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TET2 and CSMD1 genes affect SBP response to hydrochlorothiazide in never-treated essential hypertensives
Martina Chittani1, Roberta Zaninello, Chiara Lanzani
1aDepartment 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.
Insights
This study identified TET2 and CSMD1 gene variants associated with blood pressure response to hydrochlorothiazide, a common hypertension treatment. These findings could personalize antihypertensive drug selection for essential hypertension patients.
Area of Science:
- Pharmacogenomics
- Cardiovascular Genetics
- Molecular Medicine
Background:
- Thiazide diuretics are first-line hypertension treatments, but drug selection is empirical.
- Essential hypertension is a complex polygenic disease influenced by genetics and environment.
- Pharmacogenomics offers a tool to optimize antihypertensive therapy by identifying gene variants impacting drug response.
Purpose of the Study:
- To identify genetic variants associated with blood pressure response to hydrochlorothiazide.
- To explore the role of pharmacogenomics in personalizing essential hypertension treatment.
- To optimize antihypertensive therapy and minimize side effects through genetic insights.
Main Methods:
- Genome-wide association analysis in two Italian cohorts of essential hypertensive patients.
- Follow-up of blood pressure response to hydrochlorothiazide over 8 weeks.
- Replication analysis in independent cohorts of European Ancestry, including losartan-treated patients.
Main Results:
- Identified TET2 and CSMD1 as plausible candidate genes affecting systolic blood pressure (SBP) response to hydrochlorothiazide.
- Validated a polymorphism in CSMD1 and UGGT2 in independent cohorts.
- Confirmed specificity of findings for hydrochlorothiazide compared to losartan treatment.
Conclusions:
- TET2 and CSMD1 are plausible loci associated with SBP response to hydrochlorothiazide.
- TET2 is an aldosterone-responsive mediator of alphaENaC gene transcription.
- CSMD1 has been previously associated with hypertension in case-control studies.
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 αENaC gene transcription; and CSMD1, previously described as associated with hypertension in a case-control study.
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