Genotype-by-smoking interaction and the risk of atherosclerosis and its clinical sequelae

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  • March 21, 2019
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  • Avery, Christy Leigh
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
Abstract
  • Although the association between cigarette smoking and atherosclerosis is well established, the mechanisms by which smoking initiates vascular disease remain poorly understood. As heritable differences in DNA repair ability can influence the effect of environmental exposures such as cigarette smoke, we evaluated how 36 DNA repair variants from five genes (XRCC1, APEX1, hOgg1, XPD, and XRCC3) modified the association between ever-smoking and two atherosclerosis outcomes in Atherosclerosis Risk in Communities (ARIC) Study participants: intimal-medial thickness (IMT) and incident coronary heart disease (CHD). The incident CHD analysis was conducted using all cases 1987-1998 (N=1,086) and a random sample (N=1,065) selected from the entire ARIC cohort at baseline (cohort random sample, CRS). Incidence rate ratios were estimated by piecewise constant models and departures from additivity were measured with interaction contrast ratios. When priors for genetic and environmental effects were added to the first-stage model, tagSNPs rs3213282 (XRCC1), rs50871 (XPD), and rs3212024 (XRCC3) were associated with an increase in the estimated effect of ever-smoking on incident CHD while tagSNPs rs1799782 (XRCC1) and rs861531 (XRCC3) were associated with a decrease. We also evaluated the association between DNA repair variants, cigarette smoking, and baseline mean IMT using linear regression models in ARIC participants selected into the CRS. When priors for genetic and environmental effects were added to the first-stage linear regression model, tagSNPs rs3213282 (XRCC1), rs3213245 (XRCC1), rs3212024 (XRCC3), and rs3136814 (APEX1) were associated with increases in the estimated effect of ever-smoking on baseline mean IMT while tagSNPs rs3136817 (APEX1) and rs1799794 (XRCC3) were associated with decreases. Few population-based studies examining the relationship between DNA repair variants, cigarette smoking and atherosclerosis have been published. Our results can stimulate inquiries into potential mechanisms linking cigarette smoke exposure and atherosclerotic diseases and help bridge the gap between observed trends and CHD biology. Future studies in different populations will undoubtedly be required to validate our results and improve our understanding of the complex relationships between DNA repair variants, cigarette smoking, and atherothrombotic disease.
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  • North, Kari
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  • October 19, 2010

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