Epidemiology & Public Health Group, Department of Clinical & Biomedical Science, Faculty of Health & Life Sciences, University of Exeter, Exeter, UK.
Exeter Diabetes Group (ExCEED), Department of Clinical & Biomedical Science, Faculty of Health & Life Sciences, University of Exeter, Exeter, UK.
Pharmacogenomics J. 2024 Apr 17;24(3):12. doi: 10.1038/s41397-024-00333-2.
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). 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.
遗传变异与钙通道阻滞剂（CCB）治疗期间的临床结果相关，但遗传预测的临床危险因素是否会改变这些影响尚不清楚。我们分析了 32000 名接受二氢吡啶 CCB 治疗的英国生物库参与者（平均 5.9 年），包括 23 个遗传药理学变异，并计算了收缩压和舒张压、体脂肪量和其他患者特征的多基因评分。结果包括治疗中断和心力衰竭。遗传药理学变异 rs10898815-A（NUMA1）增加了停药率，在体脂肪量高的患者中最高。RYR3 变异 rs877087 T-等位基因单独使心力衰竭风险相对于非携带者略有增加（HR：1.13，p=0.02）；在体脂肪量、瘦体重和脂蛋白 A 多基因评分高的患者中，风险显著升高（HR：1.55，p=4×10）。与遗传药理学变异相比，纳入体脂和脂蛋白 A 的多基因评分可能会改善 CCB 治疗中关键临床结果（如治疗中断和心力衰竭）的风险估计。
