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 αENaC gene transcription; and CSMD1, previously described as associated with hypertension in a case-control study.

Trial registration: ClinicalTrials.gov NCT00408512.

Conflict of interest statement

Conflicts of interest

There are no conflicts of interest.

Figures

Figure 1

Local Manhattan plot for the Tet methylcytosine dioxygenase 2 (a) and CUB and Sushi multiple domains protein 1 (b) regions. Each circle represents a single nucleotide polymorphism (SNP), y-axis is the −log10 association P-value for HCTZ response, and x-axis represents the physical position on the chromosome (build 37, hg19). CSMD1, CUB and Sushi multiple domains protein 1; TET2, Tet methylcytosine dioxygenase 2; HCTZ, hydrochlorothiazide.

Figure 2

Plot of blood pressure response to hydrochlorothiazide by Tet methylcytosine dioxygenase 2 rs12505746 (a), and CUB and Sushi multiple domains protein 1 rs11993031 (b), and rs7387065 (c) genotypes of participants from the two cohorts (Pharmacogenomics of Hydrochlorothiazide Sardinian Study and hydrochlorothiazide-Milan). The blood pressure response is adjusted for pretreatment blood pressure level, age, sex and principal components. In each box the number of patients for each genotype is reported.