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(Hypertension. 2005;46:758.)
© 2005 American Heart Association, Inc.

Original Articles

WNK1 Kinase Polymorphism and Blood Pressure Response to a Thiazide Diuretic

Stephen T. Turner; Gary L. Schwartz; Arlene B. Chapman; Eric Boerwinkle

From the Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, Minn (G.L.S., S.T.T.); Renal Division, Emory University, Atlanta, Ga (A.B.C.); and Institute of Molecular Medicine and Human Genetics Center, University of Texas Health Sciences Center, Houston (E.B.).

Correspondence to Stephen T. Turner, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail turner.stephen{at}mayo.edu

Single nucleotide polymorphisms (SNPs) in genes encoding or influencing renal sodium transport systems were investigated as potential predictors of blood pressure (BP) response to a thiazide diuretic. A sample of 585 adults with essential hypertension (30 to 59.9 years of age; 50% blacks; 47% women) were treated with hydrochlorothiazide for 4 weeks (25 mg daily, orally) to determine office BP responses. Ambulatory BP responses were measured in a subset of 228 subjects. After adjustment for ethnicity, sex, age, and waist-to-hip ratio, 3 SNPs in WNK1 (rs2107614, rs2277869, and rs1159744), encoding a lysine-deficient protein kinase that regulates thiazide-sensitive sodium-potassium cotransport, made statistically significant contributions to predicting ambulatory BP responses, accounting for 2% to 4% of variation in systolic and diastolic responses (P<0.05). SNPs in the ß₂-adrenoceptor (rs2400707) and the epithelial sodium channel -subunit (rs5723 and rs5729) were associated with similar magnitude of variation in ambulatory systolic BP response (P=0.028) or office diastolic BP response (P<0.05), respectively. However, SNPs evaluated in the furosemide-sensitive sodium-potassium chloride cotransporter, potassium inwardly rectifying channel, chloride channel, thiazide-sensitive sodium chloride cotransporter, epithelial sodium channel ß-subunit, and the mineralocorticoid receptor were not associated with significant variation in ambulatory or office BP responses. Polymorphisms in genes regulating renal sodium transport, in particular WNK1, predict interindividual differences in antihypertensive responses to hydrochlorothiazide.

Key Words: polymorphism • genetics • diuretics • blood pressure

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