The Beta-Blocker Pharmacogenetic Puzzle: More Pieces of Evidence for Pharmacodynamic Candidate Variants
Recommended Citation
Luzum JA, Littleton SDR, Lopez-Medina AI, Liu B, She R, and Lanfear DE. The Beta-Blocker Pharmacogenetic Puzzle: More Pieces of Evidence for Pharmacodynamic Candidate Variants. Clin Transl Sci 2025; 18(5):e70239.
Document Type
Article
Publication Date
5-1-2025
Publication Title
Clin Transl Sci
Abstract
Previous pharmacogenetic findings for beta-blocker pharmacodynamic candidate genes (ADRB1, ADRB2, ADRA2C, GRK4, and GRK5) have been inconsistent. Therefore, the purpose of this study was to determine whether interactions of pharmacodynamic variants with beta-blocker exposure significantly associated with survival in patients with heart failure with reduced ejection (HFrEF). The 893 patients were 51% self-reported African American and 49% self-reported White race, 36% female, and 240 died (27%) over a median follow-up of 2.8 years. The primary outcome was all-cause mortality. Using Cox proportional hazards models with time-varying beta-blocker exposure and adjusted for clinical risk factors and ancestry, interactions of ADRB1 Arg389Gly, ADRB1 Ser49-Arg389Gly haplotype, ADRA2C Del(322-325), and GRK4 Ala486Val with beta-blocker exposure were significant before correction for multiple comparisons (p < 0.1), but only GRK4 Ala486Val remained significant in African Americans after correction for multiple comparisons using the adaptive Hochberg method (p = 0.022). Beta-blocker exposure only associated with a significant reduction in the risk of mortality in the African American HFrEF patients with the GRK4 Ala486/Ala486 genotype (HR = 0.44; 95% CI = 0.20-0.96; p = 0.04). In conclusion, the interaction of GRK4 Ala486Val with beta-blocker exposure significantly associated with survival in African American HFrEF patients. Larger sample sizes or meta-analyses are needed to have more statistical power to better assess beta-blocker pharmacogenetic interactions for ADRB1 Arg389Gly, ADRB1 Ser49-Arg389Gly haplotype, and ADRA2C Del(322-325) in the future.
Medical Subject Headings
Aged; Female; Humans; Male; Middle Aged; Adrenergic beta-Antagonists; Black or African American; Follow-Up Studies; G-Protein-Coupled Receptor Kinase 4; Haplotypes; Heart Failure; Pharmacogenetics; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Receptors, Adrenergic, beta-1; White
PubMed ID
40285373
Volume
18
Issue
5
First Page
70239
Last Page
70239
