Loss of Cardioprotective Effects at the ADAMTS7 Locus as a Result of Gene-Smoking Interactions

BACKGROUND: Common diseases such as coronary heart disease (CHD) are complex in etiology. The interaction of genetic susceptibility with lifestyle factors may play a prominent role. However, gene-lifestyle interactions for CHD have been difficult to identify. Here, we investigate interaction of smoking behavior, a potent lifestyle factor, with genotypes that have been shown to associate with CHD risk. METHODS: We analyzed data on 60 919 CHD cases and 80 243 controls from 29 studies for gene-smoking interactions for genetic variants at 45 loci previously reported to be associated with CHD risk. We also studied 5 loci associated with smoking behavior. Study-specific gene-smoking interaction effects were calculated and pooled using fixed-effects meta-analyses. Interaction analyses were declared to be significant at a P value of <1.0x10(-3) (Bonferroni correction for 50 tests). RESULTS: We identified novel gene-smoking interaction for a variant upstream of the ADAMTS7 gene. Every T allele of rs7178051 was associated with lower CHD risk by 12% in never-smokers (P= 1.3x10(-16)) in comparison with 5% in ever-smokers (P= 2.5x10(-4)), translating to a 60% loss of CHD protection conferred by this allelic variation in people who smoked tobacco (interaction P value= 8.7x10(-5)). The protective T allele at rs7178051 was also associated with reduced ADAMTS7 expression in human aortic endothelial cells and lymphoblastoid cell lines. Exposure of human coronary artery smooth muscle cells to cigarette smoke extract led to induction of ADAMTS7. CONCLUSIONS: Allelic variation at rs7178051 that associates with reduced ADAMTS7 expression confers stronger CHD protection in never-smokers than in ever-smokers. Increased vascular ADAMTS7 expression may contribute to the loss of CHD protection in smokers.Peer reviewe

Associations of validated CHD loci with incident coronary heart disease in African Americans.

<p>Abbreviations: LD, linkage disequilibrium; SNP, single nucleotide polymorphism; AA, African Americans from PAGE studies; NA, not available. Only SNPs with minor allele frequency>0.01 that passed quality control are included. Linkage disequilibrium in African Americans was calculated in the ARIC study and allele frequencies from the ARIC and WHI genotyped data. Thresholds for significant associations for SNPs with LD r²<0.3 with published SNP were based on the number of SNPs in each region.</p><p>^*proxy of rs1760994,</p>†<p>proxy of rs4977574. Between-study heterogeneity was not significant (p<0.05) except for SNPs rs9982601 (p = 0.009) and rs10947789 (p = 0.02). Hazard ratios are for incident CHD associations from this study; odds ratio are from published results from the publication from Deloukas, P., S. Kanoni, et al. (2013). "Large-scale association analysis identifies new risk loci for coronary artery disease." <u>Nature Genetics</u>. 45(1): 25–33.</p><p>Associations of validated CHD loci with incident coronary heart disease in African Americans.</p

Regional plots of validated loci showing replication of the published SNP or proxy (a) or novel SNPs in known CHD loci (b, c).

<p>The X-axis shows chromosomal positions and genes, the left Y-axis shows the –log10P-values and the right Y-axis shows the recombination rate across the region using HapMap CEU linkage disequilibrium. Plotted SNP is the published SNP and is marked by a purple diamond and an arrow.</p

Regional plots of the <i>MYC</i> loci showing two SNPs and their LD.

<p>The X-axis shows chromosomal positions and genes, the left Y-axis shows the –log10P-values and the right Y-axis shows the recombination rate across the region using HapMap CEU linkage disequilibrium. Plotted SNPs are marked by arrows.</p