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TET2 and CSMD1 genes affect SBP response to hydrochlorothiazide in never-treated essential hypertensives.

ABSTRACT: BACKGROUND:Thiazide diuretics have been recommended as a first-line antihypertensive treatment, although the choice of 'the right drug in the individual essential hypertensive patient' remains still empirical. Essential hypertension is a complex, polygenic disease derived from the interaction of patient's genetic background with the environment. Pharmacogenomics could be a useful tool to pinpoint gene variants involved in antihypertensive drug response, thus optimizing therapeutic advantages and minimizing side effects. METHODS AND RESULTS:We looked for variants associated with blood pressure response to hydrochlorothiazide over an 8-week follow-up by means of a genome-wide association analysis in two Italian cohorts of never-treated essential hypertensive patients: 343 samples from Sardinia and 142 from Milan. TET2 and CSMD1 as plausible candidate genes to affect SBP response to hydrochlorothiazide were identified. The specificity of our findings for hydrochlorothiazide was confirmed in an independent cohort of essential hypertensive patients treated with losartan. Our best findings were also tested for replication in four independent hypertensive samples of European Ancestry, such as GENetics of drug RESponsiveness in essential hypertension, Genetic Epidemiology of Responses to Antihypertensives, NORdic DILtiazem intervention, Pharmacogenomics Evaluation of Antihypertensive Responses, and Campania Salute Network-StayOnDiur. We validated a polymorphism in CSMD1 and UGGT2. CONCLUSION:This exploratory study reports two plausible loci associated with SBP response to hydrochlorothiazide: TET2, an aldosterone-responsive mediator of ?ENaC gene transcription; and CSMD1, previously described as associated with hypertension in a case-control study.

SUBMITTER: Chittani M

PROVIDER: S-EPMC4484731 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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TET2 and CSMD1 genes affect SBP response to hydrochlorothiazide in never-treated essential hypertensives.

Chittani Martina M Zaninello Roberta R Lanzani Chiara C Frau Francesca F Ortu Maria F MF Salvi Erika E Fresu Giovanni G Citterio Lorena L Braga Daniele D Piras Daniela A DA Carpini Simona Delli SD Velayutham Dinesh D Simonini Marco M Argiolas Giuseppe G Pozzoli Simona S Troffa Chiara C Glorioso Valeria V Kontula Kimmo K KK Hiltunen Timo P TP Donner Kati M KM Turner Stephen T ST Boerwinkle Eric E Chapman Arlene B AB Padmanabhan Sandosh S Dominiczak Anna F AF Melander Olle O Johnson Julie A JA Cooper-Dehoff Rhonda M RM Gong Yan Y Rivera Natalia V NV Condorelli Gianluigi G Trimarco Bruno B Manunta Paolo P Cusi Daniele D Glorioso Nicola N Barlassina Cristina C

Journal of hypertension 20150601 6

<h4>Background</h4>Thiazide diuretics have been recommended as a first-line antihypertensive treatment, although the choice of 'the right drug in the individual essential hypertensive patient' remains still empirical. Essential hypertension is a complex, polygenic disease derived from the interaction of patient's genetic background with the environment. Pharmacogenomics could be a useful tool to pinpoint gene variants involved in antihypertensive drug response, thus optimizing therapeutic advant ...[more]

PMID: 25695618

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Project description:IntroductionIn most treated patients with hypertension, a two or more drug combination is required to achieve adequate blood pressure (BP) control. In our study we assessed whether the combination of zofenopril + hydrochlorothiazide (HCTZ) was at least as effective as irbesartan + HCTZ in essential hypertensives with at least one additional cardiovascular risk factor, uncontrolled by a previous monotherapy.MethodsAfter a 2-week placebo washout, 361 treated hypertensive patients [office sitting diastolic BP (DBP), ≥90 mmHg], aged 18-75 years, were randomized double blind to 18-week treatment with zofenopril 30 mg plus HCTZ 12.5 mg or irbesartan 150 mg plus HCTZ 12.5 mg once daily, in an international, multicenter study. After the first 6 and 12 weeks, zofenopril and irbesartan doses could be doubled in non-normalized subjects. The primary study end point was the office sitting DBP reduction after 18 weeks of treatment. Secondary end points included office systolic BP (SBP), ambulatory BP and high sensitivity C-reactive protein (hs-CRP).ResultsThe between-treatment difference for office DBP averaged to +1.0 (95% CI -0.4, +0.8) mmHg (P = 0.150), the upper limit of the 95% confidence interval being inferior to the protocol-defined non-inferiority limit (3 mmHg). In the subset of patients with valid ambulatory BP, no difference in 24-h average DBP [n = 181; 6.7 (8.7, 4.6) zofenopril + HCTZ vs. 6.3 (8.8, 3.7) mmHg irbesartan + HCTZ, P = 0.810] and SBP reductions [11.7 (15.4, 8.0) vs. 12.6 (17.2, 8.0) mmHg, P = 0.758] were observed between the two treatment groups. hs-CRP was reduced by zofenopril + HCTZ [-0.52 (-1.05, 0.01) mg/L], while it was increased by irbesartan plus HCTZ [0.97 (0.29, 1.65) mg/L, P = 0.001 between treatments].ConclusionIn previously monotherapy-treated, uncontrolled patients with hypertension, zofenopril 30-60 mg + HCTZ 12.5 mg is as effective as irbesartan 150-300 mg plus HCTZ 12.5 mg, with the added value of a potential protective effect against vascular inflammation.

Dataset Information

TET2 and CSMD1 genes affect SBP response to hydrochlorothiazide in never-treated essential hypertensives.

Publications

TET2 and CSMD1 genes affect SBP response to hydrochlorothiazide in never-treated essential hypertensives.

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