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    Genome wide association study identifies the HMGCS2 locus to be associated with chlorthalidone induced glucose increase in hypertensive patients

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    Author
    Singh, S.
    McDonough, C.W.
    Gong, Y.
    Date
    2018
    Journal
    Journal of the American Heart Association
    Publisher
    American Heart Association Inc.
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://dx.doi.org/10.1161/JAHA.117.007339
    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.. Copyright 2018 The Authors.
    Sponsors
    Both PEAR studies were supported by the National Institute of Health (NIH) Pharmacogenetics Research Network grant U01-GM074492 and the National Center for Advancing Translational Sciences. Award numbers UL1 TR000064 (University of Florida); UL1 TR000454 (Emory University); and UL1 TR000135 (Mayo Clinic). PEAR was also supported by funds from the Mayo Foundation.
    Keyword
    Chlorthalidone
    Diabetes mellitus
    Genome-wide association study
    Glucose
    Hydrochlorothiazide
    Hyperglycemia
    Pharmacogenomics
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85043690282&doi=10.1161%2fJAHA.117.007339&partnerID=40&md5=ccc77f40f2e7abbe53f628055963607e; http://hdl.handle.net/10713/9734
    ae974a485f413a2113503eed53cd6c53
    10.1161/JAHA.117.007339
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