M. H. Shahin,1 Y. Gong,2 T. Langaee,2 A. L. Beitelshees,3 D. M. Rotroff,4 A. B. Chapman,5 J. G. Gums,2 S. T. Turner,6 A. Motsinger-Reif,4 R. F. Frye,2 O. Fiehn,7 J. A. Johnson,2 R. Cooper-DeHoff,2 X. Han,8 R. Kaddurah-Daouk9; 1University of Florida, Gainesville, FL, 2Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, 3Department of Medicine, University of Maryland, Baltimore, MD, 4Bioinformatics Research Center, North Carolina State University, Raleigh, NC, 5Department of Medicine, Emory University, Atlanta, GA, 6College of Medicine, Mayo Clinic, Rochester, MN, 7Genome Center, University of California at Davis, Davis, CA, 8Sanford-Burnham Medical Research Institute, Orlando, FL, 9Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC

BACKGROUND: Hydrochlorothiazide (HCTZ) is a first line antihypertensive in the US, yet < 50% of treated patients achieve blood pressure (BP) control. We studied metabolomics, genomics and lipidomics of HCTZ treated patients to identify novel biomarkers for BP response.
METHODS: We included 228 white hypertensive PEAR participants with BP measured at baseline and after 9 weeks of HCTZ treatment. Genotyping was done via Illumina Omni 1M Quad Chip. Untargeted metabolomics was conducted on fasting baseline plasma samples using GC TOF MS. Pathway analysis was done for BP significant metabolites (FDR < .05). Lipids were measured using Shotgun lipidomics approach.
RESULTS: 13 of 212 identified metabolites were significantly associated with systolic and diastolic BP responses (FDR < .05) and carried forward to pathway analysis which identified Sphingomyelin/ceramide metabolism as the top significant pathway (FDR p = 7x10-3). 83 variants, within 13 genes in this pathway, were tested for BP response. rs6078905 in SPTLC3, which encodes the rate limiting enzyme of sphingolipid synthesis, was significantly associated with BP response (∆SBP/∆DBP of variant carriers: -11.4/-6.9 vs. -6.8/-4.4 mmHg in non-carriers, ∆SBP p = 4x10-4 and ∆DBP p =5x10-4). rs6078905 effect on the baseline levels of 26 sphingomyelins and 23 ceramides, from lipidomics analysis, revealed a significant association between this variant and 3 sphingomyelins (N24:2, N24:3, and N16:1, FDR < .05), of which N24:2 was also significantly correlated with ∆DBP (r = - .42, p = 7x10-3) and ∆SBP (r = - .36, p = .02).
CONCLUSION: This study provides important insight into the metabolic and genetic mechanisms underlying BP response, and suggests that SPTLC3 and sphingolipids might be important biomarkers involved in the mechanism of HCTZ BP response.