Genome Wide Association Study Identifies the HMGCS2 Locus to be Associated With Chlorthalidone Induced Glucose Increase in Hypertensive Patients

Sonal Singh, Caitrin W McDonough, Yan Gong, Wael A Alghamdi, Meghan J Arwood, Salma A Bargal, Leanne Dumeny, Wen-Yi Li, Mai Mehanna, Bradley Stockard, Guang Yang, Felipe A de Oliveira, Natalie C Fredette, Mohamed H Shahin, Kent R Bailey, Amber L Beitelshees, Eric Boerwinkle, Arlene B Chapman, John G Gums, Stephen T Turner, Rhonda M Cooper-DeHoff, Julie A Johnson, Sonal Singh, Caitrin W McDonough, Yan Gong, Wael A Alghamdi, Meghan J Arwood, Salma A Bargal, Leanne Dumeny, Wen-Yi Li, Mai Mehanna, Bradley Stockard, Guang Yang, Felipe A de Oliveira, Natalie C Fredette, Mohamed H Shahin, Kent R Bailey, Amber L Beitelshees, Eric Boerwinkle, Arlene B Chapman, John G Gums, Stephen T Turner, Rhonda M Cooper-DeHoff, Julie A Johnson

Abstract

Background: Thiazide and thiazide-like diuretics are first-line medications for treating uncomplicated hypertension. However, their use has been associated with adverse metabolic events, including hyperglycemia and incident diabetes mellitus, with incompletely understood mechanisms. Our goal was to identify genomic variants associated with thiazide-like diuretic/chlorthalidone-induced glucose change.

Methods and results: Genome-wide analysis of glucose change after treatment with chlorthalidone was performed by race among the white (n=175) and black (n=135) participants from the PEAR-2 (Pharmacogenomic Evaluation of Antihypertensive Responses-2). Single-nucleotide polymorphisms with P<5×10-8 were further prioritized using in silico analysis based on their expression quantitative trait loci function. Among blacks, an intronic single-nucleotide polymorphism (rs9943291) in the HMGCS2 was associated with increase in glucose levels following chlorthalidone treatment (ß=12.5; P=4.17×10-8). G-allele carriers of HMGCS2 had higher glucose levels (glucose change=+16.29 mg/dL) post chlorthalidone treatment compared with noncarriers of G allele (glucose change=+2.80 mg/dL). This association was successfully replicated in an independent replication cohort of hydrochlorothiazide-treated participants from the PEAR study (ß=5.54; P=0.023). A meta-analysis of the 2 studies was performed by race in Meta-Analysis Helper, where this single-nucleotide polymorphism, rs9943291, was genome-wide significant with a meta-analysis P value of 3.71×10-8. HMGCS2, a part of the HMG-CoA synthase family, is important for ketogenesis and cholesterol synthesis pathways that are essential in glucose homeostasis.

Conclusions: These results suggest that HMGCS2 is a promising candidate gene involved in chlorthalidone and Hydrochlorothiazide (HCTZ)-induced glucose change. This may provide insights into the mechanisms involved in thiazide-induced hyperglycemia that may ultimately facilitate personalized approaches to antihypertensive selection for hypertension treatment.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00246519 and NCT01203852.

Keywords: chlorthalidone; diabetes mellitus; genome‐wide association study; glucose; hydrochlorothiazide; hyperglycemia; pharmacogenomics.

© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Figures

Figure 1
Figure 1
Distribution of glucose change post‐treatment showing the interindividual variability of the response among PEAR‐2 and PEAR participants. PEAR indicates Pharmacogenomic Evaluation of Antihypertensive Response.
Figure 2
Figure 2
Manhattan plots of glucose change post chlorthalidone treatment among PEAR‐2 black participants. Genome‐wide significance threshold (red line): P<5×10−8. PEAR‐2 indicates Pharmacogenomic Evaluation of Antihypertensive Response‐2.
Figure 3
Figure 3
Glucose change post chlorthalidone treatment among PEAR‐2 blacks (N=135) and PEAR blacks (N=140) post hydrochlorothiazide by HMGCS2 rs9943291 genotype. Glucose change for both studies is adjusted for pretreatment glucose levels, age, sex, and principal components 1 and 2. P values are for contrast of least square adjusted means between genotype groups. PEAR indicates Pharmacogenomic Evaluation of Antihypertensive Response.

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