Drug-gene interactions of antihypertensive medications and risk of incident cardiovascular disease: a pharmacogenomics study from the CHARGE consortium

Bis, J. C. et al. (2015) Drug-gene interactions of antihypertensive medications and risk of incident cardiovascular disease: a pharmacogenomics study from the CHARGE consortium. PLoS ONE, 10(10), e0140496. (doi: 10.1371/journal.pone.0140496) (PMID:26516778) (PMCID:PMC4627813)

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Background Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals. Methods Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases). Results Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10−8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Stott J, Professor David and Ford, Professor Ian and Sattar, Professor Naveed
Authors: Bis, J. C., Sitlani, C., Irvin, R., Avery, C. L., Smith, A. V., Sun, F., Evans, D. S., Musani, S. K., Li, X., Trompet, S., Krijthe, B. P., Harris, T. B., Quibrera, P. M., Brody, J. A., Demissie, S., Davis, B. R., Wiggins, K. L., Tranah, G. J., Lange, L. A., Sotoodehnia, N., Stott, D. J., Franco, O. H., Launer, L. J., Stürmer, T., Taylor, K. D., Cupples, L. A., Eckfeldt, J. H., Smith, N. L., Liu, Y., Wilson, J. G., Heckbert, S. R., Buckley, B. M., Ikram, M. A., Boerwinkle, E., Chen, Y.-D. I., de Craen, A. J. M., Uitterlinden, A. G., Rotter, J. I., Ford, I., Hofman, A., Sattar, N., Slagboom, P. E., Westendorp, R., Gudnason, V., Vasan, R. S., Lumley, T., Cummings, S. R., Taylor, H. A., Post, W., Jukema, J. W., Stricker, B. H., Whitsel, E. A., Psaty, B. M., and Arnett, D.
College/School:College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Robertson Centre
College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:PLoS ONE
Publisher:Public Library of Science
ISSN (Online):1932-6203
Copyright Holders:Copyright © 2015 The Authors
First Published:First published in PLoS ONE 10(10):e0140496
Publisher Policy:Reproduced under a Creative Commons License

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