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.; Duan, Q.; Stilp, A. M.; O'Donnell, C. J.; Macfarlane, P. W.; Floyd, J. S.; Kors, J. A.; Lin, H. J.; Li-Gao, R.; Sofer, T.; Mendez-Giraldez, R.; Cummings, S. R.; Heckbert, S. R.; Hofman, A.; Ford, Ian; Li, Y.; Launer, L. J.; Porthan, K.; Newton-Cheh, C.; Napier, M. D.; Kerr, K. F.; Reiner, A. P.; Rice, K. M.; Roach, J.; Buckley, Brendan M.; Soliman, E. Z.; de Mutsert, R.; Sotoodehnia, Nona; Uitterlinden, A. G.; North, K. E.; Lee, C. R.; Gudnason, V; Sturmer, T.; Rosendaal, F. R.; Taylor, K. D.; Wiggins, K. L.; Wilson, J. G.; Chen, Y-D, I; Kaplan, R. C.; Wilhelmsen, K.; Cupples, L. A.; Salomaa, V; van Duijn, C.; Jukema, J. W.; Liu, Y.; Mook-Kanamori, D. O.; Lange, L. A.; Vasan, R. S.; Smith, A., V; Stricker, B. H.; Laurie, C. C.; Rotter, J., I; Whitsel, E. A.; Psaty, B. M.; Avery, Christy L.

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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Accepted Version

Date

2018

Authors

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.

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Publisher

Nature Publishing Group

Published Version

10.1038/tpj.2017.10

Abstract

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.

Keywords

Blood-pressure response , Influencing antihypertensive response , Gene-environment interactions , Wide association , Genomewide association , Hypertensive patients , Cardiovascular drugs , Selection bias , United States , Variants

Citation

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

URI

https://hdl.handle.net/10468/6515

Collections

Pharmacology and Therapeutics - Journal Articles

Copyright

© 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

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