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G-protein-coupled receptor kinase 4 polymorphisms and blood pressure response to metoprolol among African Americans: sex-specificity and interactions.

ABSTRACT: African Americans have a disproportionate burden of hypertension and comorbid disease. Pharmacogenetic markers of blood pressure response have yet to be defined clearly. This study explores the association between G-protein-coupled receptor kinase type 4 (GRK4) variants and blood pressure response to metoprolol among African Americans with early hypertensive nephrosclerosis.Participants from the African American Study of Kidney Disease and Hypertension (AASK) trial were genotyped at three GRK4 polymorphisms: R65L, A142V, and A486V. A Cox proportional hazards model, stratified by gender, was used to determine the relationship between GRK4 variants and time to reach a mean arterial pressure (MAP) of 107 mm Hg, adjusted for other predictors of blood pressure response. Potential interactions between the three polymorphisms were explored by analyzing the effects of gene haplotypes and by stratifying the analysis by neighboring sites.The hazard ratio with 95% confidence interval by A142V among men randomized to a usual MAP (102-107 mm Hg) was 1.54 (1.11-2.44; P = 0.0009). The hazard ratio by A142V with R65/L65 or L65/L65 was 2.14 (1.35-3.39; P = 0.001). Haplotype analyses were consistent but inconclusive. There was no association between A142V and blood pressure response among women.Results suggest a sex-specific relationship between GRK4 A142V and blood pressure response among African-American men with early hypertensive nephrosclerosis. Men with a GRK4 A142 were less responsive to metoprolol if they had a GRK4 L65 variant. The effect of GRK4 variants and blood pressure response to metoprolol should be studied in larger clinical trials.

SUBMITTER: Bhatnagar V

PROVIDER: S-EPMC2715837 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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G-protein-coupled receptor kinase 4 polymorphisms and blood pressure response to metoprolol among African Americans: sex-specificity and interactions.

Bhatnagar Vibha V O'Connor Daniel T DT Brophy Victoria H VH Schork Nicholas J NJ Richard Erin E Salem Rany M RM Nievergelt Caroline M CM Bakris George L GL Middleton John P JP Norris Keith C KC Wright Jackson J Hiremath Leena L Contreras Gabriel G Appel Lawrence J LJ Lipkowitz Michael S MS

American journal of hypertension 20090101 3

<h4>Background</h4>African Americans have a disproportionate burden of hypertension and comorbid disease. Pharmacogenetic markers of blood pressure response have yet to be defined clearly. This study explores the association between G-protein-coupled receptor kinase type 4 (GRK4) variants and blood pressure response to metoprolol among African Americans with early hypertensive nephrosclerosis.<h4>Methods</h4>Participants from the African American Study of Kidney Disease and Hypertension (AASK) t ...[more]

PMID: 19119263

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Project description:BACKGROUND:African Americans (AA) are disproportionately affected by hypertension-related health disparities. Apolipoprotein L1 (APOL1) risk variants are associated with kidney disease in hypertensive AAs. OBJECTIVES:This study assessed the APOL1 risk alleles' association with blood pressure traits in AAs. METHODS:The discovery cohort included 5,204 AA participants from Mount Sinai's BioMe biobank. Replication cohorts included additional BioMe (n = 1,623), Vanderbilt BioVU (n = 1,809), and Northwestern NUgene (n = 567) AA biobank participants. Single nucleotide polymorphisms determining APOL1 G1 and G2 risk alleles were genotyped in BioMe and imputed in BioVU/NUgene participants. APOL1 risk alleles' association with blood pressure-related traits was tested in the discovery cohort, a meta-analysis of replication cohorts, and a combined meta-analysis under recessive and additive models after adjusting for age, sex, body mass index, and estimated glomerular filtration rate. RESULTS:There were 14% to 16% of APOL1 variant allele homozygotes (2 copies of G1/G2) across cohorts. APOL1 risk alleles were associated under an additive model with systolic blood pressure (SBP) and age at diagnosis of hypertension, which was 2 to 5 years younger in the APOL1 variant allele homozygotes (Cox proportional hazards analysis, p value for combined meta-analysis [pcom] = 1.9 × 10-5). APOL1 risk alleles were associated with overall SBP (pcom = 7.0 × 10-8) and diastolic blood pressure (pcom = 2.8 × 10-4). After adjustment for all covariates, those in the 20- to 29-year age range showed an increase in SBP of 0.94 ± 0.44 mm Hg (pcom = 0.01) per risk variant copy. APOL1-associated estimated glomerular filtration rate decline was observed starting a decade later in life in the 30- to 39-year age range. CONCLUSIONS:APOL1 risk alleles are associated with higher SBP and earlier hypertension diagnoses in young AAs; this relationship appears to follow an additive model.

Dataset Information

G-protein-coupled receptor kinase 4 polymorphisms and blood pressure response to metoprolol among African Americans: sex-specificity and interactions.

Publications

G-protein-coupled receptor kinase 4 polymorphisms and blood pressure response to metoprolol among African Americans: sex-specificity and interactions.

Similar Datasets

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