary disease in routine care in the UK: a retrospective study of a clinical cohort. Lancet Respir Med. 2014;2(4):267-276. Jong de K, Boezen HM, Kromhout H, Vermeulen R, Vonk JM, Postma DS; LifeLines cohort study. Occupational exposure to vapors, gases, dusts, and fumes is associated with small airways obstruction. Am J Respir Crit Care Med. 2014;189(4):487-490. Jong de K, Boezen HM, Kromhout H, Vermeulen R, Postma DS, Vonk JM; LifeLines Cohort study. Pesticides and other occupational exposures are associated with airway obstruction: the LifeLines cohort study. Occup Environ Med. 2014;71(2):88-96. Jong de K, Boezen HM, Kromhout H, Vermeulen R, Postma DS, Vonk JM. Association of Occupational Pesticide Exposure With Accelerated Longitudinal Decline in Lung Function. Am J Epidemiol. 2014;179(11):1323-1330. Jong de K, Vonk JM, Kromhout H, Vermeulen R, Postma DS, Boezen HM, LifeLines Cohort Study. NOS1: a susceptibility gene for reduced level of FEV1 in the setting of pesticide exposure. Am J Respir Crit Care Med 2014;190:1188-1190. Kerkhof M, Boezen HM, Granell R, Wijga AH, Brunekreef B, Smit HA, de Jongste JC, Thijs C, Mommers M, Penders J, Henderson J, Koppelman GH, Postma DS. Transient early wheeze and lung function in early childhood associated with chronic obstructive pulmonary disease genes. J Allergy Clin Immunol. 2014;133(1):68-76. Kirenga BJ, Levin J, Ayakaka I, Worodria W, Reilly N, Mumbowa F, Nabanjja H, Nyakoojo G, Fennelly K, Nakubulwa S, Joloba M, Okwera A, Eisenach KD, McNerney R, Elliott AM, Mugerwa RD, Smith PG, Ellner JJ, Jones-Lopez EC. Treatment outcomes of new tuberculosis patients hospitalized in Kampala, Uganda: a prospective cohort study. PLoS One 2014;9:e90614. Kistemaker LE, Bos ST, Mudde WM, Hylkema MN, Hiemstra PS, Wess J, Meurs H, Kerstjens HA, Gosens R. Muscarinic M(3) receptors contribute to allergen-induced airway remodeling in mice. Am J Respir Cell Mol Biol 2014;50:690-698. Klaassen EM, van de Kant KD, Jöbsis Q, Penders J, van Schooten FJ, Quaak M, den Hartog GJ, Koppelman GH, van Schayck CP, van Eys G, Dompeling E. Integrative genomic analysis identifies a role for intercellular adhesion molecule 1 in childhood asthma. Pediatr Allergy Immunol. 2014;25(2):166-172. Klooster K, Ten Hacken NH, Slebos DJ. The lung volume reduction coil for the treatment of emphysema: a new therapy in development. Expert Rev Med Devices. 2014;11(5):481-489. Klooster K, Ten Hacken NH, Franz I, Kerstjens HA, van Rikxoort EM, Slebos DJ. Lung volume reduction coil treatment in chronic obstructive pulmonary disease patients with homogeneous emphysema: a prospective feasibility trial. Respiration. 2014;88(2):116-125.

61

Kolahian S, Shahbazfa RAA, Tayefi-Nasrabadi H, Keyhanmanesh R, Ansarin K, Ghasemi H Rashidi AH, Gosens R, Hanifeh M. Tiotropium effects on airway inflammatory events in the cat as an animal model for acute cigarette smoke-induced lung inflammation. Exp Lung Res 2014;40: 272-287. Koning H, van Oosterhout AJ, Brouwer U, den Boef LE, Gras R, Reinders-Luinge M, Brandsma CA, van der Toorn M, Hylkema MN, Willemse BW, Sayers I, Koppelman GH, Nawijn MC. Mouse protocadherin-1 gene expression is regulated by cigarette smoke exposure in vivo. PLoS One 2014;9:e98197. Koopmans T, Anaparti V, Castro-Piedras I, Yarova P, Irechukwu N, Nelson C, Perez-Zoghbi J, Tan X, Ward JP, Wright DB. Ca2+ handling and sensitivity in airway smooth muscle: emerging concepts for mechanistic understanding and therapeutic targeting. Pulm Pharmacol Ther 2014;29:108-120. Koppelman GH, Hall IP. Asthma genetics 2014: reaching for high-hanging fruit. Clin Exp All 2014 Nov;44(11):1296-1298. Koskela J, Kilpeläinen M, Kupiainen H, Mazur W, Sintonen H, Boezen M, Lindqvist A, Postma D, Laitinen T. Co-morbidities are the key nominators of the health related quality of life in mild and moderate COPD. BMC Pulm Med. 2014;14(1):102. Kruis AL, Stallberg B, Jones RC, Tsiligianni IG, Lisspers K, van der Molen T, Kocks JW, Chavannes NH. Primary care COPD patients compared with large pharmaceutically-sponsored COPD studies: an UNLOCK validation study. PLoS One 2014;9:e90145. Kumawat K, Koopmans T, Gosens R. β-catenin as a regulator and therapeutic target for asthmatic airway remodeling. Exp Opin Ther Targets 2014;18:1023-1034. Kumawat K, Menzen MH, Slegtenhorst RM, Halayko AJ, Schmidt M, Gosens R. TGF-β-activated kinase 1 (TAK1) signaling regulates TGF-β-induced WNT-5A expression in airway smooth muscle cells via Sp1 and β-catenin. PLoS One. 2014;9:e94801. Lamontagne M, Timens W, Hao K, Bossé Y, Laviolette M, Steiling K, Campbell JD, Couture C, Conti M, Sherwood K, Hogg JC, Brandsma CA, van den Berge M, Sandford A, Lam S, Lenburg ME, Spira A, Paré PD, Nickle D, Sin DD, Postma DS. Genetic regulation of gene expression in the lung identifies CST3 and CD22 as potential causal genes for airflow obstruction. Thorax. 2014;69(11):997-1004. Landis SH, Muellerova H, Mannino DM, Menezes AM, Han MK, van der Molen T, Ichinose M, Aisanov Z, Oh YM, Davis KJ. Continuing to Confront COPD International Patient Survey: methods, COPD prevalence, and disease burden in 2012-2013. Int J Chron Obstruct Pulmon Dis 2014;9:597-611. Lexmond AJ, Kruizinga TJ, Hagedoorn P, Rottier BL, Frijlink HW, de Boer AH. Effect of inhaler design variables on paediatric use of dry powder inhalers. PLoS One. 2014;9(6):e99304. Lionis C, Petelos E, Shea S, Bagiartaki G, Tsiligianni IG, Kamekis A, Tsiantou V, Papadakaki M, Tatsioni A, Moschandreas J, Saridaki A, Bertsias A, Faresjo T, Faresjo A, Martinez L, Agius D, Uncu Y, Samoutis G, Vlcek J, Abasaeed A, Merkouris B. Irrational prescribing of over-the-counter (OTC) medicines in general practice: testing the feasibility of an educational intervention among physicians in five European countries. BMC Fam Pract 2014;15:34.

62

Loth DW, Artigas MS, Gharib SA, Wain LV, Franceschini N, Koch B, Pottinger TD, Smith AV, Duan Q, Oldmeadow C, Lee MK, Strachan DP, James AL, Huffman JE, Vitart V, Ramasamy A, Wareham NJ, Kaprio J, Wang XQ, Trochet H, Kähönen M, Flexeder C, Albrecht E, Lopez LM, de Jong K, Thyagarajan B, Alves AC, Enroth S, Omenaas E, Joshi PK, Fall T, Viñuela A, Launer LJ, Loehr LR, Fornage M, Li G, Wilk JB, Tang W, Manichaikul A, Lahousse L, Harris TB, North KE, Rudnicka AR, Hui J, Gu X, Lumley T, Wright AF, Hastie ND, Campbell S, Kumar R, Pin I, Scott RA, Pietiläinen KH, Surakka I, Liu Y, Holliday EG, Schulz H, Heinrich J, Davies G, Vonk JM, Wojczynski M, Pouta A, Johansson A, Wild SH, Ingelsson E, Rivadeneira F, Völzke H, Hysi PG, Eiriksdottir G, Morrison AC, Rotter JI, Gao W, Postma DS, White WB, Rich SS, Hofman A, Aspelund T, Couper D, Smith LJ, Psaty BM, Lohman K, Burchard EG, Uitterlinden AG, Garcia M, Joubert BR, McArdle WL, Musk AB, Hansel N, Heckbert SR, Zgaga L, van Meurs JB, Navarro P, Rudan I, Oh YM, Redline S, Jarvis DL, Zhao JH, Rantanen T, O'Connor GT, Ripatti S, Scott RJ, Karrasch S, Grallert H, Gaddis NC, Starr JM, Wijmenga C, Minster RL, Lederer DJ, Pekkanen J, Gyllensten U, Campbell H, Morris AP, Gläser S, Hammond CJ, Burkart KM, Beilby J, Kritchevsky SB, Gudnason V, Hancock DB, Williams OD, Polasek O, Zemunik T, Kolcic I, Petrini MF, Wjst M, Kim WJ, Porteous DJ, Scotland G, Smith BH, Viljanen A, Heliövaara M, Attia JR, Sayers I, Hampel R, Gieger C, Deary IJ, Boezen HM, Newman A, Jarvelin MR, Wilson JF, Lind L, Stricker BH, Teumer A, Spector TD, Melén E, Peters MJ, Lange LA, Barr RG, Bracke KR, Verhamme FM, Sung J, Hiemstra PS, Cassano PA, Sood A, Hayward C, Dupuis J, Hall IP, Brusselle GG, Tobin MD, London SJ. Genome-wide association analysis identifies six new loci associated with forced vital capacity. Nat Genet. 2014;46(7):669-677. Lusiba JK, Nakiyingi L, Kirenga BJ, Kiragga A, Lukande R, Nsereko M, Ssengooba W, Katamba A, Worodria W, Joloba ML, Mayanja-Kizza H. Evaluation of Cepheid's Xpert MTB/Rif test on pleural fluid in the diagnosis of pleural tuberculosis in a high prevalence HIV/TB setting. PLoS One 2014;9:e102702. Macintyre EA, Brauer M, Melén E, Bauer CP, Bauer M, Berdel D, Bergström A, Brunekreef B, Chan-Yeung M, Klümper C, Fuertes E, Gehring U, Gref A, Heinrich J, Herbarth O, Kerkhof M, Koppelman GH, Kozyrskyj AL, Pershagen G, Postma DS, Thiering E, Tiesler CM, Carlsten C; TAG Study Group. GSTP1 and TNF Gene Variants and Associations between Air Pollution and Incident Childhood Asthma: The Traffic, Asthma and Genetics (TAG) Study. Environ Health Perspect. 2014;122(4):418-424. MacIntyre EA, Gehring U, Mölter A, Fuertes E, Klümper C, Krämer U, Quass U, Hoffmann B, Gascon M, Brunekreef B, Koppelman GH, Beelen R, Hoek G, Birk M, de Jongste JC, Smit HA, Cyrys J, Gruzieva O, Korek M, Bergström A, Agius RM, de Vocht F, Simpson A, Porta D, Forastiere F, Badaloni C, Cesaroni G, Esplugues A, Fernández-Somoano A, Lerxundi A, Sunyer J, Cirach M, Nieuwenhuijsen MJ, Pershagen G, Heinrich J. Air pollution and respiratory infections during early childhood: an analysis of 10 European birth cohorts within the ESCAPE Project. Environ Health Perspect. 2014;122(1):107-113. Manichaikul A, Hoffman EA, Smolonska J, Gao W, Cho MH, Baumhauer H, Budoff M, Austin JH, Washko GR, Carr JJ, Kaufman JD, Pottinger T, Powell CA, Wijmenga C, Zanen P, Groen HJ, Postma DS, Wanner A, Rouhani FN, Brantly ML, Powell R, Smith BM, Rabinowitz D, Raffel LJ, Hinckley Stukovsky KD, Crapo JD, Beaty TH, Hokanson JE, Silverman EK, Dupuis J, O'Connor GT, Boezen HM, Rich SS, Barr RG. Genome-Wide Study of Percent Emphysema on Computed Tomography in the General Population. The Multi-Ethnic Study of Atherosclerosis Lung/SNP Health Association Resource Study. Am J Respir Crit Care Med. 2014;189(4):408-418. Martin RJ, Price D, Roche N, Israel E, van Aalderen WM, Grigg J, Postma DS, Guilbert TW, Hillyer EV, Burden A, von Ziegenweidt J, Colice G. Cost-effectiveness of initiating extrafine-

63

or standard size-particle inhaled corticosteroid for asthma in two health-care systems: a retrospective matched cohort study. NPJ Prim Care Respir Med. 2014;24:14081. Mayosi BM, Ntsekhe M, Bosch J, Pandie S, Jung H, Gumedze F, Pogue J, Thabane L, Smieja M, Francis V, Joldersma L, Thomas KM, Thomas B, Awotedu AA, Magula NP, Naidoo DP, Damasceno A, Chitsa Banda A, Brown B, Manga P, Kirenga B, Mondo C, Mntla P, Tsitsi JM, Peters F, Essop MR, Russell JB, Hakim J, Matenga J, Barasa AF, Sani MU, Olunuga T, Ogah O, Ansa V, Aje A, Danbauchi S, Ojji D, Yusuf S, IMPI Trial Investigators. Prednisolone and Mycobacterium indicus pranii in tuberculous pericarditis. N Engl J Med 2014;371:1121-1130. McDonnell J, De Sousa JC, Baxter N, Pinnock H, Roman-Rodriquez M, van der Molen T, Williams S. Building capacity to improve respiratory care: the education strategy of the International Primary Care Respiratory Group 2014-2020. NPJ Prim Care Respir Med 2014;24:14072. Mfinanga SG, Kirenga BJ, Chanda DM, Mutayoba B, Mthiyane T, Yimer G, Ezechi O, Connolly C, Kapotwe V, Muwonge C, Massaga J, Sinkala E, Kohi W, Lyantumba L, Nyakoojo G, Luwaga H, Doulla B, Mzyece J, Kapata N, Vahedi M, Mwaba P, Egwaga S, Adatu F, Pym A, Joloba M, Rustomjee R, Zumla A, Onyebujoh P. Early versus delayed initiation of highly active antiretroviral therapy for HIV-positive adults with newly diagnosed pulmonary tuberculosis (TB-HAART): a prospective, international, randomised, placebo-controlled trial. Lancet Infect Dis 2014;14:563-571. Midulla F, Lombardi E, Rottier B, Lindblad A, Grigg J, Bohlin K, Rusconi F, Pohunek P, Eber E. Pediatrics in Barcelona. Eur Resp J 2014;44(2):457-474. Mineshita M, Slebos DJ. Bronchoscopic interventions for chronic obstructive pulmonary disease. Respirology. 2014;19(8):1126-1137. Miravitlles M, Worth H, Soler Cataluna J, Price D, de Benedetto F, Roche N, Godtfredsen N, van der Molen T, Lofdahl CG, Padulles L, Ribera A. Observational study to characterise 24-hour COPD symptoms and their relationship with patient-reported outcomes: results from the ASSESS study. Respir Res 2014;15:122. Molen van der T, Diamant Z, Kocks JW, Tsiligianni IG. The use of health status questionnaires in the management of chronic obstructive pulmonary disease patients in clinical practice. Expert Rev Respir Med 2014;8:479-491. Molen van der T, Kocks JW. The efficacy and safety of inhaled corticosteroids: are we ignoring the potential advantages of ciclesonide? NPJ Prim Care Respir Med 2014;24:14013. Morissette MC, Lamontagne M, Berube JC, Gaschler G, Williams A, Yauk C, Couture C, Laviolette M, Hogg JC, Timens W, Halappanavar S, Stampfli MR, Bosse Y. Impact of cigarette smoke on the human and mouse lungs: a gene-expression comparison study. PLoS One 2014,9:e92498. Muraro A, Roberts G, Worm M, Bilò MB, Brockow K, Fernández Rivas M, Santos AF, Zolkipli ZQ, Bellou A, Beyer K, Bindslev-Jensen C, Cardona V, Clark AT, Demoly P, Dubois AE, DunnGalvin A, Eigenmann P, Halken S, Harada L, Lack G, Jutel M, Niggemann B, Ruëff F, Timmermans F, Vlieg-Boerstra BJ, Werfel T, Dhami S, Panesar S, Akdis CA, Sheikh A; EAACI Food Allergy and Anaphylaxis Guidelines Group. Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology. Allergy. 2014;69(8):1026-1045.

64

Muraro A, Dubois AE, DunnGalvin A, Hourihane JO, de Jong NW, Meyer R, Panesar SS, Roberts G, Salvilla S, Sheikh A, Worth A, Flokstra-de Blok BM. EAACI Food Allergy and Anaphylaxis Guidelines. Food allergy health-related quality of life measures. Allergy. 2014;69(7):845-853. Muraro A, Halken S, Arshad SH, Beyer K, Dubois AE, Du Toit G, Eigenmann PA, Grimshaw KE, Hoest A, Lack G, O'Mahony L, Papadopoulos NG, Panesar S, Prescott S, Roberts G, de Silva D, Venter C, Verhasselt V, Akdis AC, Sheikh A; EAACI Food Allergy and Anaphylaxis Guidelines Group. EAACI food allergy and anaphylaxis guidelines. Primary prevention of food allergy. Allergy. 2014;69(5):590-601. Muraro A, Werfel T, Hoffmann-Sommergruber K, Roberts G, Beyer K, Bindslev-Jensen C, Cardona V, Dubois A, duToit G, Eigenmann P, Fernandez Rivas M, Halken S, Hickstein L, Høst A, Knol E, Lack G, Marchisotto MJ, Niggemann B, Nwaru BI, Papadopoulos NG, Poulsen LK, Santos AF, Skypala I, Schoepfer A, Van Ree R, Venter C, Worm M, Vlieg-Boerstra B, Panesar S, de Silva D, Soares-Weiser K, Sheikh A, Ballmer-Weber BK, Nilsson C, de Jong NW, Akdis CA; EAACI Food Allergy and Anaphylaxis Guidelines Group. EAACI food allergy and anaphylaxis guidelines: diagnosis and management of food allergy. Allergy. 2014;69(8):1008-1025. Nguyen JD, Lamontagne M, Couture C, Conti M, Paré PD, Sin DD, Hogg JC, Nickle D, Postma DS, Timens W, Laviolette M, Bossé Y. Susceptibility loci for lung cancer are associated with mRNA levels of nearby genes in the lung. Carcinogenesis. 2014;35:2653-2659. Niedoszytko M, Bonadonna P, Oude Elberink JN, Golden DB. Epidemiology, diagnosis, and treatment of Hymenoptera venom allergy in mastocytosis patients. Immunol Allergy Clin North Am. 2014;34(2):365-381. Noble PB, Pascoe CD, Lan B, Ito S, Kistemaker LEM, Tatler AL, Pera T, Brook BS, Gosens R, West AR. Airway smooth muscle in asthma: Linking contraction and mechanotransduction to disease pathogenesis and remodeling. Pulm Pharmacol Ther 2014;29:96-107. Nwaru BI, Hickstein L, Panesar SS, Roberts G, Muraro A, Sheikh A; EAACI Food Allergy and Anaphylaxis Guidelines Group. Prevalence of common food allergies in Europe: a systematic review and meta-analysis. Allergy. 2014;69(8):992-1007. Nwaru BI, Hickstein L, Panesar SS, Muraro A, Werfel T, Cardona V, Dubois AE, Halken S, Hoffmann-Sommergruber K, Poulsen LK, Roberts G, Van Ree R, Vlieg-Boerstra BJ, Sheikh A; EAACI Food Allergy and Anaphylaxis Guidelines Group. The epidemiology of food allergy in Europe: a systematic review and meta-analysis. Allergy. 2014;69:62-75. Ojo O, Lagan AL, Rajendran V, Spanjer A, Chen L, Sohal SS, Heijink I, Jones R, Maarsingh H, Hackett TL. Pathological changes in the COPD lung mesenchyme - Novel lessons learned from in vitro and in vivo studies. Pulm Pharmacol Ther 2014; 29:121-128. Oldenburger A, Poppinga WJ, Kos F, de Bruin HG, Rijks W, Heijink I, Timens W, Meurs H, Maarsingh H, Schmidt M. A-kinase anchoring proteins contribute to loss of E-cadherin and bronchial epithelial barrier by cigarette smoke. Am J Physiol Cell Physiol 2014,306:C585-597. Oldenburger A, Timens W, Bos S, Smit M, Smrcka AV, Laurent AC, Cao J, Hylkema M, Meurs H, Maarsingh H, Lezoualc'h F, Schmidt M. Epac1 and Epac2 are differentially involved in inflammatory and remodeling processes induced by cigarette smoke. FASEB J 2014;28:4617-4628.

65

Oldenburger A, van Basten B, Kooistra W, Meurs H, Maarsingh H, Krenning G, Timens W, Schmidt M. Interaction between Epac1 and miRNA-7 in airway smooth muscle cells. Naunyn Schmiedebergs Arch Pharmacol 2014,387:795-797. Panaitescu C, Moffat MA, Williams S, Pinnock H, Boros M, Oana CS, Alexiu S, Tsiligianni I. Barriers to the provision of smoking cessation assistance: a qualitative study among Romanian family physicians. NPJ Prim Care Respir Med 2014;24:14022. Pera T, Zuidhof AB, Smit M, Menzen MH, Klein T, Flik G, Zaagsma J, Meurs H, Maarsingh H. Arginase inhibition prevents inflammation and remodeling in a guinea pig model of chronic obstructive pulmonary disease. J Pharmacol Exp Ther 2014;349:229-238. Pettersson ME, Flokstra-de Blok BM, van der Heide S, Kukler J, Dubois AE. Is 30 minutes between doses long enough in oral food challenges? Pediatr Allergy Immunol. 2014;25(6):615-617. Pinart M, Benet M, Annesi-Maesano I, von Berg A, Berdel D, Carlsen KC, Carlsen KH, Bindslev-Jensen C, Eller E, Fantini MP, Lenzi J, Gehring U, Heinrich J, Hohmann C, Just J, Keil T, Kerkhof M, Kogevinas M, Koletzko S, Koppelman GH, Kull I, Lau S, Melén E, Momas I, Porta D, Postma DS, Rancière F, Smit HA, Stein RT, Tischer CG, Torrent M, Wickman M, Wijga AH, Bousquet J, Sunyer J, Basagaña X, Guerra S, Garcia-Aymerich J, Antó JM. Comorbidity of eczema, rhinitis, and asthma in IgE-sensitised and non-IgE-sensitised children in MeDALL: a population-based cohort study. Lancet Respir Med. 2014;2(2):131-140. Poppinga WJ, Muñoz-Llancao P, González-Billault C, Schmidt M. A-kinase anchoring proteins: Cyclic AMP compartmentalization in neurodegenerative and obstructive pulmonary diseases. Brit J Pharmacol 2014;171: 5603-5623. Portelli MA, Siedlinski M, Stewart CE, Postma DS, Nieuwenhuis MA, Vonk JM, Nurnberg P, Altmuller J, Moffatt MF, Wardlaw AJ, Parker SG, Connolly MJ, Koppelman GH, Sayers I. Genome-wide protein QTL mapping identifies human plasma kallikrein as a post-translational regulator of serum uPAR levels. FASEB J. 2014;28(2):923-934. Post S, Heijink IH, Petersen AH, de Bruin HG, van Oosterhout AJ, Nawijn MC. Protease-activated receptor-2 activation contributes to House Dust Mite-induced IgE responses in mice. PlosOne 2014; 9(3):e91206. Postma DS, Reddel HK, Ten Hacken NH, van den Berge M. Asthma and Chronic Obstructive Pulmonary Disease: Similarities and Differences. Clin Chest Med. 2014;35(1):143-156. Postma DS, Koppelman GH. The child is father of the man? Am J Respir Crit Care Med. 2014;190(4):358-359. Postma DS, Roche N, Colice G, Israel E, Martin RJ, van Aalderen WM, Grigg J, Burden A, Hillyer EV, von Ziegenweidt J, Gopalan G, Price D. Comparing the effectiveness of small-particle versus large-particle inhaled corticosteroid in COPD. Int J Chron Obstruct Pulmon Dis. 2014;9:1163-1186. Pouwels SD, Heijink IH, van Oosterhout AJ, Nawijn MC. A specific DAMP profile identifies susceptibility to smoke-induced airway inflammation. Eur Respir J. 2014;43(4):1183-1186.

66

Pouwels SD, Heijink IH, ten Hacken NH, Vandenabeele P, Krysko DV, Nawijn MC, van Oosterhout AJ. DAMPs activating innate and adaptive immune responses in COPD. Mucosal Immunol. 2014;7(2):215-226. Price D, Fletcher M, van der Molen T. Asthma control and management in 8,000 European patients: the REcognise Asthma and LInk to Symptoms and Experience (REALISE) survey. NPJ Prim Care Respir Med 2014;24:14009. Price D, Fromer L, Kaplan A, van der Molen T, Roman-Rodriguez M. Is there a rationale and role for long-acting anticholinergic bronchodilators in asthma? NPJ Prim Care Respir Med 2014;24:14023. Robbe P, Spierenburg EA, Draijer C, Brandsma CA, Telenga E, van Oosterhout AJ, van den Berge M, Luinge M, Melgert BN, Heederik D, Timens W, Wouters IM, Hylkema MN. Shifted T-cell polarisation after agricultural dust exposure in mice and men. Thorax 2014;69:630-637. Roche N, Reddel H, Martin R, Brusselle G, Papi A, Thomas M, Postma D, Thomas V, Rand C, Chisholm A, Price D; Respiratory Effectiveness Group. Quality standards for real-world research. Focus on observational database studies of comparative effectiveness. Ann Am Thorac Soc. 2014;11(Suppl 2):S99-104. Rossem van L, Wijga AH, Brunekreef B, de Jongste JC, Kerkhof M, Postma DS, Gehring U, Smit HA. Overweight in infancy: which pre- and perinatal factors determine overweight persistence or reduction? A birth cohort followed for 11 years. Ann Nutr Metab 2014;65:211-219. Rossi A, van der Molen T, del Olmo R, Papi A, Wehbe L, Quinn M, Lu C, Young D, Cameron R, Bucchioni E, Altman P. INSTEAD: a randomised switch trial of indacaterol versus salmeterol/fluticasone in moderate COPD. Eur Respir J 2014;44:1548-1556. Salvilla SA, Dubois AE, Flokstra-de Blok BM, Panesar SS, Worth A, Patel S, Muraro A, Halken S, Hoffmann-Sommergruber K, DunnGalvin A, Hourihane JO, Regent L, de Jong NW, Roberts G, Sheikh A; EAACI Food Allergy and Anaphylaxis Group. Disease-specific health-related quality of life instruments for IgE-mediated food allergy. Allergy. 2014;69(7):834-844. Sanya RE, Kirenga BJ, Worodria W, Okot-Nwang M. Risk factors for asthma exacerbation in patients presenting to an emergency unit of a national referral hospital in Kampala, Uganda. Afr Health Sci 2014;14:707-715. Savenije OE, Mahachie John JM, Granell R, Kerkhof M, Dijk FN, de Jongste JC, Smit HA, Brunekreef B, Postma DS, Van Steen K, Henderson J, Koppelman GH. Association of IL33-IL-1 receptor-like 1 (IL1RL1) pathway polymorphisms with wheezing phenotypes and asthma in childhood. J Allergy Clin Immunol. 2014;134(1):170-177. Schiphof-Godart L, van der Wiel E, Ten Hacken N, van den Berge M, Postma DS, van der Molen T. Development of a tool to recognize small airways dysfunction in asthma (SADT). Health Qual Life Outcomes 2014;12:155. Scholtens S, Postma DS, Moffatt MF, Panasevich S, Granell R, Henderson AJ, Melén E, Nyberg F, Pershagen G, Jarvis D, Ramasamy A, Wjst M, Svanes C, Bouzigon E, Demenais F, Kauffmann F, Siroux V, von Mutius E, Ege MJ, Braun-Fahrländer C, Genuneit J; GABRIELA study group, Brunekreef B, Smit HA, Wijga AH, Kerkhof M, Curjuric I, Imboden M, Thun GA, Probst-Hensch N, Freidin MB, Bragina EI, Deev IA, Puzyrev VP, Daley D, Park

67

J, Becker A, Chan-Yeung M, Kozyrskyj AL, Pare P, Marenholn I, Lau S, Keil T, Lee YA, Kabesch M, Wijmenga C, Franke L, Nolte IM, Vonk J, Kumar A, Farrall M, Cookson WO, Strachan DP, Koppelman GH, Boezen HM. Novel childhood asthma genes interact with in utero and early-life tobacco smoke exposure. J Allergy Clin Immunol. 2014;133(3):885-888. Serugendo AN, Kirenga BJ, Hawkes M, Nakiyingi L, Worodria W, Okot-Nwang M. Evaluation of asthma control using Global Initiative for Asthma criteria and the Asthma Control Test in Uganda. Int J Tuberc Lung Dis 2014;18:371-376. Sidharta PN, Diamant Z, Dingemanse J. Single- and multiple-dose tolerability and pharmacokinetics of the CRTH2 antagonist setipiprant in healthy male subjects. Fundam Clin Pharmacol 2014;28:690-699. Silva de D, Geromi M, Halken S, Host A, Panesar SS, Muraro A, Werfel T, Hoffmann-Sommergruber K, Roberts G, Cardona V, Dubois AE, Poulsen LK, Van Ree R, Vlieg-Boerstra B, Agache I, Grimshaw K, O'Mahony L, Venter C, Arshad SH, Sheikh A; EAACI Food Allergy and Anaphylaxis Guidelines Group. Primary prevention of food allergy in children and adults: systematic review. Allergy. 2014;69(5):581-589. Silva de D, Geromi M, Panesar SS, Muraro A, Werfel T, Hoffmann-Sommergruber K, Roberts G, Cardona V, Dubois AE, Halken S, Host A, Poulsen LK, Van Ree R, Vlieg-Boerstra BJ, Agache I, Sheikh A; EAACI Food Allergy and Anaphylaxis Guidelines Group. Acute and long-term management of food allergy: systematic review. Allergy. 2014;69(2):159-167. Slok AH, In 't Veen JC, Chavannes NH, van der Molen T, Molken MP, Kerstjens HA, Asijee GM, Salome PL, Holverda S, Dekhuijzen RP, Schuiten D, van Breukelen G, Kotz D, van Schayck OC. Effectiveness of the Assessment of Burden of Chronic Obstructive Pulmonary Disease (ABC) tool: study protocol of a cluster randomised trial in primary and secondary care. BMC Pulm Med 2014;14:131. Slok AH, in 't Veen JC, Chavannes NH, van der Molen T, Rutten-van Molken MP, Kerstjens HA, Salome PL, Holverda S, Dekhuijzen PN, Schuiten D, Asijee GM, van Schayck OC. Development of the Assessment of Burden of COPD tool: an integrated tool to measure the burden of COPD. NPJ Prim Care Respir Med 2014;24:14021. Smit M, Zuidhof AB, Bos IST, Maarsingh H, Gosens R, Zaagsma J, Meurs H. Bronchoprotection by olodaterol is synergistically enhanced by tiotropium in a guinea pig model of allergic asthma. J Pharmacol Exp Ther 2014;348: 303-310. Smolonska J, Koppelman GH, Wijmenga C, Vonk JM, Zanen P, Bruinenberg M, Curjuric I, Imboden M, Thun GA, Franke L, Probst-Hensch NM, Nürnberg P, Riemersma RA, van Schayck CP, Loth DW, Brusselle GG, Stricker BH, Hofman A, Uitterlinden AG, Lahousse L, London SJ, Loehr LR, Manichaikul A, Barr RG, Donohue KM, Rich SS, Pare P, Bossé Y, Hao K, van den Berge M, Groen HJ, Lammers JW, Mali W, Boezen HM, Postma DS. Common genes underlying asthma and COPD? Genome-wide analysis on the Dutch hypothesis. Eur Respir J. 2014;44(4):860-872. Struik FM, Lacasse Y, Goldstein RS, Kerstjens HA, Wijkstra PJ. Nocturnal non invasive positive pressure ventilation in stable COPD:A systematic review and individual patient data meta-analysis. Respir Med. 2014 Feb;108(2):329-337. Struik FM, Sprooten RT, Kerstjens HA, Bladder G, Zijnen M, Asin J, Cobben NA, Vonk JM, Wijkstra PJ. Nocturnal non-invasive ventilation in COPD patients with prolonged hypercapnia

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after ventilatory support for acute respiratory failure: a randomised, controlled, parallel-group study. Thorax 2014;69(9):826-834. Struik FM, Wijkstra PJ. Response to: Domiciliary long term non-invasive ventilation in COPD: should we select subgroups with a better likelihood to respond to NIV in subsequent randomized controlled trails Thorax 2014;69(12):1143-1144. Tania NP, Schmidt M, Gosens R. Activin-A: active in inflammation in COPD. Eur Respir J 2014;43:954-955. Telenga ED, Hoffmann RF, Ruben t'Kindt, Hoonhorst SJ, Willemse BW, van Oosterhout AJ, Heijink IH, van den Berge M, Jorge L, Sandra P, Postma DS, Sandra K, Ten Hacken NH. Untargeted lipidomic analysis in chronic obstructive pulmonary disease. Uncovering sphingolipids. Am J Respir Crit Care Med. 2014;190(2):155-164. Valent P, Escribano L, Broesby-Olsen S, Hartmann K, Grattan C, Brockow K, Niedoszytko M, Nedoszytko B, Oude Elberink JN, Kristensen T, Butterfield JH, Triggiani M, Alvarez-Twose I, Reiter A, Sperr WR, Sotlar K, Yavuz S, Kluin-Nelemans HC, Hermine O, Radia D, van Doormaal JJ, Gotlib J, Orfao A, Siebenhaar F, Schwartz LB, Castells M, Maurer M, Horny HP, Akin C, Metcalfe DD, Arock M. Proposed diagnostic algorithm for patients with suspected mastocytosis: a proposal of the European Competence Network on Mastocytosis. Allergy. 2014;69(10):1267-1274. Valipour A, Slebos DJ, de Oliveira HG, Eberhardt R, Freitag L, Criner GJ, Herth FJ. Expert statement: pneumothorax associated with endoscopic valve therapy for emphysema--potential mechanisms, treatment algorithm, and case examples. Respiration. 2014;87(6):513-521. Valk van der JP, Dubois AE, Gerth van Wijk R, Wichers HJ, de Jong NW. Systematic review on cashew nut allergy. Allergy. 2014;69(6):692-698. Valk van der RJ, Duijts L, Timpson NJ, Salam MT, Standl M, Curtin JA, Genuneit J, Kerhof M, Kreiner-Møller E, Cáceres A, Gref A, Liang LL, Taal HR, Bouzigon E, Demenais F, Nadif R, Ober C, Thompson EE, Estrada K, Hofman A, Uitterlinden AG, van Duijn C, Rivadeneira F, Li X, Eckel SP, Berhane K, Gauderman WJ, Granell R, Evans DM, St Pourcain B, McArdle W, Kemp JP, Smith GD, Tiesler CM, Flexeder C, Simpson A, Murray CS, Fuchs O, Postma DS, Bønnelykke K, Torrent M, Andersson M, Sleiman P, Hakonarson H, Cookson WO, Moffatt MF, Paternoster L, Melén E, Sunyer J, Bisgaard H, Koppelman GH, Ege M, Custovic A, Heinrich J, Gilliland FD, Henderson AJ, Jaddoe VW, de Jongste JC; for the EArly Genetics & Lifecourse Epidemiology (EAGLE) Consortium. Fraction of exhaled nitric oxide values in childhood are associated with 17q11.2-q12 and 17q12-q21 variant. J Allergy Clin Immunol. 2014;134(1):46-55. Veer van der E, Arends S, van der Hoek S, Versluijs JB, de Monchy JG, Oude Elberink JN, van Doormaal JJ. Predictors of new fragility fractures after diagnosis of indolent systemic mastocytosis. J Allergy Clin Immunol. 2014;134(6):1413-1421. Vijverberg SJ, Tavendale R, Leusink M, Koenderman L, Raaijmakers JA, Postma DS, Koppelman GH, Turner SW, Mukhopadhyay S, Palmer CN, Maitland-van der Zee AH. Pharmacogenetic analysis of GLCCI1 in three north European pediatric asthma populations with a reported use of inhaled corticosteroids. Pharmacogenomics. 2014;15(6):799-806. Vries de M, Heijink IH, Gras R, den Boef LE, Reinders-Luinge M, Pouwels SD, Hylkema MN, van der Toorn M, Brouwer U, van Oosterhout AJ, Nawijn MC. Pim1 kinase protects airway

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epithelial cells from cigarette smoke-induced damage and airway inflammation. Am J Physiol Lung Cell Mol Physiol 2014;307:L240-251. Wekesa C, Kirenga BJ, Joloba ML, Bwanga F, Katamba A, Kamya MR. Chest X-ray vs. Xpert(R) MTB/RIF assay for the diagnosis of sputum smear-negative tuberculosis in Uganda. Int J Tuberc Lung Dis 2014;18:216-219. Wiel van der E, Ten Hacken NH, van den Berge M, Timens W, Reddel HK, Postma DS. Eosinophilic inflammation in subjects with mild-to-moderate asthma with and without obesity: disparity between sputum and biopsies. Am J Respir Crit Care Med. 2014;189(10):1281-1284. Wiel van der E, Postma DS, van der Molen T, Schiphof-Godart L, Ten Hacken NH, van den Berge M. Effects of small airway dysfunction on the clinical expression of asthma: A focus on asthma symptoms and bronchial hyperresponsiveness. Allergy. 2014;69(12):1681-1688. Wijga AH, Kerkhof M, Gehring U, de Jongste JC, Postma DS, Aalberse RC, Wolse AP, Koppelman GH, van Rossem L, Oldenwening M, Brunekreef B, Smit HA. Cohort profile: The Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort. Int J Epidemiol 2014;43(2):527-535. Wijga AH, Zuidgeest MG, Kerkhof M, Koppelman GH, Smit HA, de Jongste JC. Guideline-recommended use of asthma medication by children is associated with parental information and knowledge: the PIAMA birth cohort. Pharmacoepidemiol Drug Saf. 2014;23(4):406-410. Worth A, Hammersley V, Knibb R, Flokstra-de-Blok B, DunnGalvin A, Walker S, Dubois AE, Sheikh A. Patient-reported outcome measures for asthma: a systematic review. NPJ Prim Care Respir Med. 2014;24:14020. Wright DB, Meurs H, Dekkers BGJ. Integrins: therapeutic targets in airway hyperresponsiveness and remodelling? Trends Pharmacol Sci 2014;35: 567-574. Xie X, Dijkstra AE, Vonk JM, Oudkerk M, Vliegenthart R, Groen HJ. Chronic respiratory symptoms associated with airway wall thickening measured by thin-slice low-dose CT. AJR Am J Roentgenol. 2014;203(4):W383-390. Zetstra-van der Woude PA, De Walle HE, Hoek A, Bos HJ, Boezen HM, Koppelman GH, de Jong-van den Berg LT, Scholtens S. Maternal high-dose folic acid during pregnancy and asthma medication in the offspring. Pharmacoepidemiol Drug Saf. 2014;23(10):1059-1065. Zijlstra GJ, Fattahi F, Rozeveld D, Jonker MR, Kliphuis NM, van den Berge M, Hylkema MN, ten Hacken NH, van Oosterhout AJ, Heijink IH. Glucocorticoids induce the production of the chemoattractant CCL20 in airway epithelium. Eur Respir J 2014;44:361-370. Zuur-Telgen MC, Brusse-Keizer MG, van der Palen J, VanderValk PD, Kerstjens HA, Hendrix MG. Response. Chest 2014;146:e65-66. Zwerink M, van der Palen J, Kerstjens HA, van der Valk P, Brusse-Keizer M, Zielhuis G, Effing T. A community-based exercise programme in COPD self-management: two years follow-up of the COPE-II study. Respir Med 2014;108:1481-1490. Zysman M, Patout M, Miravitlles M, van der Molen T, Lokke A, Hausen T, Didier A, Cuvelier A, Roche N. COPD and perception of the new GOLD document in Europe. Workshop from the Societe de pneumologie de langue francaise (SPLF). Rev Mal Respir 2014;31:499-510.

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Publications in Dutch

Hesse L, Oude Elberink JNG Nawijn MC Allergeenspecifieke immunotherapie voor inhalatieallergenen: het belang van het verhogen van de effectiviteit. 2014. Ned Tijdschrift voor allergie en asthma;1:62-68 Koppelman GH, Scholtens S, Smit N, Stolk RP. De Lifelines cohort studie: Gezond ouder worden in 3 generaties. Kinderarts en Wetenschap, Juni 2014. Melgert BN. Farmaceutische immunologie. Medicines, December 2014. Oude Elberink JNG. Insectenallergie. In: Werkboek Kinderallergologie, 2e druk, pp137-145, VU University Press, 2014. Postma DS. COPD ontstaat al voor de geboorte. Topic 2014;10 12-14

Books / Book chapters

Boezen HM, de Jong K, Vonk JM. Genetic factors in asthma and COPD. In: Annesi-Maesano I, Lundbäck B, Viegi G, editors. ERS Monograph. ERS, 2014:139-151.

DunnGalvin A, Dubois AE, Flokstra-de Blok BM, Hourihane JO. Living with food allergy: Cause for concern. In: Madsen CB, Crevel RWR, Mills C and Taylor SL, editors. Risk managment for food allergy, 1st ed: Elsevier Inc.; 2014. p. 3-24.

Tol van DG, de Bree MJ, Dekker H, van der Molen T. Handboek medische professionaliteit. : Bohn Stafleu van Loghum; 2014.

Wijkstra PJ, Duiverman ML. Ventilatory support during sleep in patients with COPD. In: Babak Mokhlesi. Sleep medicine clinics Sleep hypoventilation : A state-of-the -Art overview. September 2014; 381-390

Contributions to other research institutes

Publications SCI journals Beljaars L, Schippers M, Reker-Smit C, Martinez FO, Helming L, Poelstra K, Melgert BN. Hepatic Localization of Macrophage Phenotypes during Fibrogenesis and Resolution of Fibrosis in Mice and Humans. Front Immunol 2014;5:430. Berentzen NE, Smit HA, Bekkers MB, Brunekreef B, Koppelman GH, De Jongste JC, Kerkhof M, Van Rossem L, Wijga AH. Time in bed, sleep quality and associations with cardiometabolic markers in children: the Prevention and Incidence of Asthma and Mite Allergy birth cohort study. J Sleep Res. 2014;23(1):3-12. Berentzen NE, Smit HA, van Rossem L, Gehring U, Kerkhof M, Postma DS, Boshuizen HC, Wijga AH. Screen time, adiposity and cardiometabolic markers: mediation by physical activity, not snacking, among 11-year-old children. Int J Obes (Lond). 2014;38(10):1317-1323.

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Boer de YS, van Gerven NM, Zwiers A, Verwer BJ, van Hoek B, van Erpecum KJ, Beuers U, van Buuren HR, Drenth JP, den Ouden JW, Verdonk RC, Koek GH, Brouwer JT, Guichelaar MM, Vrolijk JM, Kraal G, Mulder CJ, van Nieuwkerk CM, Fischer J, Berg T, Stickel F, Sarrazin C, Schramm C, Lohse AW, Weiler-Normann C, Lerch MM, Nauck M, Völzke H, Homuth G, Bloemena E, Verspaget HW, Kumar V, Zhernakova A, Wijmenga C, Franke L, Bouma G; Dutch Autoimmune Hepatitis Study Group; LifeLines Cohort Study; Study of Health in Pomerania. Genome-wide association study identifies variants associated with autoimmune hepatitis type 1. Gastroenterology. 2014;147(2):443-452. Cernecka H, Pradidarcheep W, Lamers, WH, Schmidt M, Michel MC. Rat β₃-adrenoceptor protein expression: antibody validation and distribution in rat gastrointestinal and urogenital tissues. Naunyn-Schmiedebergs Arch Pharmacol 2014;387:1117-1127. Cree IA, Deans Z, Ligtenberg MJ, Normanno N, Edsjo A, Rouleau E, Sole F, Thunnissen E, Timens W, Schuuring E, Dequeker E, Murray S, Dietel M, Groenen P, van Krieken JH. Guidance for laboratories performing molecular pathology for cancer patients. J Clin Pathol 2014,67:923-931. Damoiseaux VA, Proost JH, Jiawan VCR, Melgert BN. Sex differences in the pharmacokinetics of antidepressants: influence of female sex hormones and oral contraceptives. Clin Pharmacokin 2014;53:509-519. Eny KM, Lutgers HL, Maynard J, Klein BE, Lee KE, Atzmon G, Monnier VM, van Vliet-Ostaptchouk JV, Graaff R, van der Harst P, Snieder H, van der Klauw MM, Sell DR, Hosseini SM, Cleary PA, Braffett BH, Orchard TJ, Lyons TJ, Howard K, Klein R, Crandall JP, Barzilai N, Milman S, Ben-Avraham D; LifeLines Cohort Study Group; DCCT/EDIC Research Group, Wolffenbuttel BH, Paterson AD. GWAS identifies an NAT2 acetylator status tag single nucleotide polymorphism to be a major locus for skin fluorescence. Diabetologia. 2014;57(8):1623-1634. Figarska SM, Vonk JM, Boezen HM. NFE2L2 polymorphisms, mortality, and metabolism in the general population. Physiol Genomics. 2014;46(12):411-417. Gaspar L, van de Werken M, Johansson AS, Moriggi E, Owe-Larsson B, Kocks JW, Lundkvist GB, Gordijn MC, Brown SA. Human cellular differences in cAMP--CREB signaling correlate with light-dependent melatonin suppression and bipolar disorder. Eur J Neurosci 2014;40:2206-2215. Girvalaki C, Vardavas C, Papandreou C, Christaki G, Vergetaki A, Tsiligianni IG, Hatzis C, Kafatos A. Trends in metabolic syndrome risk factors among adolescents in rural Crete between 1989 and 2011. Hormones (Athens) 2014;13:259-267. Gooden MJ, Wiersma VR, Boerma A, Leffers N, Boezen HM, ten Hoor KA, Hollema H, Walenkamp AM, Daemen T, Nijman HW, Bremer E. Elevated serum CXCL16 is an independent predictor of poor survival in ovarian cancer and may reflect pro-metastatic ADAM protease activity. Br J Cancer. 2014;110(6):1535-1544. Hoggart CJ, Venturini G, Mangino M, Gomez F, Ascari G, Zhao JH, Teumer A, Winkler TW, Tšernikova N, Luan J, Mihailov E, Ehret GB, Zhang W, Lamparter D, Esko T, Macé A, Rüeger S, Bochud PY, Barcella M, Dauvilliers Y, Benyamin B, Evans DM, Hayward C, Lopez MF, Franke L, Russo A, Heid IM, Salvi E, Vendantam S, Arking DE, Boerwinkle E, Chambers JC, Fiorito G, Grallert H, Guarrera S, Homuth G, Huffman JE, Porteous D; Generation Scotland Consortium; LifeLines Cohort study; GIANT Consortium, Moradpour D, Iranzo A, Hebebrand J, Kemp JP, Lammers GJ, Aubert

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V, Heim MH, Martin NG, Montgomery GW, Peraita-Adrados R, Santamaria J, Negro F, Schmidt CO, Scott RA, Spector TD, Strauch K, Völzke H, Wareham NJ, Yuan W, Bell JT, Chakravarti A, Kooner JS, Peters A, Matullo G, Wallaschofski H, Whitfield JB, Paccaud F, Vollenweider P, Bergmann S, Beckmann JS, Tafti M, Hastie ND, Cusi D, Bochud M, Frayling TM, Metspalu A, Jarvelin MR, Scherag A, Smith GD, Borecki IB, Rousson V, Hirschhorn JN, Rivolta C, Loos RJ, Kutalik Z. Novel approach identifies SNPs in SLC2A10 and KCNK9 with evidence for parent-of-origin effect on body mass index. PLoS Genet. 2014;10(7):e1004508. Leffers N, Daemen T, Helfrich W, Boezen HM, Cohlen BJ, Melief CJ, Nijman HW. Antigen-specific active immunotherapy for ovarian cancer. Cochrane Database Syst Rev. 2014;9:CD007287. Perry JR, Day F, Elks CE, Sulem P, Thompson DJ, Ferreira T, He C, Chasman DI, Esko T, Thorleifsson G, Albrecht E, Ang WQ, Corre T, Cousminer DL, Feenstra B, Franceschini N, Ganna A, Johnson AD, Kjellqvist S, Lunetta KL, McMahon G, Nolte IM, Paternoster L, Porcu E, Smith AV, Stolk L, Teumer A, Tšernikova N, Tikkanen E, Ulivi S, Wagner EK, Amin N, Bierut LJ, Byrne EM, Hottenga JJ, Koller DL, Mangino M, Pers TH, Yerges-Armstrong LM, Hua Zhao J, Andrulis IL, Anton-Culver H, Atsma F, Bandinelli S, Beckmann MW, Benitez J, Blomqvist C, Bojesen SE, Bolla MK, Bonanni B, Brauch H, Brenner H, Buring JE, Chang-Claude J, Chanock S, Chen J, Chenevix-Trench G, Collée JM, Couch FJ, Couper D, Coviello AD, Cox A, Czene K, D'adamo AP, Davey Smith G, De Vivo I, Demerath EW, Dennis J, Devilee P, Dieffenbach AK, Dunning AM, Eiriksdottir G, Eriksson JG, Fasching PA, Ferrucci L, Flesch-Janys D, Flyger H, Foroud T, Franke L, Garcia ME, García-Closas M, Geller F, de Geus EE, Giles GG, Gudbjartsson DF, Gudnason V, Guénel P, Guo S, Hall P, Hamann U, Haring R, Hartman CA, Heath AC, Hofman A, Hooning MJ, Hopper JL, Hu FB, Hunter DJ, Karasik D, Kiel DP, Knight JA, Kosma VM, Kutalik Z, Lai S, Lambrechts D, Lindblom A, Mägi R, Magnusson PK, Mannermaa A, Martin NG, Masson G, McArdle PF, McArdle WL, Melbye M, Michailidou K, Mihailov E, Milani L, Milne RL, Nevanlinna H, Neven P, Nohr EA, Oldehinkel AJ, Oostra BA, Palotie A, Peacock M, Pedersen NL, Peterlongo P, Peto J, Pharoah PD, Postma DS, Pouta A, Pylkäs K, Radice P, Ring S, Rivadeneira F, Robino A, Rose LM, Rudolph A, Salomaa V, Sanna S, Schlessinger D, Schmidt MK, Southey MC, Sovio U, Stampfer MJ, Stöckl D, Storniolo AM, Timpson NJ, Tyrer J, Visser JA, Vollenweider P, Völzke H, Waeber G, Waldenberger M, Wallaschofski H, Wang Q, Willemsen G, Winqvist R, Wolffenbuttel BH, Wright MJ; Australian Ovarian Cancer Study; The GENICA Network; kConFab; The LifeLines Cohort Study; The InterAct Consortium; Early Growth Genetics (EGG) Consortium, Boomsma DI, Econs MJ, Khaw KT, Loos RJ, McCarthy MI, Montgomery GW, Rice JP, Streeten EA, Thorsteinsdottir U, van Duijn CM, Alizadeh BZ, Bergmann S, Boerwinkle E, Boyd HA, Crisponi L, Gasparini P, Gieger C, Harris TB, Ingelsson E, Järvelin MR, Kraft P, Lawlor D, Metspalu A, Pennell CE, Ridker PM, Snieder H, Sørensen TI, Spector TD, Strachan DP, Uitterlinden AG, Wareham NJ, Widen E, Zygmunt M, Murray A, Easton DF, Stefansson K, Murabito JM, Ong KK. Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. Nature. 2014;514(7520):92-97. Romanos J, Rosén A, Kumar V, Trynka G, Franke L, Szperl A, Gutierrez-Achury J, van Diemen CC, Kanninga R, Jankipersadsing SA, Steck A, Eisenbarth G, van Heel DA, Cukrowska B, Bruno V, Mazzilli MC, Núñez C, Bilbao JR, Mearin ML, Barisani D, Rewers M, Norris JM, Ivarsson A, Boezen HM, Liu E, Wijmenga C; PreventCD Group. Improving coeliac disease risk prediction by testing non-HLA variants additional to HLA variants. Gut. 2014 Mar;63(3):415-422. Simino J, Shi G, Bis JC, Chasman DI, Ehret GB, Gu X, Guo X, Hwang SJ, Sijbrands E, Smith AV, Verwoert GC, Bragg-Gresham JL, Cadby G, Chen P, Cheng CY, Corre T, de Boer RA, Goel A, Johnson T, Khor CC; LifeLines Cohort Study, Lluís-Ganella C, Luan J, Lyytikäinen LP, Nolte IM, Sim X, Sõber S, van der Most

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PJ, Verweij N, Zhao JH, Amin N, Boerwinkle E, Bouchard C, Dehghan A, Eiriksdottir G, Elosua R, Franco OH, Gieger C, Harris TB, Hercberg S, Hofman A, James AL, Johnson AD, Kähönen M, Khaw KT, Kutalik Z, Larson MG, Launer LJ, Li G, Liu J, Liu K, Morrison AC, Navis G, Ong RT, Papanicolau GJ, Penninx BW, Psaty BM, Raffel LJ, Raitakari OT, Rice K, Rivadeneira F, Rose LM, Sanna S, Scott RA, Siscovick DS, Stolk RP, Uitterlinden AG, Vaidya D, van der Klauw MM, Vasan RS, Vithana EN, Völker U, Völzke H, Watkins H, Young TL, Aung T, Bochud M, Farrall M, Hartman CA, Laan M, Lakatta EG, Lehtimäki T, Loos RJ, Lucas G, Meneton P, Palmer LJ, Rettig R, Snieder H, Tai ES, Teo YY, van der Harst P, Wareham NJ, Wijmenga C, Wong TY, Fornage M, Gudnason V, Levy D, Palmas W, Ridker PM, Rotter JI, van Duijn CM, Witteman JC, Chakravarti A, Rao DC. Gene-age interactions in blood pressure regulation: a large-scale investigation with the CHARGE, Global BPgen, and ICBP Consortia. Am J Hum Genet. 2014;95(1):24-38. Slagter SN, van Vliet-Ostaptchouk JV, Vonk JM, Boezen HM, Dullaart RP, Kobold AC, Feskens EJ, van Beek AP, van der Klauw MM, Wolffenbuttel BH. Combined effects of smoking and alcohol on metabolic syndrome: the LifeLines cohort study. PLoS One. 2014;9(4):e96406. Spaans F, Melgert BN, Chiang C, Borghuis T, Klok PA, de Vos P, van Goor H, Bakker WW, Faas MM. Extracellular ATP decreases trophoblast invasion, spiral artery remodeling and immune cells in the mesometrial triangle in pregnant rats. Placenta 2014;35:587-595. Spaans F, Melgert BN, Borghuis T, Klok PA, de Vos P, Bakker WW, van Goor H, Faas MM. Extracellular adenosine triphosphate affects systemic and kidney immune cell populations in pregnant rats. Am J Reprod Immunol 2014;72:305-316. Taghizadeh N, Vonk JM, Boezen HM. Serum uric acid levels and cancer mortality risk among males in a large general population-based cohort study. Cancer Causes Control. 2014;25(8):1075-1080. Tragante V, Barnes MR, Ganesh SK, Lanktree MB, Guo W, Franceschini N, Smith EN, Johnson T, Holmes MV, Padmanabhan S, Karczewski KJ, Almoguera B, Barnard J, Baumert J, Chang YP, Elbers CC, Farrall M, Fischer ME, Gaunt TR, Gho JM, Gieger C, Goel A, Gong Y, Isaacs A, Kleber ME, Mateo Leach I, McDonough CW, Meijs MF, Melander O, Nelson CP, Nolte IM, Pankratz N, Price TS, Shaffer J, Shah S, Tomaszewski M, van der Most PJ, Van Iperen EP, Vonk JM, Witkowska K, Wong CO, Zhang L, Beitelshees AL, Berenson GS, Bhatt DL, Brown M, Burt A, Cooper-DeHoff RM, Connell JM, Cruickshanks KJ, Curtis SP, Davey-Smith G, Delles C, Gansevoort RT, Guo X, Haiqing S, Hastie CE, Hofker MH, Hovingh GK, Kim DS, Kirkland SA, Klein BE, Klein R, Li YR, Maiwald S, Newton-Cheh C, O'Brien ET, Onland-Moret NC, Palmas W, Parsa A, Penninx BW, Pettinger M, Vasan RS, Ranchalis JE, M Ridker P, Rose LM, Sever P, Shimbo D, Steele L, Stolk RP, Thorand B, Trip MD, van Duijn CM, Verschuren WM, Wijmenga C, Wyatt S, Young JH, Zwinderman AH, Bezzina CR, Boerwinkle E, Casas JP, Caulfield MJ, Chakravarti A, Chasman DI, Davidson KW, Doevendans PA, Dominiczak AF, FitzGerald GA, Gums JG, Fornage M, Hakonarson H, Halder I, Hillege HL, Illig T, Jarvik GP, Johnson JA, Kastelein JJ, Koenig W, Kumari M, März W, Murray SS, O'Connell JR, Oldehinkel AJ, Pankow JS, Rader DJ, Redline S, Reilly MP, Schadt EE, Kottke-Marchant K, Snieder H, Snyder M, Stanton AV, Tobin MD, Uitterlinden AG, van der Harst P, van der Schouw YT, Samani NJ, Watkins H, Johnson AD, Reiner AP, Zhu X, de Bakker PI, Levy D, Asselbergs FW, Munroe PB, Keating BJ. Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci. Am J Hum Genet. 2014;94(3):349-360.

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Tsiligianni IG, Tyrovolas S, Bountziouka V, Zeimbekis A, Gotsis E, Metallinos G, Tyrovola D, Polychronopoulos E, Lionis C, Panagiotakos D. Depressive symptoms in postmenopausal women: results from the MEDIS Study. Women Health 2014;54:389-401. Wood AR, Esko T, Yang J, Vedantam S, Pers TH, Gustafsson S, Chu AY, Estrada K, Luan J, Kutalik Z, Amin N, Buchkovich ML, Croteau-Chonka DC, Day FR, Duan Y, Fall T, Fehrmann R, Ferreira T, Jackson AU, Karjalainen J, Lo KS, Locke AE, Mägi R, Mihailov E, Porcu E, Randall JC, Scherag A, Vinkhuyzen AA, Westra HJ, Winkler TW, Workalemahu T, Zhao JH, Absher D, Albrecht E, Anderson D, Baron J, Beekman M, Demirkan A, Ehret GB, Feenstra B, Feitosa MF, Fischer K, Fraser RM, Goel A, Gong J, Justice AE, Kanoni S, Kleber ME, Kristiansson K, Lim U, Lotay V, Lui JC, Mangino M, Mateo Leach I, Medina-Gomez C, Nalls MA, Nyholt DR, Palmer CD, Pasko D, Pechlivanis S, Prokopenko I, Ried JS, Ripke S, Shungin D, Stancáková A, Strawbridge RJ, Sung YJ, Tanaka T, Teumer A, Trompet S, van der Laan SW, van Setten J, Van Vliet-Ostaptchouk JV, Wang Z, Yengo L, Zhang W, Afzal U, Arnlöv J, Arscott GM, Bandinelli S, Barrett A, Bellis C, Bennett AJ, Berne C, Blüher M, Bolton JL, Böttcher Y, Boyd HA, Bruinenberg M, Buckley BM, Buyske S, Caspersen IH, Chines PS, Clarke R, Claudi-Boehm S, Cooper M, Daw EW, De Jong PA, Deelen J, Delgado G, Denny JC, Dhonukshe-Rutten R, Dimitriou M, Doney AS, Dörr M, Eklund N, Eury E, Folkersen L, Garcia ME, Geller F, Giedraitis V, Go AS, Grallert H, Grammer TB, Gräßler J, Grönberg H, de Groot LC, Groves CJ, Haessler J, Hall P, Haller T, Hallmans G, Hannemann A, Hartman CA, Hassinen M, Hayward C, Heard-Costa NL, Helmer Q, Hemani G, Henders AK, Hillege HL, Hlatky MA, Hoffmann W, Hoffmann P, Holmen O, Houwing-Duistermaat JJ, Illig T, Isaacs A, James AL, Jeff J, Johansen B, Johansson Å, Jolley J, Juliusdottir T, Junttila J, Kho AN, Kinnunen L, Klopp N, Kocher T, Kratzer W, Lichtner P, Lind L, Lindström J, Lobbens S, Lorentzon M, Lu Y, Lyssenko V, Magnusson PK, Mahajan A, Maillard M, McArdle WL, McKenzie CA, McLachlan S, McLaren PJ, Menni C, Merger S, Milani L, Moayyeri A, Monda KL, Morken MA, Müller G, Müller-Nurasyid M, Musk AW, Narisu N, Nauck M, Nolte IM, Nöthen MM, Oozageer L, Pilz S, Rayner NW, Renstrom F, Robertson NR, Rose LM, Roussel R, Sanna S, Scharnagl H, Scholtens S, Schumacher FR, Schunkert H, Scott RA, Sehmi J, Seufferlein T, Shi J, Silventoinen K, Smit JH, Smith AV, Smolonska J, Stanton AV, Stirrups K, Stott DJ, Stringham HM, Sundström J, Swertz MA, Syvänen AC, Tayo BO, Thorleifsson G, Tyrer JP, van Dijk S, van Schoor NM, van der Velde N, van Heemst D, van Oort FV, Vermeulen SH, Verweij N, Vonk JM, Waite LL, Waldenberger M, Wennauer R, Wilkens LR, Willenborg C, Wilsgaard T, Wojczynski MK, Wong A, Wright AF, Zhang Q, Arveiler D, Bakker SJ, Beilby J, Bergman RN, Bergmann S, Biffar R, Blangero J, Boomsma DI, Bornstein SR, Bovet P, Brambilla P, Brown MJ, Campbell H, Caulfield MJ, Chakravarti A, Collins R, Collins FS, Crawford DC, Cupples LA, Danesh J, de Faire U, den Ruijter HM, Erbel R, Erdmann J, Eriksson JG, Farrall M, Ferrannini E, Ferrières J, Ford I, Forouhi NG, Forrester T, Gansevoort RT, Gejman PV, Gieger C, Golay A, Gottesman O, Gudnason V, Gyllensten U, Haas DW, Hall AS, Harris TB, Hattersley AT, Heath AC, Hengstenberg C, Hicks AA, Hindorff LA, Hingorani AD, Hofman A, Hovingh GK, Humphries SE, Hunt SC, Hypponen E, Jacobs KB, Jarvelin MR, Jousilahti P, Jula AM, Kaprio J, Kastelein JJ, Kayser M, Kee F, Keinanen-Kiukaanniemi SM, Kiemeney LA, Kooner JS, Kooperberg C, Koskinen S, Kovacs P, Kraja AT, Kumari M, Kuusisto J, Lakka TA, Langenberg C, Le Marchand L, Lehtimäki T, Lupoli S, Madden PA, Männistö S, Manunta P, Marette A, Matise TC, McKnight B, Meitinger T, Moll FL, Montgomery GW, Morris AD, Morris AP, Murray JC, Nelis M, Ohlsson C, Oldehinkel AJ, Ong KK, Ouwehand WH, Pasterkamp G, Peters A, Pramstaller PP, Price JF, Qi L, Raitakari OT, Rankinen T, Rao DC, Rice TK, Ritchie M, Rudan I, Salomaa V, Samani NJ, Saramies J, Sarzynski MA, Schwarz PE, Sebert S, Sever P, Shuldiner AR, Sinisalo J, Steinthorsdottir V, Stolk RP, Tardif JC, Tönjes A, Tremblay A, Tremoli E, Virtamo J, Vohl MC; Electronic Medical Records and Genomics (eMEMERGEGE)

75

Consortium; MIGen Consortium; PAGEGE Consortium; LifeLines Cohort Study, Amouyel P, Asselbergs FW, Assimes TL, Bochud M, Boehm BO, Boerwinkle E, Bottinger EP, Bouchard C, Cauchi S, Chambers JC, Chanock SJ, Cooper RS, de Bakker PI, Dedoussis G, Ferrucci L, Franks PW, Froguel P, Groop LC, Haiman CA, Hamsten A, Hayes MG, Hui J, Hunter DJ, Hveem K, Jukema JW, Kaplan RC, Kivimaki M, Kuh D, Laakso M, Liu Y, Martin NG, März W, Melbye M, Moebus S, Munroe PB, Njølstad I, Oostra BA, Palmer CN, Pedersen NL, Perola M, Pérusse L, Peters U, Powell JE, Power C, Quertermous T, Rauramaa R, Reinmaa E, Ridker PM, Rivadeneira F, Rotter JI, Saaristo TE, Saleheen D, Schlessinger D, Slagboom PE, Snieder H, Spector TD, Strauch K, Stumvoll M, Tuomilehto J, Uusitupa M, van der Harst P, Völzke H, Walker M, Wareham NJ, Watkins H, Wichmann HE, Wilson JF, Zanen P, Deloukas P, Heid IM, Lindgren CM, Mohlke KL, Speliotes EK, Thorsteinsdottir U, Barroso I, Fox CS, North KE, Strachan DP, Beckmann JS, Berndt SI, Boehnke M, Borecki IB, McCarthy MI, Metspalu A, Stefansson K, Uitterlinden AG, van Duijn CM, Franke L, Willer CJ, Price AL, Lettre G, Loos RJ, Weedon MN, Ingelsson E, O'Connell JR, Abecasis GR, Chasman DI, Goddard ME, Visscher PM, Hirschhorn JN, Frayling TM. Defining the role of common variation in the genomic and biological architecture of adult human height. Nat Genet. 2014;46(11):1173-1186.