Calcium-channel blockers: Clinical outcome associations with reported pharmacogenetics variants in 32 000 patients.

Abstract

Pharmacogenetic variants impact dihydropyridine calcium-channel blockers (dCCBs; e.g., amlodipine) treatment efficacy, yet evidence on clinical outcomes in routine primary care is limited. Reported associations in pharmacogenomics knowledge base PharmGKB have weak supporting evidence. We aimed to estimate associations between reported pharmacogenetic variants and incident adverse events in a community-based cohort prescribed dCCB. We analysed up to 32 360 UK Biobank participants prescribed dCCB in primary care (from UK general practices, 1990-2017). We investigated 23 genetic variants. Outcomes were incident diagnosis of coronary heart disease, heart failure (HF), chronic kidney disease, oedema and switching antihypertensive medication. Participants were aged 40-79 years at first dCCB prescription. Carriers of rs877087 T allele in RYR3 had increased risk of hazard ratio (HF 1.13: 95% confidence interval 1.02 to 1.25, P= .02). Although nonsignificant after multiple testing correction, the association is consistent with prior evidence. We estimated that if rs877087 T allele could experience the same treatment effect as noncarriers, the incidence of HF in patients prescribed dCCB would reduce by 9.2% (95% confidence interval 3.1 to 15.4). In patients with a history of heart disease prior to dCCB (n =2296), rs877087 homozygotes had increased risk of new coronary heart disease or HF compared to CC variant. rs10898815 in NUMA1 and rs776746 in CYP3A5 increased likelihood of switching to an alternative antihypertensive. The remaining variants were not strongly or consistently associated with studied outcomes. Patients with common genetic variants in NUMA1, CYP3A5 and RYR3 had increased adverse clinical outcomes. Work is needed to establish whether outcomes of dCCB prescribing could be improved by prior knowledge of pharmacogenetics variants supported by clinical evidence of association with adverse events.