Sphingolipid metabolic pathway impacts thiazide diuretics blood pressure response: Insights from genomics, metabolomics, and lipidomics

Background--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 (ΔSBP/ΔDBP: -11.4/-6.9 versus -6.8/-3.5 mm Hg; ΔSBP P=6.7E-04; ΔDBP 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.