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Epigenetic Mechanisms of Environmentally-mediated Cardiovascular Disease Risk in the WHI

Andrea Baccarelli, MD, PhD, MPH Lab of Environmental Epigenetics Harvard School of Public Health. Epigenetic Mechanisms of Environmentally-mediated Cardiovascular Disease Risk in the WHI. abaccare@hsph.harvard.edu . Epigenetics. Programming of gene expression that:

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Epigenetic Mechanisms of Environmentally-mediated Cardiovascular Disease Risk in the WHI

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  1. Andrea Baccarelli, MD, PhD, MPHLab of Environmental Epigenetics Harvard School of Public Health Epigenetic Mechanisms of Environmentally-mediated Cardiovascular Disease Risk in the WHI abaccare@hsph.harvard.edu

  2. Epigenetics • Programming of gene expression that: • does not depend on the DNA code • (relatively) stable, i.e., replicated through: • cell mitosis • meiosis, i.e. transgenerational (limited evidence in humans) • Characteristics of Epigenetic Programming • Modifiable (can be reprogrammed) • Active or poised to be activated: • Potentially associated with current health states or predict future events A. Baccarelli, Harvard School of Public Health

  3. Phenotype Epigenetics A Symphonic Example DNA A. Baccarelli, Harvard School of Public Health

  4. A Symphonic Example A. Baccarelli, Harvard School of Public Health

  5. DNA Methylation A. Baccarelli, Harvard School of Public Health From the Royal Society of Chemistry website (www.rsc.org)

  6. Changes during mitosis • Fidelity of “transcription” of DNA methylation varies between 97-99.9% • De-novo methylation: 3-5% mitosis • Much more dynamic compared to DNA sequence! • DNA methylation is known to be modified: • through aging • oxidative stress, inflammation, micronutrients A. Baccarelli, Harvard School of Public Health

  7. Triggers of cardiovascular events at the population level Exposure to traffic and air pollution are estimated to trigger more heart attacks than: -Heavy alcohol consumpion (2.5 fold) -Cocaine abuse (10 fold) Long term exposure to air pollution leads to: -Atherosclerosis -Cardiovascular morbidity and death Figure from Editorial by Baccarelli & BenjaminThe Lancet 2011 A. Baccarelli, Harvard School of Public Health

  8. Protein coding genes 1-2% Unique non-coding DNA ≈45% Pseudogenes <1% Repetitive sequences ≈50%LINEs (e.g., LINE-1): 21%SINEs (e.g., Alu): 11%Both LINEs & SINEs are retrotranspons Coding & non-coding DNA in the human genome Chromosomal stability Limits retrotransposition Limits inflammation Heavily methylated A. Baccarelli, Harvard School of Public Health

  9. Effects of Air Pollution on Repetitive Element DNA Methylation LINE-1 Alu βunadj=-0.18; P=0.04 βadj=-0.19; P=0.04 βunadj=-0.30; P=0.07 βadj=-0.34; P=0.04 Effects of PM10 found both at the beginning and at the end of the work week β for an increment equal to the difference between the 90th and 10th percentile of PM10 Mixed models: unadjusted or adjusted for age, BMI, smoking, cigarettes/day Tarantini, et al. Environment Health Perspect, 2009 A. Baccarelli, Harvard School of Public Health

  10. DNA Methylation and Incidence of non-fatal IHD or Stroke in the NAS Adj. Hazard Ratio3.6 (95%CI 1.8-7.0) p<0.001 HR=2.8 (95%CI 1.3-5.9), p=0.009 for IHD HR=4.3 (95%CI 0.7-25.8), p=0.11 for stroke Baccarelli et al., Epidemiology 2010 A. Baccarelli, Harvard School of Public Health

  11. DNA Methylation and Deathfrom IHD or Stroke in the NAS Adj. Hazard Ratio2.9 (95%CI 1.4-6.3) P=0.006 HR=3.5 (95%CI 1.4-8.8), p=0.007 for IHD HR=2.2 (95%CI 0.5-10.0), p=0.30 for stroke Baccarelli et al., Epidemiology 2010 A. Baccarelli, Harvard School of Public Health

  12. Potential Roles of Epigenetics Baccarelli, Rienstra & Benjamin Circulation: Cardiovascular Genetics 2010 A. Baccarelli, Harvard School of Public Health

  13. Conclusions and Research Needs • DNA methylation: • Sensitive to the environment • Predicts risk of cardiovascular disease • Limitations: • Limited power • Unreplicated • Limited to repeat elements (or other candidate sequence) • environmentally homogeneous, single-city populations of white men • Research needs: • Investigating a diverse population • Studies of women • Characterizing DNA methylation changes over time and their association with CVD-related risk factors A. Baccarelli, Harvard School of Public Health

  14. R01 ES020836MPIs, Whitsel, Hou, Baccarelli Pending (Score=19; Percentile 11%) Epigenetic mechanisms of PM-mediated cardiovascular risk A. Baccarelli, Harvard School of Public Health

  15. A. Baccarelli, Harvard School of Public Health

  16. Illumina 450K BeadChip Coverage CpG shelves, shores & islands classification (UCSC CpGi annotation) The 450K BeadChip covers a total of 77,537 CpG Islands and CpG Shores (N+S) N Shelf N Shore CpG Island S Shore S Shelf TSS1500 TSS200 5’ UTR 3’ UTR

  17. Study Population • Two-stage, longitudinal study of associations between PM air pollution, DNA methylation, and CVD risk factors: • exam site- and race-stratified, randomly selected 6% minority oversample • approximately 4,300 Women’s Health Initiative clinical trial (WHI CT) women • fasting blood draws and resting, standard, twelve-lead electrocardiograms (ECGs) • repeated at three-year intervals from 1993 to 2004. A. Baccarelli, Harvard School of Public Health

  18. Study Design • Stage 1 (Discovery) • interrogation, discovery and ranking of >450,000 DNA methylation sites potentially sensitive to PM in 1999-2001 blood samples from 800 participants • Stage II (Validation) • Longitudinal validation of the 10 most PM-sensitive DNA methylation sites identified by Stage 1 in up to three blood samples collected serially from the remaining 3,500 participants (1993-2004) • Focus on the temporal relationship between PM and DNA methylation at those sites, and that between site-specific DNA methylation and CVD risk factors. • Other Features: • Phenomics framework to incorporate phenotypes • Epigenetic data analyses adjusted for both ancestral admixture and multiple comparisons • External validation with cohorts with different participants characteristics (ARIC, NAS) A. Baccarelli, Harvard School of Public Health

  19. DNA methylation in the WHI A. Baccarelli, Harvard School of Public Health

  20. The WHI team for the Environmental Epigenomics proposal • Eric Whitsel, University of North Carolina (PI) • Lifang Hou, Northwestern University (PI) • Andrea Baccarelli, Harvard University (PI) • Yun Li, University of North Carolina • Duanping Liao, Penn State • Simon Lin, Northwestern University • Lesley Tinker, Fred Hutchinson • Linda Van Horn, Northwestern University A. Baccarelli, Harvard School of Public Health

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