Genetic variants involved in Blood Pressure response to hydrochlorothiazide identified by GWAS methodology

Aim: To identify new loci regulating blood pressure response to thiazide diuretics (HCTZ) with a genome wide association analysis, thus optimizing therapeutic advantages and minimizing side effects.Methods: Treatment started after a 8 week run-in period under standardized dietary regimen to qualify patients as “essential hypertensives”. Never treated mild-to-moderate hypertensive patients were studied in two Italian cohorts: n=343 patients in Sardinia and 142 in Milano. A genome-wide association study and imputation were performed: variants associated with blood pressure response to HCTZ over an 8-weeks follow up period were analysed. The specificity of our findings was confirmed in an independent cohort of never treated essential hypertensives treated with Losartan.Results: We identified 141 SNPs and 130 SNPs showing a significant association with for deltaSBP8 for deltaDBP8 (P≤10-5). Six SNPs showed the best association with deltaSBP8 and five SNPs with deltaDBP8, respectively. TET2 and CSMD1 gene variants showed the best effect on deltaSBP after 8 weeks of HCTZ treatment. No association was found in Losartan sample. We looked for replication in other studies (GENRES, GERA1, NORDIL, PEAR and CSN-StayOnDiur).Conclusions: TET2 and CSMD1 affect SBP response to HCTZ. TET2, may affect the transcription of αENaC gene thus acting as an aldosterone-responsive mediator. CSMD1 gene was associated with increased risk of hypertension: its putative role in BP regulation remains to be clarified.