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 m), 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.
Original language | English (US) |
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Pages (from-to) | 215-226 |
Number of pages | 12 |
Journal | Pharmacogenomics Journal |
Volume | 18 |
Issue number | 2 |
DOIs | |
State | Published - Apr 1 2018 |
Externally published | Yes |
ASJC Scopus subject areas
- Molecular Medicine
- Genetics
- Pharmacology