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Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology
Seyerle, A. A.; Sitlani, C. M.; Noordam, R.; Gogarten, S. M.; Li, J.; Li, X.; Evans, Daniel S.; Sun, F.; Laaksonen, M. A.; Isaacs, A.; Kristiansson, K.; Highland, H. M.; Stewart, J. D.; Harris, T. B.; Trompet, S.; Bis, Joshua C.; Peloso, G. M.; Brody, Jennifer A.; Broer, L.; Busch, E. L.
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.
Keyword(s): Blood-pressure response; Influencing antihypertensive response; Gene-environment interactions; Wide association; Genomewide association; Hypertensive patients; Cardiovascular drugs; Selection bias; United States; Variants
Publication Date:
2018
Type: Journal article
Peer-Reviewed: Yes
Language(s): English
Institution: University College Cork
Citation(s): 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
Publisher(s): Nature Publishing Group
File Format(s): application/pdf
First Indexed: 2018-07-31 06:32:02 Last Updated: 2019-06-18 06:35:06