Conceptual Model of Epigenetic Influence on Obesity Risk

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1 Andrea Baccarelli, MD, PhD, MPH Laboratory of Environmental Epigenetics Conceptual Model of Epigenetic Influence on Obesity Risk IOM Meeting, Washington, DC Feb 26 th 2015

2 A musical example DNA Phenotype Epigenetics

3 Epigenetics & Music Use the Same Markings

4 Epigenetics & Music Use the Same Markings markings in ink (permanent) pencil markings (can be erased)

5 Before conception Preconceptional exposures Fetal life In-utero exposures Early life exposures Childhood & adult life Later life exposures Exposure of gametes Epigenome at birth Epigenome in childhood Adult/aging epigenome Epigenome (Parental) Genome (parental) Genome (offspring) Programming of disease risks Disease programming throughout the lifecourse Figure adapted from Fleisch, Wright & Baccarelli, J Mol Endocrinol, 2012

6 Now applied to obesity Fetal life exposure Birth Childhood Adult life Maternal BMI Gestational weight gain Gestational Diabetes Epigenome at birth* BMI & adiposity Central adiposity Insulin Resistance Blood Pressure Environmental Factors Lipids *Possible/probable dynamic changes in pre- and post-natal life Graphic inspired by naïve reading and oversimplified interpretation of Gillman and Ludwig, New Eng J Med 2013

7 DNA methylation and body-mass index: a genome-wide analysis Katherine J Dick, et al. EWAS of DNA methylation and BMI (using Infinium 450K BeadChip) Discovery in the Cardiogenics Consortium (n=479) Replication in MARTHA (n=339) and KORA (n=1789) BMI and blood DNA methylation measured at the same visit Findings 3 methylation sites in HIF3A (hypoxia inducible factor 3A) positively correlated with BMI, consistently across cohorts (blood). 1 of 3 sites correlated with BMI if measured in fat tissue, but not skin This site fails mendelian randomization: Two SNPs associated with HIF3A methylation, but not with BMI. Conclusions Perturbation of hypoxia inducible transcription factor pathways could have an important role in the response to increased weight in people

8 The ideal world Relton and Davey-Smith Int J Epidemiol 2012 Epigenetic Inheritance Systems Stochastic Events Germ-line Genetic Variation Epigenome Intermediate Phenotypes / Biomarkers Disease Environment

9 The real world Relton and Davey-Smith Int J Epidemiol 2012 Epigenetic Inheritance Systems Stochastic Events Germ-line Genetic Variation Epigenome Intermediate Phenotypes / Biomarkers Disease Environment

10 Reverse causation In reverse causation: Cause and effect are reversed Applied to BMI: If interested in determining if methylation BMI We need to consider whether BMI methylation Need to identify temporal/causal sequence of events Study design Cross-sectional and case-control studies are more susceptible to reverse causation Should longitudinal studies be preferred in human epigenetics?

11 1990 Learning from past experience (in genetics) Relative odds of alcohol dependency associated with Taq1A polymorphism 1995 Odds Ratio as a Function of Publication Year Original OR= Final OR=1.4 Smith et al. (2008) American Journal of Epidemiology, 167(2):

13 The winner s curse On ebay Given the lack of information on the true value of the item being auctioned High variance in the estimated (dollar) values many over-and many under-estimates (bids) The winner is likely to have made the largest overestimate of value i.e., he or she is paying (way) too much In genetics The winner s curse has been common the first report of an association of genetic variation with disease is likely to overestimate the effect size In epigenetics: Does the same apply?

14 NIH funding for epigenetics, by institute Burris and Baccarelli, J Appl Toxicol 2014

Environment, genetics, epigenetics ENVIRONMENTAL EXPOSURES GENETICS EPIGENETICS E G G X E E Epi Epi X E DNA DAMAGE/ MUTATIONS GENETIC MAKE UP EPIGENETIC CHANGES EPIGENETIC MAKE UP HIGHLY PERSISTENT

15 Environment, genetics, epigenetics ENVIRONMENTAL EXPOSURES GENETICS EPIGENETICS E G G X E E Epi Epi X E DNA DAMAGE/ MUTATIONS GENETIC MAKE UP EPIGENETIC CHANGES EPIGENETIC MAKE UP HIGHLY PERSISTENT HIGH/LOW SUSCEPTIBILITY REVERSIBLE HIGH/LOW SUSCEPTIBILITY TRANSMITTED TRANSGENERATIONALLY (if in germline) TRANSMITTED TRANSGENERATIONALLY TRANSMITTED TRANSGENERATIONALLY (limited human evidence) TRANSMITTED TRANSGENERATIONALLY (on selected genes) HEALTH EFFECTS Adapted from Bollati & Baccarelli, Heredity 2010

16 Environment, genetics, epigenetics ENVIRONMENTAL EXPOSURES GENETICS EPIGENETICS E G G X E E Epi Epi X E DNA DAMAGE/ MUTATIONS GENETIC MAKE UP EPIGENETIC CHANGES EPIGENETIC MAKE UP HIGHLY PERSISTENT HIGH/LOW SUSCEPTIBILITY REVERSIBLE HIGH/LOW SUSCEPTIBILITY TRANSMITTED TRANSGENERATIONALLY (if in germline) TRANSMITTED TRANSGENERATIONALLY TRANSMITTED TRANSGENERATIONALLY (limited human evidence) TRANSMITTED TRANSGENERATIONALLY (on selected genes) HEALTH EFFECTS Adapted from Bollati & Baccarelli, Heredity 2010

17 Summary of questions Interpretation of epigenetic findings How to discriminate antecedent changes vs. responses? If antecedent, are they the driver or passengers? Are we at risk of the winner s curse? If so, how to avoid it? New directions What are the most promising, less explored epigenetic mechanisms? Is Environment Epigenome enough? The meaning of it all Why are we doing this? Are we looking for mechanisms or biomarkers? What are the benefits to patients and society?

18 Environmental Epigenetics Lab Post-doc positions open now!

Epigenetics and Environmental Health A Step-by-Step Tutorial

Powerful ideas for a healthier world Epigenetics and Environmental Health A Step-by-Step Tutorial Andrea Baccarelli, MD, PhD, MPH Laboratory of Environmental Epigenetics Objective of my presentation To