title: Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium.
abstract: 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.
authors.affiliation: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Bis
authors.affiliation: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Colleen
authors.initials: C
authors.lastname: Sitlani
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Ryan
authors.initials: R
authors.lastname: Irvin
authors.affiliation: Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, North Carolina, United States of America.
authors.forename: Christy L
authors.initials: CL
authors.lastname: Avery
authors.affiliation: Icelandic Heart Association, Kopavogur, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Albert Vernon
authors.initials: AV
authors.lastname: Smith
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Fangui
authors.initials: F
authors.lastname: Sun
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco, California, United States of America.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Evans
authors.affiliation: Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, United States of America.
authors.forename: Solomon K
authors.initials: SK
authors.lastname: Musani
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America; Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, United States of America.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Cardiology, Leiden University Medical Center, The Netherlands; Department of Gerontology and Geriatrics, Leiden University Medical Center, The Netherlands.
authors.forename: Stella
authors.initials: S
authors.lastname: Trompet
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Bouwe P
authors.initials: BP
authors.lastname: Krijthe
authors.affiliation: Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Tamara B
authors.initials: TB
authors.lastname: Harris
authors.affiliation: Collaborative Studies Coordinating Center, University of North Carolina Gillings School of Global Public Health, Chapel Hill, North Carolina, United States of America.
authors.forename: P Miguel
authors.initials: PM
authors.lastname: Quibrera
authors.affiliation: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Brody
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Serkalem
authors.initials: S
authors.lastname: Demissie
authors.affiliation: Department of Biostatistics, University of Texas School of Public Health, Houston, Texas, United States of America.
authors.forename: Barry R
authors.initials: BR
authors.lastname: Davis
authors.affiliation: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Kerri L
authors.initials: KL
authors.lastname: Wiggins
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco, California, United States of America; Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Tranah
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, 27599, United States of America.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Lange
authors.affiliation: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America; Cardiology Division, University of Washington, Seattle, Washington, United States of America.
authors.forename: Nona
authors.initials: N
authors.lastname: Sotoodehnia
authors.affiliation: Institute of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, Glasgow, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Stott
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Oscar H
authors.initials: OH
authors.lastname: Franco
authors.affiliation: Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Lenore J
authors.initials: LJ
authors.lastname: Launer
authors.affiliation: Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, North Carolina, United States of America; University of North Carolina-GSK Center of Excellence in Pharmacoepidemiology, Chapel Hill, North Carolina, United States of America.
authors.forename: Til
authors.initials: T
authors.lastname: Stürmer
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America; Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, United States of America.
authors.forename: Kent D
authors.initials: KD
authors.lastname: Taylor
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America; The Framingham Heart Study, Framingham, Massachusetts, United States of America.
authors.forename: L Adrienne
authors.initials: LA
authors.lastname: Cupples
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: John H
authors.initials: JH
authors.lastname: Eckfeldt
authors.affiliation: Department of Epidemiology, University of Washington, Seattle, Washington, United States of America; Seattle Epidemiologic Research and Information Center of the Department of Veterans Affairs Office of Research and Development, Seattle, Washington, United States of America; Group Health Research Institute, Group Health, Seattle, Washington, United States of America.
authors.forename: Nicholas L
authors.initials: NL
authors.lastname: Smith
authors.affiliation: Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University, Winston-Salem, North Carolina, United States of America.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, United States of America.
authors.forename: James G
authors.initials: JG
authors.lastname: Wilson
authors.affiliation: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America; Department of Epidemiology, University of Washington, Seattle, Washington, United States of America; Group Health Research Institute, Group Health, Seattle, Washington, United States of America.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Heckbert
authors.affiliation: Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland.
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Buckley
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: M Arfan
authors.initials: MA
authors.lastname: Ikram
authors.affiliation: Institute for Molecular Medicine, University of Texas Health Science Center, Houston, Texas, United States of America.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America; Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, United States of America.
authors.forename: Yii-Der Ida
authors.initials: YD
authors.lastname: Chen
authors.affiliation: Department of Gerontology and Geriatrics, Leiden University Medical Center, The Netherlands.
authors.forename: Anton J M
authors.initials: AJ
authors.lastname: de Craen
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, United States of America; Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, United States of America.
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.affiliation: Robertson Center for Biostatistics, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Ian
authors.initials: I
authors.lastname: Ford
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine, Glasgow, United Kingdom.
authors.forename: Naveed
authors.initials: N
authors.lastname: Sattar
authors.affiliation: Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: P Eline
authors.initials: PE
authors.lastname: Slagboom
authors.affiliation: Faculty of Health and Medical Sciences, Department of Public Health, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Rudi G J
authors.initials: RG
authors.lastname: Westendorp
authors.affiliation: Icelandic Heart Association, Kopavogur, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Vilmundur
authors.initials: V
authors.lastname: Gudnason
authors.affiliation: The Framingham Heart Study, Framingham, Massachusetts, United States of America; Boston University School of Medicine, Boston, Massachusetts, United States of America; Boston University School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Ramachandran S
authors.initials: RS
authors.lastname: Vasan
authors.affiliation: Department of Statistics, University of Auckland, Auckland, New Zealand.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lumley
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco, California, United States of America.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Cummings
authors.affiliation: Department of Medicine, Morehouse School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Herman A
authors.initials: HA
authors.lastname: Taylor
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Wendy
authors.initials: W
authors.lastname: Post
authors.affiliation: Department of Cardiology, Leiden University Medical Center, The Netherlands.
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands; Inspectorate for Health Care, the Hague, The Netherlands.
authors.forename: Bruno H
authors.initials: BH
authors.lastname: Stricker
authors.affiliation: Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, North Carolina, United States of America; Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina United States of America.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Whitsel
authors.affiliation: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, United States of America; Department of Epidemiology, University of Washington, Seattle, Washington, United States of America; Department of Health Services, University of Washington, Seattle, Washington, United States of America; Group Health Research Institute, Group Health, Seattle, Washington, United States of America.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Donna
authors.initials: D
authors.lastname: Arnett
mesh_terms: D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000453:epidemiology* / Q000209:etiology; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics; D015994:Incidence; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016896:Treatment Outcome; D044465:White People / Q000235:genetics*
chemical_list: D000959:Antihypertensive Agents