Sphingolipid metabolic pathway impacts thiazide diuretics blood pressure response: Insights from genomics, metabolomics, and lipidomics
JournalJournal of the American Heart Association
PublisherAmerican Heart Association Inc.
MetadataShow full item record
AbstractBackground--Although hydrochlorothiazide (HCTZ) is a well-established first-line antihypertensive in the United States, < 50% of HCTZ treated patients achieve blood pressure (BP) control. Thus, identifying biomarkers that could predict the BP response to HCTZ is critically important. In this study, we utilized metabolomics, genomics, and lipidomics to identify novel pathways and biomarkers associated with HCTZ BP response. Methods and Results--First, we conducted a pathway analysis for 13 metabolites we recently identified to be significantly associated with HCTZ BP response. From this analysis, we found the sphingolipid metabolic pathway as the most significant pathway (P=5.8E-05). Testing 78 variants, within 14 genes involved in the sphingolipid metabolic canonical pathway, with the BP response to HCTZ identified variant rs6078905, within the SPTLC3 gene, as a novel biomarker significantly associated with the BP response to HCTZ in whites (n=228). We found that rs6078905 C-allele carriers had a better BP response to HCTZ versus noncarriers (?SBP/?DBP: -11.4/-6.9 versus -6.8/-3.5 mm Hg; ?SBP P=6.7E-04; ?DBP P=4.8E-04). Additionally, in blacks (n=148), we found genetic signals in the SPTLC3 genomic region significantly associated with the BP response to HCTZ (P < 0.05). Last, we observed that rs6078905 significantly affects the baseline level of 4 sphingomyelins (N24:2, N24:3, N16:1, and N22:1; false discovery rate < 0.05), from which N24:2 sphingomyelin has a significant correlation with both HCTZ DBP-response (r =-0.42; P=7E-03) and SBP-response (r=-0.36; P=2E-02). Conclusions--This study provides insight into potential pharmacometabolomic and genetic mechanisms underlying HCTZ BP response and suggests that SPTLC3 is a potential determinant of the BP response to HCTZ. Copyright 2017 The Authors.
SponsorsPEAR was supported by the National Institute of Health Pharmacogenetics Research Network grant U01-GM074492 and the National Center for Advancing Translational Sciences under the award number UL1 TR000064 (University of Florida); UL1 TR000454 (Emory University); and UL1 TR000135 (Mayo Clinic). PEAR was also supported by funds from the Mayo Foundation. The metabolomics work was funded by NIGMS (National Institute of General Medical Sciences) grant RC2-GM092729 "Metabolomics Network for Drug Response Phenotype." Additional support for this work includes: Shahin is supported by AHA predoctoral fellowship award #14PRE20460115, and Fiehn is funded through NIH DK097154.
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85040526567&doi=10.1161%2fJAHA.117.006656&partnerID=40&md5=70d1c14c90d9c51152b7817be321a3b3; http://hdl.handle.net/10713/9696
- Genome-Wide Prioritization and Transcriptomics Reveal Novel Signatures Associated With Thiazide Diuretics Blood Pressure Response.
- Authors: Shahin MH, Sá AC, Webb A, Gong Y, Langaee T, McDonough CW, Riva A, Beitleshees AL, Chapman AB, Gums JG, Turner ST, Boerwinkle E, Scherer SE, Sadee W, Cooper-DeHoff RM, Johnson JA
- Issue date: 2017 Jan
- A Genetic Response Score for Hydrochlorothiazide Use: Insights From Genomics and Metabolomics Integration.
- Authors: Shahin MH, Gong Y, McDonough CW, Rotroff DM, Beitelshees AL, Garrett TJ, Gums JG, Motsinger-Reif A, Chapman AB, Turner ST, Boerwinkle E, Frye RF, Fiehn O, Cooper-DeHoff RM, Kaddurah-Daouk R, Johnson JA
- Issue date: 2016 Sep
- Genetic Variants Associated With Uncontrolled Blood Pressure on Thiazide Diuretic/β-Blocker Combination Therapy in the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) and INVEST (International Verapamil-SR Trandolapril Study) Trials.
- Authors: Magvanjav O, Gong Y, McDonough CW, Chapman AB, Turner ST, Gums JG, Bailey KR, Boerwinkle E, Beitelshees AL, Tanaka T, Kubo M, Pepine CJ, Cooper-DeHoff RM, Johnson JA
- Issue date: 2017 Nov 2
- Blood pressure signature genes and blood pressure response to thiazide diuretics: results from the PEAR and PEAR-2 studies.
- Authors: Sá ACC, Webb A, Gong Y, McDonough CW, Shahin MH, Datta S, Langaee TY, Turner ST, Beitelshees AL, Chapman AB, Boerwinkle E, Gums JG, Scherer SE, Cooper-DeHoff RM, Sadee W, Johnson JA
- Issue date: 2018 Jun 20
- Nocturnal reduction of blood pressure and the antihypertensive response to a diuretic or angiotensin converting enzyme inhibitor in obese hypertensive patients. TROPHY Study Group.
- Authors: Weir MR, Reisin E, Falkner B, Hutchinson HG, Sha L, Tuck ML
- Issue date: 1998 Aug