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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.

TitlePharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology.
Publication TypePublication
Year2018
AuthorsSeyerle AA, Sitlani CM, Noordam R, Gogarten SM, Li J, Li X, Evans DS, Sun F, Laaksonen MA, Isaacs A, Kristiansson K, Highland HM, Stewart JD, Harris TB, Trompet S, Bis JC, Peloso GM, Brody JA, Broer L, Busch EL, Duan Q, Stilp AM, O'Donnell CJ, Macfarlane PW, Floyd JS, Kors JA, Lin HJ, Li-Gao R, Sofer T, Méndez-Giráldez R, Cummings SR, Heckbert SR, Hofman A, Ford I, Li Y, Launer LJ, Porthan K, Newton-Cheh C, Napier MD, Kerr KF, Reiner AP, Rice KM, Roach J, Buckley BM, Soliman EZ, de Mutsert R, Sotoodehnia N, Uitterlinden AG, North KE, Lee CR, Gudnason V, Stürmer T, Rosendaal FR, Taylor KD, Wiggins KL, Wilson JG, Di Chen Y-, Kaplan RC, Wilhelmsen K, Cupples LA, Salomaa V, van Duijn C, Jukema JW, Liu Y, Mook-Kanamori DO, Lange LA, Vasan RS, Smith AV, Stricker BH, Laurie CC, Rotter JI, Whitsel EA, Psaty BM, Avery CL
JournalPharmacogenomics J
Volume18
Issue2
Pagination215-226
Date Published2018 04
ISSN1473-1150
KeywordsAdult, Aged, Aged, 80 and over, aging, Cohort Studies, Electrocardiography, ethnic groups, Female, Genomics, heart rate, Humans, Longitudinal Studies, Male, Middle Aged, Pharmacogenetics, Polymorphism, Single Nucleotide, Sodium Chloride Symporter Inhibitors
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), we found suggestive evidence (P<5 × 10) 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.

DOI10.1038/tpj.2017.10
Alternate JournalPharmacogenomics J
PubMed ID28719597
PubMed Central IDPMC5773415
Grant ListP30 ES010126 / ES / NIEHS NIH HHS / United States
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MS#: 
0395
Manuscript Lead/Corresponding Author Affiliation: 
Coordinating Center - Collaborative Studies Coordinating Center - UNC at Chapel Hill
ECI: 
Manuscript Affiliation: 
Coordinating Center - Collaborative Studies Coordinating Center - UNC at Chapel Hill
Manuscript Status: 
Published