biostudies-literatureUnknown18(5)Luzum JAPrevious 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.Clinical and translational sciencee70239https://www.ebi.ac.uk/biostudies/studies/S-EPMC12031879biostudies-literatureThe Beta-Blocker Pharmacogenetic Puzzle: More Pieces of Evidence for Pharmacodynamic Candidate Variants.PMC12031879She RLopez-Medina AILittleton SDRLanfear DELuzum JALiu BfalseThe Beta-Blocker Pharmacogenetic Puzzle: More Pieces of Evidence for Pharmacodynamic Candidate Variants.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.2025-01-01T00:00:00Z2025 May2026-06-02T04:12:34.942Z2025-07-07T03:08:19.156ZS-EPMC120318794028537310.1111/cts.70239