Yao Zehui, Qin Dailei, Cao Jianzhong, Gao Chun, Xi Pu, Li Shengping, Wei Ran
Department of Pancreatobiliary Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
BMC Cancer. 2025 Mar 14;25(1):476. doi: 10.1186/s12885-025-13824-7.
Conventional epidemiological studies have reported inconsistent results regarding the potential adverse effects of long-term use of antihypertensive drugs on cancer risk. Nevertheless, evidence of their impact on pancreatic cancer risk is limited and deserves further elucidation.
We selected genetic variants from the genes encoding the target proteins (angiotensin-converting enzyme, beta-1 adrenergic receptor, and solute carrier family 12 member 3) of the examined antihypertensive drugs as instruments based on expression quantitative trait loci (eQTL) studies. Genetic summary statistics of blood pressure and pancreatic cancer were obtained from genome-wide association studies (GWASs) in Europeans and East Asians. Inverse-variance weight and MR-Egger methods were employed to estimate the effect of genetic variations in the drug targets on pancreatic cancer risk, and meta-analysis was used to combine the results from 3 independent datasets. Positive control analysis was conducted by using Wald ratio test to justify the genetic instruments of the drug by demonstrating the expected effect on the blood pressure which has an established causal relationship with the drug of interest.
Genetically proxied ACEIs were associated with lower pancreatic risk (OR = 0.506, 95% CI: 0.284-0.901, P = 0.021; OR = 0.265, 95% CI: 0.094-0.751, P = 0.012; OR = 0.236, 95% CI:0.078-0.712, P = 0.010, respectively) in 3 independent datasets and the combined results were validated in a meta-analysis using a random effects model (OR = 0.37, 95% CI: 0.22-0.64, P < 0.01) or fixed effects model (OR = 0.39, 95% CI: 0.25-0.62, P < 0.01). Other drug targets did not show consistent significant associations with pancreatic cancer risk in all 3 independent datasets.
Our study indicated that genetically proxied therapeutic inhibition of ACE was associated with a lower risk of pancreatic cancer, which may have translational potential in clinical practice. However, further long-term randomized controlled trials and observational studies are needed to clarify the effect of ACEIs on the pancreatic cancer risk.
传统流行病学研究报告了长期使用抗高血压药物对癌症风险的潜在不良影响，结果并不一致。然而，其对胰腺癌风险影响的证据有限，值得进一步阐明。
基于表达数量性状位点（eQTL）研究，我们从所检测的抗高血压药物的靶蛋白（血管紧张素转换酶、β-1肾上腺素能受体和溶质载体家族12成员3）编码基因中选择遗传变异作为工具变量。血压和胰腺癌的遗传汇总统计数据来自欧洲人和东亚人的全基因组关联研究（GWAS）。采用逆方差加权法和MR-Egger方法估计药物靶点基因变异对胰腺癌风险的影响，并使用荟萃分析合并3个独立数据集的结果。通过Wald比率检验进行阳性对照分析，通过证明对血压的预期影响来验证药物的遗传工具变量，血压与所关注药物具有既定的因果关系。
在3个独立数据集中，遗传代理的血管紧张素转换酶抑制剂（ACEIs）与较低的胰腺癌风险相关（OR分别为0.506，95%CI：0.284 - 0.901，P = 0.021；OR为0.265，95%CI：0.094 - 0.751，P = 0.012；OR为0.236，95%CI：0.078 - 0.712，P = 0.010），使用随机效应模型（OR = 0.37，95%CI：0.22 - 0.64，P < 0.01）或固定效应模型（OR = 0.39，95%CI：0.25 - 0.62，P < 0.01）的荟萃分析验证了合并结果。在所有3个独立数据集中，其他药物靶点与胰腺癌风险未显示一致的显著关联。
我们的研究表明，遗传代理的ACE治疗性抑制与较低的胰腺癌风险相关，这在临床实践中可能具有转化潜力。然而，需要进一步的长期随机对照试验和观察性研究来阐明ACEIs对胰腺癌风险的影响。
