Journal
PHARMACOGENOMICS JOURNAL
Volume 14, Issue 1, Pages 6-13Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/tpj.2013.4
Keywords
gene-environment interaction; genetic epidemiology; QT interval
Categories
Funding
- National Heart, Lung and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]
- National Human Genome Research Institute [U01HG004402]
- National Institutes of Health [HHSN268200625226C]
- National Institutes of Health and NIH Roadmap for Medical Research. Cardiovascular Health Study (CHS) [UL1RR025005]
- National Heart, Lung and Blood Institute (NHLBI) [N01-HC-85239, N01-HC-85079-N01-HC-85086, N01-HC35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HHSN268201200036C]
- NHLBI [HL080295, HL075366, HL087652, HL105756, N02-HL-6-4278]
- NINDS [HL080295, HL075366, HL087652, HL105756]
- NIA [AG-023629, AG-15928, AG-20098, AG-027058, N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]
- National Center for Research Resources CTSI [DK063491]
- National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine [N01-HC-25195]
- SNP Health Association Resource (SHARe) project [N02-HL-6-4278]
- Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center
- Doris Duke Charitable Foundation and the Burroughs Wellcome Fund (Newton-Cheh)
- NIH [HL080025]
- Orion-Farmos Research Foundation
- Finnish Foundation for Cardiovascular Research
- Academy of Finland [29494, 139635]
- National Institutes of Health to The Johns Hopkins University [HHSN268200782096C]
- Intramural Research Program of the NIH, National Institute on Aging
- National Heart, Lung and Blood Institute (NHLBI) in collaboration with MESA investigators
- Clinical Translational Science Institute [UL1RR033176]
- Cedars-Sinai General Clinical Research Center Grant [RR00425]
- Established Clinical Investigator of the Netherlands Heart Foundation [2001 D 032]
- seventh framework program of the European commission [223004]
- Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging Grant) [050-060-810]
- Erasmus Medical Center and Erasmus University Rotterdam
- Netherlands Organization for Scientific Research
- Netherlands Organization for Health Research and Development (ZonMw)
- Research Institute for Diseases in the Elderly
- Netherlands Heart Foundation
- Ministry of Education, Culture and Science
- Ministry of Health Welfare and Sports
- European Commission
- and the Municipality of Rotterdam
- Netherlands Organization for Scientific Research (NWO) [175.010.2005.011, 911.03.012]
- Research Institute for Diseases in the Elderly (RIDE)
- Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) [050-060-810]
- National Heart, Lung, and Blood Institute
- [N01 HC-95159-N01-HC-95169]
- [RR-024156]
Ask authors/readers for more resources
Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the ` missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use = 13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction > 5.0 x 10(-8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.
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