Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval.
Avery CL., Sitlani CM., Arking DE., Arnett DK., Bis JC., Boerwinkle E., Buckley BM., Ida Chen Y-D., de Craen AJM., Eijgelsheim M., Enquobahrie D., Evans DS., Ford I., Garcia ME., Gudnason V., Harris TB., Heckbert SR., Hochner H., Hofman A., Hsueh W-C., Isaacs A., Jukema JW., Knekt P., Kors JA., Krijthe BP., Kristiansson K., Laaksonen M., Liu Y., Li X., Macfarlane PW., Newton-Cheh C., Nieminen MS., Oostra BA., Peloso GM., Porthan K., Rice K., Rivadeneira FF., Rotter JI., Salomaa V., Sattar N., Siscovick DS., Slagboom PE., Smith AV., Sotoodehnia N., Stott DJ., Stricker BH., Stürmer T., Trompet S., Uitterlinden AG., van Duijn C., Westendorp RGJ., Witteman JC., Whitsel EA., Psaty BM.
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 × 10(-8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.