Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium.
<h4>Background</h4>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 antihyp...
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Public Library of Science (PLoS)
2015-01-01
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| Online Access: | https://doi.org/10.1371/journal.pone.0140496 |
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| author | Joshua C Bis Colleen Sitlani Ryan Irvin Christy L Avery Albert Vernon Smith Fangui Sun Daniel S Evans Solomon K Musani Xiaohui Li Stella Trompet Bouwe P Krijthe Tamara B Harris P Miguel Quibrera Jennifer A Brody Serkalem Demissie Barry R Davis Kerri L Wiggins Gregory J Tranah Leslie A Lange Nona Sotoodehnia David J Stott Oscar H Franco Lenore J Launer Til Stürmer Kent D Taylor L Adrienne Cupples John H Eckfeldt Nicholas L Smith Yongmei Liu James G Wilson Susan R Heckbert Brendan M Buckley M Arfan Ikram Eric Boerwinkle Yii-Der Ida Chen Anton J M de Craen Andre G Uitterlinden Jerome I Rotter Ian Ford Albert Hofman Naveed Sattar P Eline Slagboom Rudi G J Westendorp Vilmundur Gudnason Ramachandran S Vasan Thomas Lumley Steven R Cummings Herman A Taylor Wendy Post J Wouter Jukema Bruno H Stricker Eric A Whitsel Bruce M Psaty Donna Arnett |
| author_facet | Joshua C Bis Colleen Sitlani Ryan Irvin Christy L Avery Albert Vernon Smith Fangui Sun Daniel S Evans Solomon K Musani Xiaohui Li Stella Trompet Bouwe P Krijthe Tamara B Harris P Miguel Quibrera Jennifer A Brody Serkalem Demissie Barry R Davis Kerri L Wiggins Gregory J Tranah Leslie A Lange Nona Sotoodehnia David J Stott Oscar H Franco Lenore J Launer Til Stürmer Kent D Taylor L Adrienne Cupples John H Eckfeldt Nicholas L Smith Yongmei Liu James G Wilson Susan R Heckbert Brendan M Buckley M Arfan Ikram Eric Boerwinkle Yii-Der Ida Chen Anton J M de Craen Andre G Uitterlinden Jerome I Rotter Ian Ford Albert Hofman Naveed Sattar P Eline Slagboom Rudi G J Westendorp Vilmundur Gudnason Ramachandran S Vasan Thomas Lumley Steven R Cummings Herman A Taylor Wendy Post J Wouter Jukema Bruno H Stricker Eric A Whitsel Bruce M Psaty Donna Arnett |
| author_sort | Joshua C Bis |
| collection | DOAJ |
| description | <h4>Background</h4>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.<h4>Methods</h4>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).<h4>Results</h4>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. |
| format | Article |
| id | doaj-art-4783d750331d4a3ebd7298fdecd6c1fc |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-4783d750331d4a3ebd7298fdecd6c1fc2025-08-20T02:34:13ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-011010e014049610.1371/journal.pone.0140496Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium.Joshua C BisColleen SitlaniRyan IrvinChristy L AveryAlbert Vernon SmithFangui SunDaniel S EvansSolomon K MusaniXiaohui LiStella TrompetBouwe P KrijtheTamara B HarrisP Miguel QuibreraJennifer A BrodySerkalem DemissieBarry R DavisKerri L WigginsGregory J TranahLeslie A LangeNona SotoodehniaDavid J StottOscar H FrancoLenore J LaunerTil StürmerKent D TaylorL Adrienne CupplesJohn H EckfeldtNicholas L SmithYongmei LiuJames G WilsonSusan R HeckbertBrendan M BuckleyM Arfan IkramEric BoerwinkleYii-Der Ida ChenAnton J M de CraenAndre G UitterlindenJerome I RotterIan FordAlbert HofmanNaveed SattarP Eline SlagboomRudi G J WestendorpVilmundur GudnasonRamachandran S VasanThomas LumleySteven R CummingsHerman A TaylorWendy PostJ Wouter JukemaBruno H StrickerEric A WhitselBruce M PsatyDonna Arnett<h4>Background</h4>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.<h4>Methods</h4>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).<h4>Results</h4>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.https://doi.org/10.1371/journal.pone.0140496 |
| spellingShingle | Joshua C Bis Colleen Sitlani Ryan Irvin Christy L Avery Albert Vernon Smith Fangui Sun Daniel S Evans Solomon K Musani Xiaohui Li Stella Trompet Bouwe P Krijthe Tamara B Harris P Miguel Quibrera Jennifer A Brody Serkalem Demissie Barry R Davis Kerri L Wiggins Gregory J Tranah Leslie A Lange Nona Sotoodehnia David J Stott Oscar H Franco Lenore J Launer Til Stürmer Kent D Taylor L Adrienne Cupples John H Eckfeldt Nicholas L Smith Yongmei Liu James G Wilson Susan R Heckbert Brendan M Buckley M Arfan Ikram Eric Boerwinkle Yii-Der Ida Chen Anton J M de Craen Andre G Uitterlinden Jerome I Rotter Ian Ford Albert Hofman Naveed Sattar P Eline Slagboom Rudi G J Westendorp Vilmundur Gudnason Ramachandran S Vasan Thomas Lumley Steven R Cummings Herman A Taylor Wendy Post J Wouter Jukema Bruno H Stricker Eric A Whitsel Bruce M Psaty Donna Arnett Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium. PLoS ONE |
| title | Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium. |
| title_full | Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium. |
| title_fullStr | Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium. |
| title_full_unstemmed | Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium. |
| title_short | Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium. |
| title_sort | drug gene interactions of antihypertensive medications and risk of incident cardiovascular disease a pharmacogenomics study from the charge consortium |
| url | https://doi.org/10.1371/journal.pone.0140496 |
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