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 , 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 , Mendez-Giraldez , R , Cummings , S R , Heckbert , S R , Hofman , A , Ford , D , 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 & Chen , Y-D 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 , vol. 18 , no. 2 , pp. 215-226 . https://doi.org/10.1038/tpj.2017.10

Title: Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations : the cohorts for heart and aging research in genomic epidemiology
Author: 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.; Mendez-Giraldez, R.; Cummings, S. R.; Heckbert, S. R.; Hofman, A.; Ford, David; 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.; Chen, Y-D
Contributor: University of Helsinki, Kardiologian yksikkö
Date: 2018-03
Language: eng
Number of pages: 12
Belongs to series: Pharmacogenomics Journal
ISSN: 1470-269X
URI: http://hdl.handle.net/10138/301995
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.
Subject: BLOOD-PRESSURE RESPONSE
INFLUENCING ANTIHYPERTENSIVE RESPONSE
GENE-ENVIRONMENT INTERACTIONS
WIDE ASSOCIATION
GENOMEWIDE ASSOCIATION
HYPERTENSIVE PATIENTS
CARDIOVASCULAR DRUGS
SELECTION BIAS
UNITED-STATES
VARIANTS
317 Pharmacy
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