Epidemiology and Public Health Group, College of Medicine and Health, University of Exeter, Exeter, UK.
Department of Healthcare for Older People, Royal Devon and Exeter Hospital, Exeter, UK.
Br J Clin Pharmacol. 2023 Feb;89(2):853-864. doi: 10.1111/bcp.15541. Epub 2022 Oct 6.
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.
药物遗传学变异会影响二氢吡啶类钙通道阻滞剂（DCCB；如氨氯地平）的治疗效果，但在常规初级保健中关于临床结果的证据有限。 PharmGKB 药物遗传学知识库中报告的关联证据支持较弱。我们旨在评估在接受 DCCB 治疗的基于社区的队列中，报告的药物遗传学变异与不良事件发生之间的关联。
我们分析了英国生物库中多达 32360 名在初级保健中接受 DCCB 治疗的参与者（来自英国的普通诊所，1990-2017 年）。我们研究了 23 个遗传变异。结果是冠心病、心力衰竭（HF）、慢性肾脏病、水肿和转换抗高血压药物的新诊断。
参与者在首次服用 DCCB 时年龄在 40-79 岁之间。RYR3 中的 rs877087 T 等位基因携带者发生 HF 的风险比（HR）为 1.13：95%置信区间为 1.02 至 1.25，P=0.02）。尽管经过多次测试校正后无统计学意义，但该关联与先前的证据一致。我们估计，如果 rs877087 T 等位基因能经历与非携带者相同的治疗效果，那么接受 DCCB 治疗的患者 HF 的发生率将降低 9.2%（95%置信区间为 3.1 至 15.4）。在 DCCB 治疗前有心脏病史的患者（n=2296）中，与 CC 变异相比，rs877087 纯合子发生新发冠心病或 HF 的风险增加。NUMA1 中的 rs10898815 和 CYP3A5 中的 rs776746 增加了转换为替代抗高血压药物的可能性。其余变异与研究结果无强关联或不一致。
NUMA1、CYP3A5 和 RYR3 中的常见遗传变异患者发生不良临床结局的风险增加。需要开展工作，以确定在与不良事件相关的临床证据支持下，预先了解药物遗传学变异是否可以改善 DCCB 处方的结果。
