钠-葡萄糖协同转运蛋白 2 (SGLT2) 抑制剂与前列腺癌之间的关系仍不清楚。尽管这些抑制剂可以影响肿瘤糖酵解，但其潜在机制需要进一步探索。使用两个样本的两步MR来确定1）SGLT2抑制对前列腺癌的因果影响； 2) 1,400 种循环代谢物或代谢物比率对前列腺癌的因果影响； 3）这些循环代谢物的调节作用。 SGLT2 抑制的遗传代理被确定为 SLC5A2 基因和糖化血红蛋白水平 (HbA1c) 的变异。此外，还对 2 型糖尿病 (T2DM) 进行了阳性对照分析，以测试遗传代理的选择。表型组广泛关联研究 (PheWAS) 和 MR-PheWAS 分析用于探索 SGLT2 抑制剂潜在的可治疗疾病和不良后果。基因预测的 SGLT2 抑制（HbA1c 每减少 1 个 SD）与降低 T2DM 风险相关 [比值比 (OR) ) = 0.66 (95% CI 0.53, 0.82), P = 1.57 × 10-4];前列腺癌 [0.34 (0.23, 0.49), P = 2.21 × 10-8] 和前列腺特异性抗原 [0.26 (0.08, 0.81), P = 2.07 × 10-2]。 SGLT2抑制对前列腺癌的作用是由尿苷水平介导的，介导的比例占总作用的9.34%。在MR-PheWAS中，发现65个性状与SLGT2抑制剂相关（P < 1.78 × 10-5），其中13个与糖尿病相关。我们的研究表明，SGLT2抑制可以通过尿苷介导降低前列腺癌风险。需要更多的机制和临床研究来探索尿苷如何介导 SGLT2 抑制与前列腺癌之间的联系。版权所有 © 2024 Lin、Zhang、Wang、Cao、Zhao、Ma、Yang、Zhang 和 Yang。

The relationship between sodium-glucose cotransporter 2 (SGLT2) inhibitors and prostate cancer is still unknown. Although these inhibitors can influence tumor glycolysis, the underlying mechanism requires further exploration.A two-sample two-step MR was used to determine 1) causal effects of SGLT2 inhibition on prostate cancer; 2) causal effects of 1,400 circulating metabolites or metabolite ratios on prostate cancer; and 3) mediation effects of these circulating metabolites. Genetic proxies for SGLT2 inhibition were identified as variants in the SLC5A2 gene and glycated hemoglobin level (HbA1c). Additionally, positive control analysis on type 2 diabetes mellitus (T2DM) was conducted to test the selection of genetic proxies. Phenome Wide Association Study (PheWAS) and MR-PheWAS analysis were used to explore potential treatable diseases and adverse outcomes of SGLT2 inhibitors.Genetically predicted SGLT2 inhibition (per 1 SD decrement in HbA1c) was associated with reduced risk of T2DM [odds ratio (OR) = 0.66 (95% CI 0.53, 0.82), P = 1.57 × 10-4]; prostate cancer [0.34 (0.23, 0.49), P = 2.21 × 10-8] and prostate-specific antigen [0.26 (0.08, 0.81), P = 2.07 × 10-2]. The effect of SGLT2 inhibition on prostate cancer was mediated by uridine level, with a mediated proportion of 9.34% of the total effect. In MR-PheWAS, 65 traits were found to be associated with SLGT2 inhibitors (P < 1.78 × 10-5), and among them, 13 were related to diabetes.Our study suggested that SGLT2 inhibition could lower prostate cancer risk through uridine mediation. More mechanistic and clinical research is necessary to explore how uridine mediates the link between SGLT2 inhibition and prostate cancer.Copyright © 2024 Lin, Zhang, Wang, Cao, Zhao, Ma, Yang, Zhang and Yang.