biostudies-literatureTurkmen DClaude D. Pepper Older American Independence Centers (OAIC) programExpanding Excellence in EnglandAlzheimer's SocietyMedical Research CouncilUniversity of ExeterNational Institute for Health Research (NIHR)Alzheimer's SocietyAlzheimer's SocietyUniversity of Exeter Medical Schoolthe Ministry of National Education, Republic of Turkey12https://www.ebi.ac.uk/biostudies/studies/S-EPMC11023935biostudies-literatureUnknown24(3)Pharmacogenetic variants are associated with clinical outcomes during Calcium Channel Blocker (CCB) treatment, yet whether the effects are modified by genetically predicted clinical risk factors is unknown. We analyzed 32,000 UK Biobank participants treated with dihydropiridine CCBs (mean 5.9 years), including 23 pharmacogenetic variants, and calculated polygenic scores for systolic and diastolic blood pressures, body fat mass, and other patient characteristics. Outcomes included treatment discontinuation and heart failure. Pharmacogenetic variant rs10898815-A (NUMA1) increased discontinuation rates, highest in those with high polygenic scores for fat mass. The RYR3 variant rs877087 T-allele alone modestly increased heart failure risks versus non-carriers (HR:1.13, p = 0.02); in patients with high polygenic scores for fat mass, lean mass, and lipoprotein A, risks were substantially elevated (HR:1.55, p = 4 × 10^-5). Incorporating polygenic scores for adiposity and lipoprotein A may improve risk estimates of key clinical outcomes in CCB treatment such as treatment discontinuation and heart failure, compared to pharmacogenetic variants alone.The pharmacogenomics journalPolygenic scores for cardiovascular risk factors improve estimation of clinical outcomes in CCB treatment compared to pharmacogenetic variants alone.PMC11023935grant: 338 (AS-JF-16b-007)007338NIHR301445MR/X011372/1Pilling LCDelgado JMelzer DTurkmen DKuo CLMasoli JAHBowden JfalsePolygenic scores for cardiovascular risk factors improve estimation of clinical outcomes in CCB treatment compared to pharmacogenetic variants alone.Pharmacogenetic variants are associated with clinical outcomes during Calcium Channel Blocker (CCB) treatment, yet whether the effects are modified by genetically predicted clinical risk factors is unknown. We analyzed 32,000 UK Biobank participants treated with dihydropiridine CCBs (mean 5.9 years), including 23 pharmacogenetic variants, and calculated polygenic scores for systolic and diastolic blood pressures, body fat mass, and other patient characteristics. Outcomes included treatment discontinuation and heart failure. Pharmacogenetic variant rs10898815-A (NUMA1) increased discontinuation rates, highest in those with high polygenic scores for fat mass. The RYR3 variant rs877087 T-allele alone modestly increased heart failure risks versus non-carriers (HR:1.13, p = 0.02); in patients with high polygenic scores for fat mass, lean mass, and lipoprotein A, risks were substantially elevated (HR:1.55, p = 4 × 10^-5). Incorporating polygenic scores for adiposity and lipoprotein A may improve risk estimates of key clinical outcomes in CCB treatment such as treatment discontinuation and heart failure, compared to pharmacogenetic variants alone.2024-01-01T00:00:00Z2024 Apr2026-05-29T17:44:57.405Z2025-04-20T02:15:24.934ZS-EPMC110239353863227610.1038/s41397-024-00333-2