抗高血压药物最近被报道有普通癌症的致癌作用，但是这些药物是否会影响肝细胞癌（HCC）的风险仍然不清楚。本研究采用药物靶标门捷连随机化方法，检测12种抗高血压药物类在欧洲和东亚人群中对HCC风险的长期影响。以收缩压（SBP）为代理抗高血压药物，我们利用与药物靶标基因附近或内部相关的遗传变异与SBP相关。在初步分析中，将与冠状动脉疾病风险降低相关的遗传代理药物包括进来。SBP和HCC的遗传总结统计数从公开的欧洲和东亚大型基因组关联研究中获取。药物靶标基因的表达定量性状位点（eQTLs）用于代理敏感性分析中的药物。在欧洲和东亚人群中，基因代理噻嗪类和相关利尿剂与HCC风险降低相关（每降低1mmHg的SBP，OR [95％CI]：分别为0.79 [0.73,0.86]和0.60 [0.45,0.82]，P <0.001和P = 0.001）。在欧洲人群中，基因代理β-肾上腺素受体阻滞剂（BBs）与HCC风险明显相关（1.46 [1.12,1.91]; P = 0.004）。这些发现在deCODE基因研究中得到重复，并且当使用eQTLs来代替抗高血压药物时保持一致。我们的发现表明，噻嗪类和相关利尿剂可能会降低欧洲人和东亚人的HCC风险，而BBs可能会增加欧洲人的HCC风险。进一步的研究有必要探讨重新用途或重新定位抗高血压药物进行HCC预防的潜力。本文章受版权保护。版权所有。

Antihypertensive drugs were recently reported to have an oncogenic role in common cancer, however, whether these drugs would affect the risk of hepatocellular carcinoma (HCC) remains unclear.A drug-target Mendelian randomization method was adopted to examine the long-term effect of 12 antihypertensive drugs classes on the risk of HCC in Europeans and East Asians. To proxy antihypertensive drugs, we leveraged genetic variants located near or within drug target genes that were associated with systolic blood pressure (SBP). Genetically proxied drugs associated with reduced risk of coronary artery disease were included in primary analysis. Genetic summary statistics of SBP and HCC were derived from publicly available large-scale genome-wide association studies in Europeans and East Asians, respectively. Expression quantitative trait loci (eQTLs) of drugs target genes were used to proxy drugs in a sensitivity analysis.Genetically proxied thiazides and related diuretics were associated with decreased risk of HCC in both Europeans (OR [95% CI]:0.79 [0.73,0.86] per 1mmHg reduction in SBP; P<0.001) and East Asians (0.60 [0.45,0.82]; P=0.001). Genetically proxied beta-adrenoceptor blockers (BBs) were strongly associated with increased risk of HCC in Europeans (1.46 [1.12,1.91]; P=0.004). These findings were replicated in deCODE genetics study and remained consistent when using eQTLs to proxy antihypertensive drugs.Our findings suggested that thiazides diuretics may lower the risk of HCC in both Europeans and East Asians, while BBs may increase the risk of HCC specifically in Europeans. Further studies are warranted to explore the potential of repurposing or retargeting antihypertensive drugs for HCC prevention.This article is protected by copyright. All rights reserved.