Piras, Daniela Antonella (2016) Genetic variants involved in Blood Pressure response to hydrochlorothiazide identified by GWAS methodology. Doctoral Thesis.
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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.
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.
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).
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.
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