Biomarkers, genetics, epigenetics & metabolomics: Experience from the

Birth to Twenty Plus cohort

Shane Norris

MRC/Wits Developmental Pathways for Health Research

Unit

The term “biomarker” was introduced in 1989 as a Medical

Subject Heading term (MeSH) – measurable and quantifiable

biological parameter

In 2001, an NIH working group standardized the definition of a

biomarker as “a characteristic that is objectively measured and

evaluated as an indicator of normal biological processes,

pathogenic processes, or pharmacologic responses to a

therapeutic intervention” - biosample (as a blood, urine, or tissue

test), or recording obtained from a person (blood pressure,

ECG), or it may be an imaging test (echocardiogram or CT scan)

Biomarker

Prospective birth cohort (Johannesburg-Soweto; South Africa)

Recruited 3273 mothers and babies (households) in 1990 to

understand growth and development in a transitioning urban

setting

70% (67%) still in contact with the study

21 data collection waves completed

recently completed the age 22-24 year survey

3 generations

approx 720+ 3G babies

Birth to Twenty PLUS

Birth to Ten

Biomarkers

1990: Cord blood

1995: Fasting blood sample

(insulin, glucose, lipids)

Blood pressure

1997: Blood pressure

2000: Blood pressure

Birth to Ten

Biomarkers

1990: Cord blood

1995: Fasting blood sample

(insulin, glucose, lipids)

Blood pressure

1997: Blood pressure

2000: Blood pressure

Samples

thrown away

Birth to Twenty

Biomarkers

2011 onwards Wellcome Trust Funding

Generation 1 (mothers) & 2 (index participant) multiple waves:

• DXA body composition and hip & spine bone mass/density

• Ultrasound abdominal adiposity assessment

• Skeletal maturity (bone age hand x-ray)

• Blood pressure (central blood pressure; 24hr monitoring)

• Respiratory function

• Biobank

• Fasting blood samples

• Urine samples

• DNA

Birth to Twenty

Benefits

• Detailed phenotype & biobank - unique

• Developed capacity to implement such measures (infrastructure, standard operating procedures )

• Ethics – participant understanding, consent, delegation to ethics committee

• Respond to the emergence of new biomarkers (In adults, homocysteine more predictive power than the Framingham risk score – cardiovascular mortality)

• Replace/supplement questionnaires

• Cotinine (smoking)

• Objective measures of physical activity (Actigraph)

• Objective measures on nutrition (vit D; Na/Cr; K/Cr)

Birth to Twenty

Opportunities

• Collaboration with geneticists – studies on African population

genetics; obesity, body composition, bone health,

pharmocogenetics (GWAS, metabochip, metabolomics)

• Multi-site study collaborations – NIH/Wellcome Trust H3A

(Human Heredity and Health in Africa)

• 6 African Site study on the genetics of obesity (n=12000)

• Birth to Twenty mothers

• H3A broader network – all studies involved (harmonisation;

maximal benefit, governance, open access to data, central

biobanks, bioinformatics, capacity development, etc)

• Consortia – contribute samples (need for large numbers);

African Genome Variation Project

Birth to Twenty

Opportunities

• Epigenetics = mechanism by which environmental factors can

affect physiological function and disease risk

• Study designs that make use of multiple time points are being

increasingly recognized as the most suitable to analyze the

epigenetics of common complex diseases

• Birth cohorts - intergenerational epigenetic studies (pregnant

women & offspring)

Birth to Twenty

Opportunities

• Early life biomarkers that are good surrogates for later life

outcomes

• HAPO study of Gestational Diabetes (C-peptide, neonatal

anthropometry & body composition) – adolescent follow-up

• Critical for early life interventions that cannot wait 20+ years to

confirm impact on outcome

• Technology rapidly developing – more objective measures,

easier repeat measures (mobile phones; personal devices, etc)

• New standards – ultrasound foetal growth curves

Birth to Twenty

Challenges

• Ethical, legal and social issues

• Community engagement

• Provision of clinical care

• “Blanket” consent & ethics committees

• Country specific regulations of receiving or sending

biological samples

• Multi-site pooled analyses – harmonisation (COHORTS)

• Capacity (INDEPTH sites)

• Costs – once off, maintenance, test costs (but get quicker, less

sample volume and less expensive0

Conclusion

• We have used the Bt20 cohort experience to inform current and

future studies – The Soweto First 1000 Days Cohort inclusion

of much more detailed biomarkers to understand how maternal

factors and morbidities (HIV, GDM, obesity, etc) impact foetal

growth, delivery outcomes, neontal and infant growth, body

composition and development.

• Longitudinal cohorts can offer a great deal in the context of

epigenetic epidemiology - better understanding of the

epigenetic patterns and how changes occur in response to a

wide range of environmental, lifestyle, and behavioral factors