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.

TET2 and CSMD1 genes affect SBP response to hydrochlorothiazide in never-treated essential hypertensives / M. Chittani, R. Zaninello, C. Lanzani, F. Frau, M.F. Ortu, E. Salvi, G. Fresu, L. Citterio, D. Braga, D.A. Piras, S.D. Carpini, D. Velayutham, M. Simonini, G. Argiolas, S. Pozzoli, C. Troffa, V. Glorioso, K.K. Kontula, T.P. Hiltunen, K.M. Donner, S.T. Turner, E. Boerwinkle, A.B. Chapman, S. Padmanabhan, A.F. Dominiczak, O. Melander, J.A. Johnson, R.M. Cooper Dehoff, Y. Gong, N.V. Rivera, G. Condorelli, B. Trimarco, P. Manunta, D. Cusi, N. Glorioso, C. Barlassina. - In: JOURNAL OF HYPERTENSION. - ISSN 0263-6352. - 33:6(2015), pp. 1301-1309. [10.1097/HJH.0000000000000541]

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

M. Chittani
Primo
;
F. Frau;E. Salvi;D. Braga;D. Velayutham;G. Condorelli;D. Cusi;C. Barlassina
2015

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.
essential hypertension; genome-wide association study; genomics; pharmacogenomics; thiazides diuretics; Adult; Aged; Aldosterone; Antihypertensive Agents; Blood Pressure; Case-Control Studies; DNA-Binding Proteins; European Continental Ancestry Group; Genome-Wide Association Study; Humans; Hydrochlorothiazide; Hypertension; Italy; Losartan; Male; Membrane Proteins; Middle Aged; Pharmacogenetics; Proto-Oncogene Proteins; Sodium Chloride Symporter Inhibitors; Systole; Internal Medicine; Physiology; Cardiology and Cardiovascular Medicine
Settore MED/14 - Nefrologia
European Network for Genetic-Epidemiological Studies: building a method to dissect complex genetic traits, using essential hypertension as a disease model
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/446643
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