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. et al. (2018) 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(2), pp. 215-226. (doi: 10.1038/tpj.2017.10) (PMID:28719597) (PMCID:PMC5773415)

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, trans-ethnic 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 × 10(-8)), we found suggestive evidence (P<5 × 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Macfarlane, Professor Peter and Ford, Professor Ian
• Authors: Seyerle, A. A., Sitlani, C. M., Noordam, R., Gogarten, S. M., Li, J., Li, X., Evans, D. S., Sun, F., Laaksonen, M. A., Isaacs, A., Kristiansson, K., Highland, H. M., Stewart, J. D., Harris, T. B., Trompet, S., Bis, J. C., Peloso, G. M., Brody, J. 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., Méndez-Giráldez, R., Cummings, S. R., Heckbert, S. R., Hofman, A., Ford, I., 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, B. M., Soliman, E. Z., de Mutsert, R., Sotoodehnia, N., Uitterlinden, A. G., North, K. E., Lee, C. R., Gudnason, V., Stürmer, T., Rosendaal, F. R., Taylor, K. D., Wiggins, K. L., Wilson, J. G., Chen, Y.-D., 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., and Avery, C. L.
• Subjects: R Medicine > R Medicine (General)
• College/School: College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Robertson Centre
• Journal Name: Pharmacogenomics Journal
• Publisher: Nature Publishing Group
• ISSN: 1470-269X
• ISSN (Online): 1473-1150
• Published Online: 18 July 2017
• Copyright Holders: Copyright © 2017 Macmillan Publishers Limited, part of Springer Nature
• First Published: First published in Pharmacogenomics Journal 18(2): 215-226
• Publisher Policy: Reproduced in accordance with the publisher copyright policy