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dc.contributor.authorShahin, M.H.
dc.contributor.authorGong, Y.
dc.contributor.authorFrye, R.F.
dc.date.accessioned2019-06-21T18:46:26Z
dc.date.available2019-06-21T18:46:26Z
dc.date.issued2018
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85040526567&doi=10.1161%2fJAHA.117.006656&partnerID=40&md5=70d1c14c90d9c51152b7817be321a3b3
dc.identifier.urihttp://hdl.handle.net/10713/9696
dc.description.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.en_US
dc.description.sponsorshipPEAR 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.en_US
dc.description.urihttps://dx.doi.org/10.1161/JAHA.117.006656en_US
dc.language.isoen-USen_US
dc.publisherAmerican Heart Association Inc.en_US
dc.relation.ispartofJournal of the American Heart Association
dc.subjectBlood pressureen_US
dc.subjectLipid metabolitesen_US
dc.subjectMetabolomicsen_US
dc.subjectPharmacogeneticsen_US
dc.subjectThiazide diureticsen_US
dc.titleSphingolipid metabolic pathway impacts thiazide diuretics blood pressure response: Insights from genomics, metabolomics, and lipidomicsen_US
dc.typeArticleen_US
dc.identifier.doi10.1161/JAHA.117.006656
dc.identifier.pmid29288159


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