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

Tuesday,2015-11-03 11:11 America/Los_Angeles — zdrager
TitleDrug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium.
Publication TypeJournal Article
Year of Publication2015
AuthorsBis, JC, Sitlani, C, Irvin, R, Avery, CL, Smith, AVernon, Sun, F, Evans, DS, Musani, SK, Li, X, Trompet, S, Krijthe, BP, Harris, TB, P Quibrera, M, 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, AL, Eckfeldt, JH, Smith, NL, Liu, Y, Wilson, JG, Heckbert, SR, Buckley, BM, Ikram, AM, Boerwinkle, E, Chen, Y-DI, de Craen, AJM, Uitterlinden, AG, Rotter, JI, Ford, I, Hofman, A, Sattar, N, P Slagboom, E, Westendorp, RGJ, Gudnason, V, Vasan, RS, Lumley, T, Cummings, SR, Taylor, HA, Post, W, J Jukema, W, Stricker, BH, Whitsel, EA, Psaty, BM, Arnett, D
JournalPLoS One
Volume10
Issue10
Paginatione0140496
Date Published2015
ISSN1932-6203
KeywordsAfrican Americans, Aged, Antihypertensive Agents, Cardiovascular Diseases, European Continental Ancestry Group, Female, Genome-Wide Association Study, Humans, Hypertension, Incidence, Male, Middle Aged, Polymorphism, Single Nucleotide, Treatment Outcome
Abstract<p><b>BACKGROUND: </b>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.</p><p><b>METHODS: </b>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).</p><p><b>RESULTS: </b>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.</p>
DOI10.1371/journal.pone.0140496
Alternate JournalPLoS ONE
PubMed ID26516778
PubMed Central IDPMC4627813
Grant List1R01AG032098-01A1 / AG / NIA NIH HHS / United States
5 R01 HL-63082 / HL / NHLBI NIH HHS / United States
DK063491 / DK / NIDDK NIH HHS / United States
HHSN268200625226C / / PHS HHS / United States
HHSN268200782096C / / PHS HHS / United States
HHSN268200800007C / / PHS HHS / United States
HHSN268201100005C / / PHS HHS / United States
HHSN268201100006C / / PHS HHS / United States
HHSN268201100007C / / PHS HHS / United States
HHSN268201100008C / / PHS HHS / United States
HHSN268201100009C / / PHS HHS / United States
HHSN268201100010C / / PHS HHS / United States
HHSN268201100011C / / PHS HHS / United States
HHSN268201100012C / / PHS HHS / United States
HHSN268201200036C / / PHS HHS / United States
HHSN268201300047C / / PHS HHS / United States
HHSN268201300048C / / PHS HHS / United States
HHSN268201300049C / / PHS HHS / United States
HHSN268201300050C / / PHS HHS / United States
HHSN268201500001I / / PHS HHS / United States
HL068986 / HL / NHLBI NIH HHS / United States
HL073410 / HL / NHLBI NIH HHS / United States
HL085251 / HL / NHLBI NIH HHS / United States
HSN268201300046C / / PHS HHS / United States
N01 HC-95159 / HC / NHLBI NIH HHS / United States
N01 HC-95160 / HC / NHLBI NIH HHS / United States
N01 HC-95161 / HC / NHLBI NIH HHS / United States
N01-AG-1-2100 / AG / NIA NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
N01-HC-95162 / HC / NHLBI NIH HHS / United States
N01-HC-95163 / HC / NHLBI NIH HHS / United States
N01-HC-95164 / HC / NHLBI NIH HHS / United States
N01-HC-95165 / HC / NHLBI NIH HHS / United States
N01-HC-95166 / HC / NHLBI NIH HHS / United States
N01-HC-95167 / HC / NHLBI NIH HHS / United States
N01-HC-95168 / HC / NHLBI NIH HHS / United States
N01-HC-95169 / HC / NHLBI NIH HHS / United States
N01AG62101 / AG / NIA NIH HHS / United States
N01AG62103 / AG / NIA NIH HHS / United States
N01AG62106 / AG / NIA NIH HHS / United States
N01HC55222 / HC / NHLBI NIH HHS / United States
N01HC85079 / HC / NHLBI NIH HHS / United States
N01HC85080 / HC / NHLBI NIH HHS / United States
N01HC85081 / HC / NHLBI NIH HHS / United States
N01HC85082 / HC / NHLBI NIH HHS / United States
N01HC85083 / HC / NHLBI NIH HHS / United States
N01HC85086 / HC / NHLBI NIH HHS / United States
N02-HL-6-4278 / HL / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
R01AG023629 / AG / NIA NIH HHS / United States
R01HL086694 / HL / NHLBI NIH HHS / United States
R01HL087641 / HL / NHLBI NIH HHS / United States
R01HL087652 / HL / NHLBI NIH HHS / United States
R01HL103612 / HL / NHLBI NIH HHS / United States
R01HL105756 / HL / NHLBI NIH HHS / United States
R01HL120393 / HL / NHLBI NIH HHS / United States
R01HL59367 / HL / NHLBI NIH HHS / United States
RR-024156 / RR / NCRR NIH HHS / United States
U01HG004402 / HG / NHGRI NIH HHS / United States
U01HL080295 / HL / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
UL1RR025005 / RR / NCRR NIH HHS / United States
UL1TR000124 / TR / NCATS NIH HHS / United States
/ / Intramural NIH HHS / United States

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