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Pharmacogenet Genomics. 2018 Nov;28(11):251-255. doi: 10.1097/FPC.0000000000000353.

Targeted sequencing identifies a missense variant in the BEST3 gene associated with antihypertensive response to hydrochlorothiazide.

Author information

1
Departments of Pharmacotherapy and Translational Research and Center for Pharmacogenomics.
2
Human Genetics and Institute of Molecular Medicine, University of Texas Health Science Center.
3
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota.
4
Division of Nephrology, University of Chicago, Chicago, Illinois, USA.
5
Department of Health Sciences Research, Division of Biostatistics.
6
College of Medicine, University of Maryland, Baltimore, Maryland.
7
Medicine, Division of Cardiovascular Medicine, University of Florida, Gainesville, Florida.
8
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.

Abstract

Chromosome 12q15 was identified in Genetic Epidemiology of Response Assessment (GERA) and replicated in Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) for its association with blood pressure (BP) response to hydrochlorothiazide (HCTZ). However, the functional variant is unknown and we aimed to identify the likely functional variants through targeted sequencing. The chromosome 12q15 region was sequenced in 397 best and worst responders to HCTZ in PEAR (N=199) and GERA (N=198) hypertensive study participants. Logistic regression was used for the association analysis adjusting for age, sex, race, and principal components 1 and 2. For validation, the significant single nucleotide polymorphism was tested for association with the change in systolic (ΔSBP) and diastolic BP (ΔDBP) post-treatment in the entire PEAR (N=370) and GERA (N=570) cohorts. A novel missense polymorphism (G>A, Pro383Leu) in BEST3, rs61747221, was significantly associated with better HCTZ response (P=0.0021, odds ratio=2.05). It was validated in the entire cohort of PEAR (ΔSBP: P=0.021, β=-1.60, ΔDBP: P=0.023, β=-1.08) and GERA (ΔSBP: P=0.028, β=-1.95, ΔDBP: P=0.032, β=-1.28). BEST3 encodes the calcium sensitive chloride channel in the vascular smooth muscle implicated in the regulation of BP, especially in response to vasoconstrictors like angiotensin II. These results suggest that BEST3 is involved in the chronic BP lowering mechanism of thiazides and highlight its importance as a genetic predictor of the BP response to thiazide diuretics.

PMID:
30289819
PMCID:
PMC6262886
[Available on 2019-11-01]
DOI:
10.1097/FPC.0000000000000353
[Indexed for MEDLINE]

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