A Genetic Response Score for Hydrochlorothiazide Use Insights From Genomics and Metabolomics Integration

作者：Shahin Mohamed H; Gong Yan; McDonough Caitrin W; Rotroff Daniel M; Beitelshees Amber L; Garrett Timothy J; Gums John G; Motsinger Reif Alison; Chapman Arlene B; Turner Stephen T; Boerwinkle Eric; Frye Reginald F; Fiehn Oliver; Cooper DeHoff Rhonda M; Kaddurah Daouk Rima; Johnson Julie A^*

来源：Hypertension, 2016, 68(3): 621-+.

DOI：10.1161/HYPERTENSIONAHA.116.07328

• hydrochlorothiazide
• hypertension
• genome-wide association study
• metabolomics
• pharmacogenetics

Hydrochlorothiazide is among the most commonly prescribed antihypertensives; yet, < 50% of hydrochlorothiazidetreated patients achieve blood pressure (BP) control. Herein, we integrated metabolomic and genomic profiles of hydrochlorothiazide-treated patients to identify novel genetic markers associated with hydrochlorothiazide BP response. The primary analysis included 228 white hypertensives treated with hydrochlorothiazide from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study. Genome-wide analysis was conducted using Illumina Omni 1 mol/L-Quad Chip, and untargeted metabolomics was performed on baseline fasting plasma samples using a gas chromatographytime-of-flight mass spectrometry platform. We found 13 metabolites significantly associated with hydrochlorothiazide systolic BP (SBP) and diastolic BP (DBP) responses (false discovery rate, < 0.05). In addition, integrating genomic and metabolomic data revealed 3 polymorphisms (rs2727563 PRKAG2, rs12604940 DCC, and rs13262930 EPHX2) along with arachidonic acid, converging in the netrin signaling pathway (P= 1x10(-5)), as potential markers, significantly influencing hydrochlorothiazide BP response. We successfully replicated the 3 genetic signals in 212 white hypertensives treated with hydrochlorothiazide and created a response score by summing their BP-lowering alleles. We found patients carrying 1 response allele had a significantly lower response than carriers of 6 alleles (triangle SBP/triangle DBP: -1.5/ 1.2 versus -16.3/-10.4 mm Hg, respectively, SBP score, P= 1x10(-8) and DBP score, P= 3x10(-9)). This score explained 11.3% and 11.9% of the variability in hydrochlorothiazide SBP and DBP responses, respectively, and was further validated in another independent study of 196 whites treated with hydrochlorothiazide (DBP score, P= 0.03; SBP score, P= 0.07). This study suggests that PRKAG2, DCC, and EPHX2 might be important determinants of hydrochlorothiazide BP response.

• 出版日期2016-9