Genomic association analysis suggests chromosome 12 locus influencing antihypertensive response to thiazide diuretic

Abstract

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=2.39 x 10(-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.

Figure 1

Plots of P values from haplotype trend logistic regression analysis in the sample of 194 black subjects with essential hypertension, consisting of 97 good responders and 97 poor responders to hydrochlorothiazide. The -log₁₀ P values are plotted as a function of location across the 22 autosomes (A, top), across chromosome 12 (B, middle), and across a region of chromosome 12q15 designated by reference sequence numbers of the SNPs genotyped on the Affymetrix 100K Human Mapping Array Set (C, bottom). In the bottom panel, separate horizontal lines depict the -log₁₀ P value of each 3-SNP haplotype window above the component SNPs, and separate dots depict the -log₁₀ P value of each SNP.

Figure 2

Three genes in the chromosome 12q15 region: LYZ, YEATS4, and FRS2. The top portion depicts location and lengths of the genes, represented by heavy bars, in relationship to each other and to the 3 SNPs from the Affymetrix 100K Human Mapping Array Set, used to compose the 3-SNP haplotype significantly associated with diastolic blood pressure response category in black subjects (see Figure 1). The middle portion depicts the arrangement of introns and exons within each gene and the locations of 35 tag SNPs genotyped for fine mapping of the region. The bottom portion depicts pairwise linkage disequilibrium between the 35 tag SNPs.