July 1, 2008Open Access
View Full PaperGenomic Association Analysis Suggests Chromosome 12 Locus Influencing Antihypertensive Response to Thiazide Diuretic
Structured PICO
Do specific genetic loci influence the diastolic blood pressure response to hydrochlorothiazide in patients with essential hypertension?
P
Population
194 non-Hispanic black and 195 non-Hispanic white subjects with essential hypertension, selected from opposite tertiles of diastolic BP response to hydrochlorothiazide. Corroboration cohorts included 291 black subjects and 294 white subjects.
I
Intervention
Hydrochlorothiazide 25 mg daily, PO, for 4 weeks
C
Comparator
Good responders vs poor responders (opposite tertiles of diastolic BP response)
O
Outcome
Diastolic blood pressure response to hydrochlorothiazide and its association with single nucleotide polymorphismssurrogate
Genetic variation in chromosome 12q15, specifically near LYZ and YEATS4, is associated with the diastolic blood pressure response to hydrochlorothiazide in patients with essential hypertension.
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.