Abstract

To identify genes influencing blood pressure response to an angiotensin II receptor blocker, single nucleotide polymorphisms identified by genome-wide association analysis of the response to candesartan were validated by opposite direction associations with the response to a thiazide diuretic, hydrochlorothiazide. We sampled 198 white and 193 blacks with primary hypertension from opposite tertiles of the race-sex-specific distributions of age-adjusted diastolic blood pressure response to candesartan. There were 285 polymorphisms associated with the response to candesartan at P<10(-4) in whites. A total of 273 of the 285 polymorphisms, which were available for analysis in a separate sample of 196 whites, validated for opposite direction associations with the response to hydrochlorothiazide (Fisher χ(2) 1-sided P=0.02). Among the 273 polymorphisms, those in the chromosome 11q21 region were the most significantly associated with response to candesartan in whites (eg, rs11020821 near FUT4, P=8.98 × 10(-7)), had the strongest opposite direction associations with response to hydrochlorothiazide (eg, rs3758785 in GPR83, P=7.10 × 10(-3)), and had the same direction associations with response to candesartan in the 193 blacks (eg, rs16924603 near FUT4, P=1.52 × 10(-2)). Also notable among the 273 polymorphisms was rs11649420 on chromosome 16 in the amiloride-sensitive sodium channel subunit SCNN1G involved in mediating renal sodium reabsorption and maintaining blood pressure when the renin-angiotensin system is inhibited by candesartan. These results support the use of genomewide association analyses to identify novel genes predictive of opposite direction associations with blood pressure responses to inhibitors of the renin-angiotensin and renal sodium transport systems.

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Publisher Full Text

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Authors

Turner ST, Bailey KR, Schwartz GL, Chapman AB, Chai HS, Boerwinkle E

Institution

Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, College of Medicine, Rochester, MN 55905, USA. turner.stephen@mayo.edu

Source

Hypertension 59:6 2012 Jun pg 1204-11

MeSH

Adult
African Americans
Angiotensin II Type 1 Receptor Blockers
Benzimidazoles
Blood Pressure
Case-Control Studies
Chi-Square Distribution
Chromosomes, Human, Pair 11
Chromosomes, Human, Pair 16
Diuretics
Drug Administration Schedule
Epithelial Sodium Channel
European Continental Ancestry Group
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Humans
Hydrochlorothiazide
Hypertension
Male
Middle Aged
Polymorphism, Single Nucleotide
Receptors, G-Protein-Coupled
Renin-Angiotensin System
Tetrazoles

Pub Type(s)

Clinical Trial
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22566498