Background\nHypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including\nmyocardial infarction, sudden death, and stroke. In the US, over 65 million people have\nhigh blood pressure and a large proportion of these individuals are prescribed antihypertensive\nmedications. Although large long-term clinical trials conducted in the last several\ndecades have identified a number of effective antihypertensive treatments that reduce the\nrisk of future clinical complications, responses to therapy and protection from cardiovascular\nevents vary among individuals.\nMethods\nUsing a genome-wide association study among 21,267 participants with pharmaceutically\ntreated hypertension, we explored the hypothesis that genetic variants might influence or modify\nthe effectiveness of common antihypertensive therapies on the risk ofmajor cardiovascular\noutcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors,\nbeta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart\nand Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed\narray-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and\nused additive genetic models in proportional hazards or logistic regressionmodels to evaluate\ndrug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to\ncombine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms\n(SNPs) in a discovery analysis among 15,375 European Ancestry participants\n(3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry\nGenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases).\nResults\nAlthough drug-SNP interactions were biologically plausible, exposures and outcomes were\nwell measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses\n(Pinteraction > 5.0Ã?â??10âË?â??8). Similarly, findings were null for meta-analyses restricted to 66\nSNPs with significant main effects on coronary artery disease or blood pressure from large\npublished genome-wide association studies (Pinteraction 0.01). Our results suggest that\nthere are no major pharmacogenetic influences of common SNPs on the relationship\nbetween blood pressure medications and the risk of incident CVD.
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