Association between antihypertensive drugs and hepatocellular carcinoma: A trans‐ancestry and drug‐target Mendelian randomization study

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 1 mmHg 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.