Genetic substudies of randomized controlled trials demonstrate that high coronary heart disease (CHD) polygenic risk score modifies statin CHD relative risk reduction; it is unknown if the association extends to statin users undergoing routine care. We sought to determine how statin effectiveness is modified by CHD polygenic risk score in a real-world cohort of participants without previous myocardial infarction. We determined CHD polygenic risk scores in participants of the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. Covariate-adjusted Cox regression models were used to compare the risk of cardiovascular outcomes between statin users and matched nonusers. Statin effectiveness on incident myocardial infarction showed no gradient with increasing 10-year Pooled Cohort Equations atherosclerotic cardiovascular disease (ASCVD) risk across low, borderline, intermediate, and high ASCVD risk score groups. In contrast, statin effectiveness by polygenic risk was largest in the high polygenic risk score group (hazard ratio (HR) 0.41, 95% confidence interval (CI), 0.31–0.53; P = 1.5E-11), intermediate in the intermediate polygenic risk score group (HR 0.56, 95% CI, 0.47–0.66; P = 8.4E-12), and smallest in the low polygenic risk score group (HR 0.67, 95% CI, 0.47–0.97; P = 0.03; P for high vs. low = 0.01). ASCVD risk and statin low-density lipoprotein cholesterol (LDL-C) lowering did not differ across polygenic risk score groups. In patients undergoing routine care, CHD polygenic risk modified statin relative risk reduction of incident myocardial infarction independent of LDL-C lowering. Our findings extend prior work by identifying a subset (i.e., self-identified White individuals with low CHD polygenic risk scores) with attenuated clinical benefit from statins.

中文翻译：

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真实世界人群心肌梗死一级预防的多基因风险评分和他汀类药物相对风险降低

随机对照试验的遗传子研究表明，高冠心病 (CHD) 多基因风险评分可改变他汀类药物 CHD 相对风险降低；尚不清楚该关联是否扩展到接受常规护理的他汀类药物使用者。我们试图确定在没有既往心肌梗死的真实世界参与者队列中，他汀类药物的有效性如何被 CHD 多基因风险评分所改变。我们确定了成人健康和衰老遗传流行病学研究 (GERA) 队列参与者的冠心病多基因风险评分。协变量调整的 Cox 回归模型用于比较他汀类药物使用者和匹配的非使用者之间心血管结局的风险。他汀类药物对心肌梗死事件的有效性显示，在低、临界、中等和高 ASCVD 风险评分组中，随着 10 年合并队列方程动脉粥样硬化心血管疾病 (ASCVD) 风险的增加，他汀类药物的有效性没有梯度。相比之下，多基因风险的他汀类药物有效性在高多基因风险评分组中最高（风险比 (HR) 0.41，95% 置信区间 (CI)，0.31–0.53；P  = 1.5E-11），在中间多基因风险评分组中居中（HR 0.56, 95% CI, 0.47–0.66；P  = 8.4E-12），在低多基因风险评分组中最小（HR 0.67, 95 % CI，0.47–0.97；P  = 0.03；高与低的P = 0.01）。ASCVD 风险和他汀类药物低密度脂蛋白胆固醇 (LDL-C) 降低在多基因风险评分组之间没有差异。在接受常规护理的患者中，CHD 多基因风险改变了他汀类药物相对降低心肌梗死事件的相对风险，而与 LDL-C 的降低无关。我们的研究结果扩展了之前的工作，确定了他汀类药物临床获益减弱的子集（即自我认定的具有低 CHD 多基因风险评分的白人个体）。