Published Online
on April 28, 2003

A more recent version of this article appeared on June 1, 2003

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Submitted on November 12, 2002
Revised on December 31, 2002

Genetic Variants of WNK4 in Whites and African Americans With Hypertension

Porat M. Erlich; Jing Cui; Irmarie Chazaro; Lindsay A. Farrer; Clinton T. Baldwin; Haralambos Gavras; and Anita L. DeStefano^*

From the Departments of Medicine (Genetics Program [P.M.E., L.A.F.] and Hypertension Section [J.C., I.C., H.G.]) and Neurology (L.A.F., A.L.D.) and the Center for Human Genetics (C.T.B.), Boston University School of Medicine, and the Departments of Epidemiology (L.A.F.) and Biostatistics (I.C., L.A.F., A.L.D.), Boston University School of Public Health, Boston, Mass.

^* To whom correspondence should be addressed. E-mail: adestef{at}bu.edu.

Abstract--Human chromosome 17q has been implicated to contain a gene that influences hypertension susceptibility. This region contains the WNK4 gene that causes the mendelian disorder pseudohypoaldosteronism type II, characterized by high potassium levels and hypertension. The goal of this study was to identify genetic variants in all exons of WNK4 in hypertensive individuals and to examine the association of these variants with essential hypertension. Single-nucleotide polymorphims (SNPs) were identified by sequencing the entire coding region in 32 whites and 32 African Americans with hypertension. A single SNP in whites and 8 SNPs in African Americans were genotyped in a larger cohort of whites (165 hypertensives; 91 normotensives) and African Americans (120 hypertensives; 98 normotensives). The frequency of the rare allele differed significantly between hypertensive whites (13.0%) and normotensive whites (7.1%, P=0.040) for the single intronic SNP (bp 1 156 666). This difference remained significant after adjusting for body mass index and sex (P=0.035). Genotypic frequencies differed significantly between hypertensive and normotensive individuals when a dominant model either with (P=0.027) or without (P=0.028) covariate adjustment was assumed. The odds ratio for hypertension was 2.28 for AA or AG individuals vs those with the GG genotype (95% confidence interval, 1.09 to 4.75). No significant differences in allelic or genotypic frequencies were observed in African Americans for any SNPs. The finding in whites is consistent with the hypothesis that polymorphisms in WNK4 influence the risk of hypertension. However, because the associated SNP does not appear to be a functional variant and the limitations of case/control association studies, confirmation of these results in additional cohorts is warranted.

Key words: gene expression • hypertension, essential • genetics • polymorphism

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