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Hypertension susceptibility loci and blood pressure response to antihypertensives: results from the pharmacogenomic evaluation of antihypertensive responses study.

ABSTRACT: To date, 39 single nucleotide polymorphisms (SNPs) have been associated with blood pressure (BP) or hypertension in genome-wide association studies in whites. Our hypothesis is that the loci/SNPs associated with BP/hypertension are also associated with BP response to antihypertensive drugs.We assessed the association of these loci with BP response to atenolol or hydrochlorothiazide monotherapy in 768 hypertensive participants in the Pharmacogenomics Responses of Antihypertensive Responses study. Linear regression analysis was performed on whites for each SNP in an additive model adjusting for baseline BP, age, sex, and principal components for ancestry. Genetic scores were constructed to include SNPs with nominal associations, and empirical P values were determined by permutation test. Genotypes of 37 loci were obtained from Illumina 50K cardiovascular or Omni1M genome-wide association study chips. In whites, no SNPs reached Bonferroni-corrected ? of 0.0014, 6 reached nominal significance (P<0.05), and 3 were associated with atenolol BP response at P<0.01. The genetic score of the atenolol BP-lowering alleles was associated with response to atenolol (P=3.3 × 10(-6) for systolic BP; P=1.6 × 10(-6) for diastolic BP). The genetic score of the hydrochlorothiazide BP-lowering alleles was associated with response to hydrochlorothiazide (P=0.0006 for systolic BP; P=0.0003 for diastolic BP). Both risk score P values were <0.01 based on the empirical distribution from the permutation test.These findings suggest that selected signals from hypertension genome-wide association studies may predict BP response to atenolol and hydrochlorothiazide when assessed through risk scoring. Clinical Trial Registration Information- clinicaltrials.gov; Identifier: NCT00246519.

SUBMITTER: Gong Y

PROVIDER: S-EPMC3529147 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Hypertension susceptibility loci and blood pressure response to antihypertensives: results from the pharmacogenomic evaluation of antihypertensive responses study.

Gong Yan Y McDonough Caitrin W CW Wang Zhiying Z Hou Wei W Cooper-DeHoff Rhonda M RM Langaee Taimour Y TY Beitelshees Amber L AL Chapman Arlene B AB Gums John G JG Bailey Kent R KR Boerwinkle Eric E Turner Stephen T ST Johnson Julie A JA

Circulation. Cardiovascular genetics 20121019 6

<h4>Background</h4>To date, 39 single nucleotide polymorphisms (SNPs) have been associated with blood pressure (BP) or hypertension in genome-wide association studies in whites. Our hypothesis is that the loci/SNPs associated with BP/hypertension are also associated with BP response to antihypertensive drugs.<h4>Methods and results</h4>We assessed the association of these loci with BP response to atenolol or hydrochlorothiazide monotherapy in 768 hypertensive participants in the Pharmacogenomics ...[more]

PMID: 23087401

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Project description:Background Genome-wide association studies have identified >1000 genetic variants cross-sectionally associated with blood pressure variation and prevalent hypertension. These discoveries might aid the early identification of subpopulations at risk of developing hypertension or provide targets for drug development, amongst other applications. The aim of the present study was to analyze the association of blood pressure-associated variants with long-term changes (10 years) in blood pressure and also to assess their ability to predict hypertension incidence compared with traditional risk variables in a Swedish population. Methods and Results We constructed 6 genetic risk scores (GRSs) by summing the dosage of the effect allele at each locus of genetic variants previously associated with blood pressure traits (systolic blood pressure GRS (GRSSBP): 554 variants; diastolic blood pressure GRS (GRSDBP): 481 variants; mean arterial pressure GRS (GRSMAP): 20 variants; pulse pressure GRS (GRSPP): 478 variants; hypertension GRS (GRSHTN): 22 variants; combined GRS (GRScomb): 1152 variants). Each GRS was longitudinally associated with its corresponding blood pressure trait, with estimated effects per GRS SD unit of 0.50 to 1.21 mm Hg for quantitative traits and odds ratios (ORs) of 1.10 to 1.35 for hypertension incidence traits. The GRScomb was also significantly associated with hypertension incidence defined according to European guidelines (OR, 1.22 per SD; 95% CI, 1.10‒1.35) but not US guidelines (OR, 1.11 per SD; 95% CI, 0.99‒1.25) while controlling for traditional risk factors. The addition of GRScomb to a model containing traditional risk factors only marginally improved discrimination (Δarea under the ROC curve = 0.001-0.002). Conclusions GRSs based on discovered blood pressure-associated variants are associated with long-term changes in blood pressure traits and hypertension incidence, but the inclusion of genetic factors in a model composed of conventional hypertension risk factors did not yield a material increase in predictive ability.

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Hypertension susceptibility loci and blood pressure response to antihypertensives: results from the pharmacogenomic evaluation of antihypertensive responses study.

Publications

Hypertension susceptibility loci and blood pressure response to antihypertensives: results from the pharmacogenomic evaluation of antihypertensive responses study.

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