GENOME-WIDE AND GENE-BASED META-ANALYSES IDENTIFY NOVEL LOCI INFLUENCING BLOOD PRESSURE RESPONSE TO HYDROCHLOROTHIAZIDE

摘要

This study aimed to identify novel loci influencing the antihypertensive response to hydrochlorothiazide monotherapy. A genome-wide meta-analysis of blood pressure response to hydrochlorothiazide was performed in 1739 white hypertensives from six clinical trials within the International Consortium for Antihypertensive Pharmacogenomics Studies (ICAPS), making it the largest study to date of its kind. No signals reached genome-wide significance (P<5×10⁻⁸) and the suggestive regions (P<10⁻⁵) were cross-validated in two black cohorts treated with hydrochlorothiazide. Additionally, a gene-based analysis was performed on candidate genes with previous evidence of involvement in diuretic response, in blood pressure regulation or in hypertension susceptibility. Using the genome-wide meta-analysis approach, with validation in blacks, we identified two suggestive regulatory regions linked to GJA1 and FOXA1, relevant for cardiovascular and kidney function. With the gene-based approach, we identified HSD3B1 as significantly associated with blood pressure response (P<2.28×10⁻⁴). HSD3B1 encodes the 3beta-HSD enzyme and plays a crucial role in the biosynthesis of aldosterone and endogenous ouabain. By amassing all of the available pharmacogenomic studies of blood pressure response to hydrochlorothiazide, and using two different analytical approaches, we identified three novel loci influencing blood pressure response to hydrochlorothiazide. The gene-based analysis, never before applied to pharmacogenomics of antihypertensive drugs to our knowledge, provided a powerful strategy to identify a locus of interest, and which was not identified in the single-SNP analysis due to high allelic heterogeneity. These data pave the way for future investigations on new pathways and drug targets to enhance the current understanding of personalized antihypertensive treatment.