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Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium.

Publication ,  Journal Article
Bis, JC; Sitlani, C; Irvin, R; Avery, CL; Smith, AV; Sun, F; Evans, DS; Musani, SK; Li, X; Trompet, S; Krijthe, BP; Harris, TB; Quibrera, PM ...
Published in: PLoS One
2015

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.

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Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2015

Volume

10

Issue

10

Start / End Page

e0140496

Location

United States

Related Subject Headings

  • White People
  • Treatment Outcome
  • Polymorphism, Single Nucleotide
  • Middle Aged
  • Male
  • Incidence
  • Hypertension
  • Humans
  • Genome-Wide Association Study
  • General Science & Technology
 

Citation

APA
Chicago
ICMJE
MLA
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Bis, J. C., Sitlani, C., Irvin, R., Avery, C. L., Smith, A. V., Sun, F., … Arnett, D. (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. https://doi.org/10.1371/journal.pone.0140496
Bis, Joshua C., Colleen Sitlani, Ryan Irvin, Christy L. Avery, Albert Vernon Smith, Fangui Sun, Daniel S. Evans, et al. “Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium.PLoS One 10, no. 10 (2015): e0140496. https://doi.org/10.1371/journal.pone.0140496.
Bis, Joshua C., et al. “Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium.PLoS One, vol. 10, no. 10, 2015, p. e0140496. Pubmed, doi:10.1371/journal.pone.0140496.
Bis JC, Sitlani C, Irvin R, Avery CL, Smith AV, Sun F, Evans DS, Musani SK, Li X, Trompet S, Krijthe BP, Harris TB, Quibrera PM, Brody JA, Demissie S, Davis BR, Wiggins KL, Tranah GJ, Lange LA, Sotoodehnia N, Stott DJ, Franco OH, Launer LJ, Stürmer T, Taylor KD, Cupples LA, Eckfeldt JH, Smith NL, Liu Y, Wilson JG, Heckbert SR, Buckley BM, Ikram MA, Boerwinkle E, Chen Y-DI, de Craen AJM, Uitterlinden AG, Rotter JI, Ford I, Hofman A, Sattar N, Slagboom PE, Westendorp RGJ, Gudnason V, Vasan RS, Lumley T, Cummings SR, Taylor HA, Post W, Jukema JW, Stricker BH, Whitsel EA, Psaty BM, Arnett D. Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium. PLoS One. 2015;10(10):e0140496.

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2015

Volume

10

Issue

10

Start / End Page

e0140496

Location

United States

Related Subject Headings

  • White People
  • Treatment Outcome
  • Polymorphism, Single Nucleotide
  • Middle Aged
  • Male
  • Incidence
  • Hypertension
  • Humans
  • Genome-Wide Association Study
  • General Science & Technology