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(Hypertension. 2008;52:359.)
© 2008 American Heart Association, Inc.

Original Articles

Genomic Association Analysis Suggests Chromosome 12 Locus Influencing Antihypertensive Response to Thiazide Diuretic

Stephen T. Turner; Kent R. Bailey; Brooke L. Fridley; Arlene B. Chapman; Gary L. Schwartz; High Seng Chai; Hugues Sicotte; Jean-Pierre Kocher; Andréi S. Rodin; Eric Boerwinkle

From the Division of Nephrology and Hypertension (S.T.T., G.L.S.), Department of Medicine, and Divisions of Biostatistics (K.R.B., B.L.F.) and Biomedical Informatics (H.S.C., H.S., J.-P.K.), Department of Health Sciences Research, Mayo Clinic, College of Medicine, Rochester, Minn; the Renal Division (A.B.C.), Department of Medicine, Emory University, Atlanta, Ga; and the Human Genetics Center (A.S.R., E.B.), School of Public Health, University of Texas-Houston Health Science Center.

Correspondence to Stephen T. Turner, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905. E-mail turner.stephen{at}mayo.edu

We conducted a genome-wide association study to identify novel genes influencing diastolic blood pressure (BP) response to hydrochlorothiazide, a commonly prescribed thiazide diuretic preferred for the treatment of high BP. Affymetrix GeneChip Human Mapping 100K Arrays were used to measure single nucleotide polymorphisms across the 22 autosomes in 194 non-Hispanic black subjects and 195 non-Hispanic white subjects with essential hypertension selected from opposite tertiles of the race- and sex-specific distributions of age-adjusted diastolic BP response to hydrochlorothiazide (25 mg daily, PO, for 4 weeks). The black sample consisted of 97 "good" responders (diastolic BP response [mean±SD]=–18.3±4.2 mm Hg; age=47.1±6.1 years; 51.5% women) and 97 "poor" responders (diastolic BP response=–0.18±4.3; age=47.4±6.5 years; 51.5% women). Haplotype trend regression identified a region of chromosome 12q15 in which haplotypes constructed from 3 successive single nucleotide polymorphisms (rs317689, rs315135, and rs7297610) in proximity to lysozyme (LYZ), YEATS domain containing 4 (YEATS4), and fibroblast growth receptor substrate 2 (FRS2) were significantly associated with diastolic BP response (nominal P=2.39x10^–7; Bonferroni corrected P=0.024; simulated experiment-wise P=0.040). Genotyping of 35 additional single nucleotide polymorphisms selected to "tag" linkage disequilibrium blocks in these genes provided corroboration that variation in LYZ and YEATS4 was associated with diastolic BP response in a statistically independent data set of 291 black subjects and in the sample of 294 white subjects. These results support the use of genome-wide association analyses to identify novel genes influencing antihypertensive drug responses.

Key Words: hypertension • pharmacogenetics • diuretic • blood pressure • genome

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