Genetic epidemiology:

a new era in glaucoma?

Panayiota Founti, MD, PhD, FEBO (Hons)

Glaucoma Fellow

St Thomas‘ Hospital, London, UK

Possible changes in medicine in the future

The genomic promise for glaucoma

Evidence to support that this concept is

realistic

What is the current status of genetic

epidemiology in glaucoma

Events/trends that are likely to affect the practice of

medicine

elucidation of the human genome

aging of the population

health care economics

increasing interest in public health

rapid development of technology

“How will medicine be practiced in 10 years?”

Wiener CM et al. ―Genes to Society‖—The Logic and Process of the New

Curriculum for the Johns Hopkins University School of Medicine. Acad Med 2010.

Reframe the context of health and illness more broadly (rejects dichotomous state)

Patients are seen along a phenotypic continuum from ―asymptomatic and latent‖ to ―critically ill‖

Patient‘s phenotypeinternal factors (genes, molecules, cells, tissues, organs,

individual) external factors (environment, family, and society)

+

―To prepare medical students for an era when patients

will expect individualized medicine and physicians will

have the tools in hand to provide such care”

Medicine has always been personalised!

Until recently

Genetic data: family history and race/ethnicity

Genetics/genomics: basic science to study the

pathophysiology of diseases

New approach

Use genomic information in clinical practice, for decision

making

Preventive measures or treatment interventions on the

basis of individual characteristics

Salari K et al. Personalized medicine: hope or hype?

European Heart Journal 2012

Large phenotypic variability1

Risk factors

Disease occurrence/clinical characteristics

Progression /Rate of progression

Response to treatment

The genomic promise for glaucoma2

Effective screening

Establishing a precise diagnosis

Predicting rate of progression

Predicting response to treatment

1. Lander ES, Schork NJ. Science. 1994

2. Wiggs JL. Arch Ophthalmol. 2008

Μilestones

Completion of human genome project

Advances in bioinformatics

Advances in statistics

Focus on single nucleotide polymorphisms (SNPs)

within pre-specified genes of interest

1. Patnala R et al. Candidate gene association studies: a comprehensive guide to useful

in silico tools. BMC Genet. 2013

2. Manolio TA. Genomewide Association Studies and Assessment of the Risk of

Disease. N Engl J Med 2010

Hundreds of thousands of SNPs are tested for association

with a disease or a trait in hundreds or thousands of people

Case-control studies (association with disease)

QTL analyses (association with traits)

Identify idividuals at risk for a disease

Breast-cancer risk models1

Genotype score to predict cardiovascular event (based on

nine SNPs associated with modulation of cholesterol2)

Establish a precise diagnosis and predict prognosis

Genotyping test to assess intratumour heterogeneity for

treatment stratification3

1. Wacholder S et al. N Engl J Med 2010

2. Kathiresan S et al N Engl J Med. 2008

3. Crockford A et al. J Pathol 2014

Pharmacogenomics

The study of how genes modulate drug responses among individuals

One of the first direct applications of personal genomics to clinical medicine

More than 2000 genes listed in the

Pharmacogenomics Knowledge Base

(www.pharmgkb.org)

Oncology

the genetic analysis of tumors can help predict

resistance to treatment (colorectal cancer)1

Cardiovascular medicine

pharmacogenetic algorithm to help estimate

warfarin dosing2

prediction of risk for statin-induced myopathy

(simvastatin)3

1. Van Cutsem E et al. N Engl J Med 2009

2. Klein TE et al. N Engl J Med 2009

3. Link E et al. N Engl J Med 2008

RCTs have been already completed (!) on clinical

benefit and cost effectiveness

Complex conditions have been referred to as ―the

geneticist‘s nightmare‖2

Difficult to replicate associations

Genetic associations may not be applicable across all

populations

The clinical utility of each pharmacogenetic test needs

to be evaluated

Sensitivity

Specificity

Positive and negative predictive values

1. Salari K et al. Eur Heart J. 2012

2. Scott LJ et al. Science 2007

Are there advances in the genomics of common

eye diseases?

New knowledge on pathophysiology

AMD: complement activation , inflammation, lipid

metabolism and angiogenesis

DR: pro-inflammatory, antivascular barrier and

neurodegenerative pathways

Myopia: retinoic acid metabolism and extracellular matrix

remodeling

What about glaucoma?

Typically adult-onset, complex disease

Insidious, neurodegenerative disease of the optic nerve

Environmental and genetic factors

Progressive retinal ganglion cell death

It is not known where the sequence of events leading to

glaucoma starts

There may be multiple starting points, each setting in motion a

chain of events

Janssen SF et al. The vast complexity of primary open angle glaucoma: Disease genes,

risks, molecular mechanisms and pathobiology. Prog Retin Eye Res. 2013

Glaucoma develops slowly along a continuum from

health to pathology

Clinical signs may be present at below the threshold

for definite classification

Some phenotypes may not have all the clinical signs

(e.g IOP may be high or not)

Different glaucoma phenotypes (e.g POAG, PEXG,

PDG) share similar clinical signs (e.g similar

appearance of optic disc damage)

Different clinical manifestations might represent

different genetic bases for glaucoma*

# Wilson, M.R., and Martone, J.F. (1996) The epidemiology of chronic open-angle glaucoma

and ocular hypertension. In Ritch, R., Shields, M.B. and Kruptin, T. (eds), The Glaucomas.

A Multi-volume Reference. Mosby-Year Book, St Louis, MO, pp. 753–768

Optimum approach is to ‗‗dissect‘‘ the disease

into endophenotypes (traits)

simpler genetic architecture and can be measured

on a continuous scale

Familial linkage studies1

17 gene loci

MYOC, OPTN, WDR36

ASB10 (Pasutto et al. 2012)

outflow decreases after knockdown of the gene

Genetic association studies2

POAG: 5 genomic regions

PACG: 3 genomic regions

PEX: 1 genomic region (LOXL 1 gene)

1. Janssen SF et al. Prog Retin Eye Res. 2013

2. Cooke Bailey JN et al. Hum Mol Genet. 2013

Quantitative Trait Locus (QTL) analyses

IOP (GAS7 and TMCO1)

C/D ratio (CDKN2BAS and SIX1SIX6)

Disc size (ATOH7)

CCT (16 loci)

Cooke Bailey JN et al. Hum Mol Genet. 2013

Underlying molecular heterogeneity

Inadequately powered study designs

Imprecise definition of phenotypes

Wiggs JL. Genetic etiologies of glaucoma. Arch Ophthalmol. 2007.

Underlying molecular heterogeneity

Inadequately powered study designs

Consortia/international collaborations

Meta-analyses

Imprecise definition of phenotypes

Wiggs JL. Genetic etiologies of glaucoma. Arch Ophthalmol. 2007.

Underlying molecular heterogeneity

Inadequately powered study designs

Consortia/international collaborations

Meta-analyses

Imprecise definition of phenotypes

Emphasis on detailed phenotyping in biobanks

Wiggs JL. Genetic etiologies of glaucoma. Arch Ophthalmol. 2007.

Pan-european, genetic epidemiology network

Major resource for glaucoma research

Feasibility study

Validation study

Br J Ophthalmol. 2009 May

Aristotle University of

Thessaloniki

University of

Mainz

University of

Genoa

Moorfields

Eye Hospital

ARVO annual meeting

2014

Anastasopoulos E, Coleman AL, Wilson MR, Sinsheimer J, Yu F, Katafigiotis S, Founti P, Salonikiou A, Pappas T, Koskosas A,

Katopodi T, Lambropoulos A, Topouzis F.

Association of LOXL1 polymorphisms with pseudoexfoliation,

glaucoma, intraocular pressure, and systemic diseases in a Greek

population. The Thessaloniki Eye Study

IOVS, 2014 (Accepted for publication)

Identification of novel genes and pathways

contributing to glaucoma

Develop clinically useful gene-based tests

Screening

Diagnosis/ Classification

Develop therapeutic strategies targeted to the

disease-related molecular events

Manolio, T.A. Bringing genome-wide association findings into

clinical use. Nat. Rev. Genet. 2013

Medicine seems to be changing

Incorporating genome-based approaches in clinical

practice is a reality for other fields of medicine

Significant advances in genomics of common eye

diseases

Personalised approach in glaucoma: unmet need

Realistic goal

Thank you