Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology
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Seyerle, A. A.
Sitlani, C. M.
Gogarten, S. M.
Evans, Daniel S.
Laaksonen, M. A.
Nature Publishing Group
Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, transethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N = 78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P < 5 x 10(-8)), we found suggestive evidence (P < 5 x 10(-6)) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.
Blood-pressure response , Influencing antihypertensive response , Gene-environment interactions , Wide association , Genomewide association , Hypertensive patients , Cardiovascular drugs , Selection bias , United States , Variants
Seyerle, A. A., et al. (2017) ‘Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology’, Pharmacogenomics Journal, 18, pp. 215-226. doi. 10.1038/tpj.2017.10
© 2017, Nature Publishing Group. All rights reserved. This is the peer reviewed version of the following article: Seyerle, A. A. et al. (2017) ‘Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology’, The Pharmacogenomics Journal, 18, pp. 215-226. doi. 10.1038/tpj.2017.10, which has been published in final form at https://doi.org/10.1038/tpj.2017.10