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Beta-1-adrenoceptor genetic variants and ethnicity independently affect response to beta-blockade.

ABSTRACT: Black patients may be less responsive to beta-blockers than whites. Genetic variants in the beta1-adrenergic receptor (beta1-AR) associated with lesser response to beta-blockers are more common in blacks than in whites. The purpose of this study was to determine whether ethnic differences in response to beta-blockade can be explained by differing distributions of functional genetic variants in the beta1-AR.We measured sensitivity to beta-blockade by the attenuation of exercise-induced tachycardia in 165 patients (92 whites), who performed a graded bicycle exercise test before and 2.5 h after oral atenolol (25 mg). We determined heart rate at rest and at three exercise levels from continuous ECG recordings and calculated the area under the curve. We also measured plasma atenolol concentrations and determined genotypes for variants of the beta1-AR (Ser49Gly, Arg389Gly) and alpha2C-AR (del322-325). The effects of ethnicity, genotype, and other covariates on the heart rate reduction after atenolol were estimated in multiple regression analyses.Atenolol resulted in a greater reduction in exercise heart rate in whites than in blacks (P=0.006). beta1-AR Arg389 (P=0.003), but not the alpha2C-AR 322-325 insertion allele (P=0.31), was independently associated with a greater reduction in heart rate area under the curve. Ethnic differences in sensitivity to atenolol remained significant (P=0.006) after adjustment for beta1-AR and alpha2C-AR genotypes.Ethnic differences in sensitivity to the beta1-blocker atenolol persist even after accounting for different distributions of functional genetic beta1-AR variants, suggesting that additional, as yet unidentified factors contribute to such ethnic differences.

SUBMITTER: Kurnik D

PROVIDER: S-EPMC2757009 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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Beta-1-adrenoceptor genetic variants and ethnicity independently affect response to beta-blockade.

Kurnik Daniel D Li Chun C Sofowora Gbenga G GG Friedman Eitan A EA Muszkat Mordechai M Xie Hong-Guang HG Harris Paul A PA Williams Scott M SM Nair Usha B UB Wood Alastair J J AJ Stein C Michael CM

Pharmacogenetics and genomics 20081001 10

<h4>Objectives</h4>Black patients may be less responsive to beta-blockers than whites. Genetic variants in the beta1-adrenergic receptor (beta1-AR) associated with lesser response to beta-blockers are more common in blacks than in whites. The purpose of this study was to determine whether ethnic differences in response to beta-blockade can be explained by differing distributions of functional genetic variants in the beta1-AR.<h4>Methods</h4>We measured sensitivity to beta-blockade by the attenua ...[more]

PMID: 18794726

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Project description:Anabolic treatment options for osteoporosis remain limited. One approach to discovering novel anabolic drug targets is to identify genetic causes of extreme high bone mass (HBM). We investigated a pedigree with unexplained HBM within the UK HBM study, a national cohort of probands with HBM and their relatives. Whole exome sequencing (WES) in a family with HBM identified a rare heterozygous missense variant (NM_004482.4:c.1657C > T, p.Arg553Trp) in GALNT3, segregating appropriately. Interrogation of data from the UK HBM study and the Anglo-Australasian Osteoporosis Genetics Consortium (AOGC) revealed an unrelated individual with HBM with another rare heterozygous variant (NM_004482.4:c.831 T > A, p.Asp277Glu) within the same gene. In silico protein modeling predicted that p.Arg553Trp would disrupt salt-bridge interactions, causing instability of GALNT3, and that p.Asp277Glu would disrupt manganese binding and consequently GALNT3 catalytic function. Bi-allelic loss-of-function GALNT3 mutations alter FGF23 metabolism, resulting in hyperphosphatemia and causing familial tumoral calcinosis (FTC). However, bone mineral density (BMD) in FTC cases, when reported, has been either normal or low. Common variants in the GALNT3 locus show genome-wide significant associations with lumbar, femoral neck, and total body BMD. However, no significant associations with BMD are observed at loci coding for FGF23, its receptor FGFR1, or coreceptor klotho. Mendelian randomization analysis, using expression quantitative trait loci (eQTL) data from primary human osteoblasts and genome-wide association studies data from UK Biobank, suggested increased expression of GALNT3 reduces total body, lumbar spine, and femoral neck BMD but has no effect on phosphate concentrations. In conclusion, rare heterozygous loss-of-function variants in GALNT3 may cause HBM without altering phosphate concentration. These findings suggest that GALNT3 may affect BMD through pathways other than FGF23 regulation, the identification of which may yield novel anabolic drug targets for osteoporosis. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Dataset Information

Beta-1-adrenoceptor genetic variants and ethnicity independently affect response to beta-blockade.

Publications

Beta-1-adrenoceptor genetic variants and ethnicity independently affect response to beta-blockade.

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