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J Hypertens. 2015 Jun;33(6):1301-9. doi: 10.1097/HJH.0000000000000541.

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

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aDepartment of Health Sciences, University of Milan at San Paolo Hospital, and Filarete Foundation, Genomic and Bioinformatics Unit, Milan bHypertension and Related Disease Centre, AOU-University of Sassari, Sassari cUniversità Vita Salute San Raffaele, Nephrology and Dialysis and Hypertension Unit, San Raffaele Scientific Institute, Milan, Italy dDepartment of Medicine, University of Helsinki and Helsinki University Central Hospital eInstitute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland fDivision of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota gHuman Genetics and Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas hRenal Division, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA iInstitute of Cardiovascular and Medical Sciences, College of Medicine Veterinary and Life Sciences, University of Glasgow, Glasgow, UK jDepartment of Clinical Sciences, Lund University, Malmö, Sweden kDepartment of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, Florida, USA lRespiratory Medicine Unit, Department of Medicine and CMM, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden mDepartment of Medical Biotechnologies and Translational Medicine, University of Milan, and Humanitas Clinical and Research Center, University of Milan, and National Research Council of Italy, Rozzano (MI) nDepartment of Clinical Medicine, Cardiovascular and Immunological Sciences, University of Naples 'Federico II', Naples, Italy *Martina Chittani and Roberta Zaninello contributed equally to the writing of this article.



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.


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.


This exploratory study reports two plausible loci associated with SBP response to hydrochlorothiazide: TET2, an aldosterone-responsive mediator of αENaC gene transcription; and CSMD1, previously described as associated with hypertension in a case-control study.


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