Tang Kefu, Li Binbin, Wu Xi, Wang Meng
Department of Clinical Laboratory, Prenatal Diagnosis Center, Changning Maternity and Infant Health Hospital, East China Normal University, Shanghai, 200051, China.
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
Sci Rep. 2025 Jul 23;15(1):26716. doi: 10.1038/s41598-025-12788-9.
Observational studies found that phosphodiesterase 5 (PDE5) inhibitors use is linked to both increased and decreased risk of cancer; while the causal relationship remains unclear. To clarify whether PDE5 inhibitors medication may affect the risk of cancer, 2-sample cis-Mendelian randomisation (MR) analysis was therefore performed. Uncorrelated (linkage disequilibrium [LD] r < 0.001) single-nucleotide polymorphisms (SNPs) in PDE5A gene associated (P < 5.0 × 10) with circulating levels of PDE5A protein identified from UKB-PPP were used as genetic instrument to mimic the action of PDE5 inhibition. Summary-level data for 22 types of cancer obtained from site-specific GWAS were analyzed in discovery stage (428,361 cancer cases) and then replicated in the FinnGen study (87,505 cancer cases). Inverse-variance weighted random-effects models were used as primary analysis. After multiple testing correction, genetically predicted, per-standard deviation (SD) decrease in PDE5A protein was associated with decreased risk of colorectal cancer with a pooled odds ratio (OR) of 0.80 (95% confidence interval [CI]: 0.75-0.86; P = 6.15 × 10). A significant MR association (OR = 0.48, 95% CI: 0.34-0.68; P = 4.70 × 10) with gastric cancer (GC) was also observed in combined analysis. There was little evidence to support associations between genetically proxied PDE5 inhibition and other 20 studied cancers. We found an protective effect of genetically proxied PDE5 inhibition on CRC and GC risk. Our drug target MR analyses provide genetic evidence in predicting long-term safety profiles of PDE5 inhibitors on cancer risk and highlight the potential of drug repurposing in CRC and GC.
观察性研究发现，磷酸二酯酶5（PDE5）抑制剂的使用与癌症风险的增加和降低均有关联；然而，因果关系仍不明确。因此，为了阐明PDE5抑制剂药物治疗是否会影响癌症风险，进行了两样本顺式孟德尔随机化（MR）分析。从英国生物银行精准医学项目（UKB-PPP）中确定的与PDE5A蛋白循环水平相关（P＜5.0×10⁻⁸）的PDE5A基因中的不相关（连锁不平衡[LD]r＜0.001）单核苷酸多态性（SNP）被用作遗传工具，以模拟PDE5抑制的作用。在发现阶段（428361例癌症病例）分析了从特定部位全基因组关联研究（GWAS）获得的22种癌症的汇总数据，然后在芬兰基因研究（87505例癌症病例）中进行重复验证。采用逆方差加权随机效应模型作为主要分析方法。经过多重检验校正后，遗传预测的PDE5A蛋白每标准差（SD）降低与结直肠癌风险降低相关，合并优势比（OR）为0.80（95%置信区间[CI]：0.75-0.86；P=6.15×10⁻⁶）。在合并分析中还观察到与胃癌（GC）有显著的MR关联（OR=0.48，95%CI：0.34-0.68；P=4.70×10⁻⁴）。几乎没有证据支持遗传代理的PDE5抑制与其他20种研究的癌症之间存在关联。我们发现遗传代理的PDE5抑制对结直肠癌和胃癌风险具有保护作用。我们的药物靶点MR分析为预测PDE5抑制剂对癌症风险的长期安全性提供了遗传证据，并突出了在结直肠癌和胃癌中药物重新利用的潜力。
