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

SMR association of <i>PCSK9</i> and <i>USP24</i> gene-expression levels with phenotypes of interest.

The Y-axis represents the -log10 p-value of the MR association, while the direction signifies the direction of effect of gene-expression reduction, which serves as a proxy for PCSK9i. SMR multi-SNP analyses association of the available 25 tissues for PCSK9 and USP24 gene-expression in GTEx v8 for outcomes PCSK9 levels, LDL-C levels, and MDD. The blue and red lines signify p-value of 0.05 and Bonferroni-corrected threshold for 5 traits per gene of 0.005, respectively. (TIF)</p

Power calculations.

Cohort: study used for eQTL data, Tissue: eQTL summary statistics obtained from this tissue, n eQTL: sample size for eQTL specific to tissue, r2 eQTL: proportion of variance in exposure variable explained by SNPs in gene expression GWAS, Outcome: trait used as outcome for MR, Outcome category: trait category, βOLS: regression coefficient for the observational association between the exposure and continuous outcome variables, βyx: unknown true causal association between exposure and continuous outcome, σ2 eQTL: variance of the exposure variable, σ2 GWAS: variance of the continuous outcome variable, n GWAS: sample size of GWAS, n cases GWAS: sample size of cases for binary outcomes, True OR: true odds ratio of the outcome variable per standard deviation of the exposure variable, K: proportion of cases in binary outcome, Power: estimated power for the exposure-outcome combination. (XLSX)</p

Details of GWAS used as outcomes.

IEUGWAS id: study ID in the IEU GWAS database, Outcome trait: name of the GWAS trait, Cohort: name of the GWAS cohort, Sex: sex of the GWAS population, Population: ethnicity of the GWAS population, Unit: measurement unit of the GWAS trait, Sample size: sample size of the GWAS cohort, Ref (see manuscript): reference for the study. Please refer to the manuscript. (XLSX)</p