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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.

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.

SUBMITTER: Seyerle AA

PROVIDER: S-EPMC5773415 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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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 AA Sitlani C M CM Noordam R R Gogarten S M SM Li J J Li X X Evans D S DS Sun F F Laaksonen M A MA Isaacs A A Kristiansson K K Highland H M HM Stewart J D JD Harris T B TB Trompet S S Bis J C JC Peloso G M GM Brody J A JA Broer L L Busch E L EL Duan Q Q Stilp A M AM O'Donnell C J CJ Macfarlane P W PW Floyd J S JS Kors J A JA Lin H J HJ Li-Gao R R Sofer T T Méndez-Giráldez R R Cummings S R SR Heckbert S R SR Hofman A A Ford I I Li Y Y Launer L J LJ Porthan K K Newton-Cheh C C Napier M D MD Kerr K F KF Reiner A P AP Rice K M KM Roach J J Buckley B M BM Soliman E Z EZ de Mutsert R R Sotoodehnia N N Uitterlinden A G AG North K E KE Lee C R CR Gudnason V V Stürmer T T Rosendaal F R FR Taylor K D KD Wiggins K L KL Wilson J G JG Chen Y-Di YD Kaplan R C RC Wilhelmsen K K Cupples L A LA Salomaa V V van Duijn C C Jukema J W JW Liu Y Y Mook-Kanamori D O DO Lange L A LA Vasan R S RS Smith A V AV Stricker B H BH Laurie C C CC Rotter J I JI Whitsel E A EA Psaty B M BM Avery C L CL

The pharmacogenomics journal 20170718 2

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%) populat ...[more]

PMID: 28719597

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Project description:Chlorthalidone (CTD) is more potent than hydrochlorothiazide (HCTZ) in reducing blood pressure (BP) in hypertensive patients, though both are plagued with BP response variability. However, there is a void in the literature regarding the genetic determinants contributing to the variability observed in BP response to CTD. We performed a discovery genome wide association analysis of BP response post CTD treatment in African Americans (AA) and European Americans (EA) from the Pharmacogenomic Evaluation of Antihypertensive Responses-2 (PEAR-2) study and replication in an independent cohort of AA and EA treated with HCTZ from the PEAR study, followed by a race specific meta-analysis of the two studies. Successfully replicated SNPs were further validated in beta-blocker treated participants from PEAR-2 and PEAR for opposite direction of association. The replicated and validated signals were further evaluated by protein-protein interaction network analysis. An intronic SNP rs79237970 in the WDR92 (eQTL for PPP3R1) was significantly associated with better DBP response to CTD (p?=?5.76?×?10-6, ??=?-15.75) in the AA cohort. This SNP further replicated in PEAR (p?=?0.00046, ??=?-9.815) with a genome wide significant meta-analysis p-value of 8.49?×?10-9. This variant was further validated for opposite association in two ?-blockers treated cohorts from PEAR-2 metoprolol (p?=?9.9?×?10-3, ??=?7.47) and PEAR atenolol (p?=?0.04, ??=?4.36) for association with DBP. Studies have implicated WDR92 in coronary artery damage. PPP3R1 is the regulatory subunit of the calcineurin complex. Use of calcineurin inhibitors is associated with HTN. Studies have also shown polymorphisms in PPP3R1 to be associated with ventricular hypertrophy in AA hypertensive patients. Protein-protein interaction analysis further identified important hypertension related pathways such as inositol phosphate-mediated signaling and calcineurin-NFAT signaling cascade as important biological process associated with PPP3R1 which further strengthen the potential importance of this signal. These data collectively suggest that WDR92 and PPP3R1 are novel candidates that may help explain the genetic underpinnings of BP response of thiazide and thiazide-like diuretics and help identify the patients better suited for thiazide and thiazide-like diuretics compared to ?-blockers for improved BP management. This may further help advance personalized approaches to antihypertensive therapy.

Dataset Information

Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology.

Publications

Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology.

Similar Datasets

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