Abstract 18153: Gene-Smoking Interactions in CHD Risk - Analyses of the CARDIoGRAMplusC4D Data in 60,000 CHD Cases and 80,000 Controls
Background: Tobacco use is one of the most important avoidable causes of coronary heart disease (CHD). GWAS have discovered variants that lead separately to CHD and smoking behaviour; however no large scale studies exist that have investigated the interaction of sequence variants and tobacco use on CHD.
Objective: To investigate gene-smoking interaction in CHD at known genetic loci related to CHD (n=45) and smoking (n=5) behavior.
Methods: Studies participating in the CARDIoGRAMplusC4D consortium (n=37) with available genetic data (GWAS and/or CARDIOMETABOCHIP) and information on smoking exposure were invited to participate. For all genetic variants, each participating study was asked to provide effect estimates and standard errors in relation to CHD separately in current smokers, ever smokers and never smokers. Within each study, beta(s) were quantitatively compared between (i) current smokers vs. never smokers, and (ii) ever smokers vs. never smokers. Study specific interaction beta(s) and se(s) were calculated, which were pooled across using a fixed-effects meta-analysis. Interaction analyses were declared to be significant at a P-value of < 1.0x10-3 (Bonferroni correction for 50 tests).
Results: Genetic data and information on smoking exposure was available on 60,919 CHD cases and 80,243 controls from 29 studies. Of the 45 CHD loci investigated, the reported CHD SNP at the ADAMTS7 locus had differential CHD association in non-smokers compared to ever smokers (P-value of interaction: 7.1 x 10-5). Multiple additional variants at the ADAMTS7 locus were observed to have similar gene-smoking interactions on CHD risk. Of the 5 smoking loci, variants at the CHRNA5 locus were found associated with CHD risk at GWAS levels of significance (P-value: 4x10-8). The reported lead variant for smoking behavior at CHRNA5 was associated with CHD only in “ever” or “current smokers” but not in “never-smokers” (P-value of interaction: 1x10-3).
Conclusions: We report a novel association of the CHRNA5 locus with CHD and provide novel evidence for interaction effects of smoking behavior at the ADAMTS7 and CHRNA5 loci in relation to CHD. These findings are likely to provide novel biological and therapeutic insights into the etiology, risk and prevention of CHD.
- © 2013 by American Heart Association, Inc.