肠道菌群及其代谢通路与胰腺癌的因果关系-两样本孟德尔随机化分析

Two⁃sample Mendelian randomization:Gut microbiota and its metabolic pathways and pancreatic cancer

目的:利用两样本孟德尔随机化分析探讨肠道菌群及其代谢通路与胰腺癌的因果关系。方法:采用公共数据库GWAS Catalog获取The Dutch Microbiome Project研究的肠道菌群及其代谢通路的GWAS数据,及芬兰数据库的胰腺癌GWAS数据,依据P<1×10^(-5),F>10提取与肠道菌群相对丰度和细菌通路富集度显著相关的独立遗传位点作为工具变量。分析方法主要采用逆方差加权法,根据效应值优势比OR及95%置信区间CI评估结果。在敏感性分析中,采用了留一法、Cochran Q检验、MR-Egger法以及MR-PRESSO法等多种方法,以确保分析结果的稳定性和可靠性。结果:普氏菌Prevotella copri和嗜热链球菌Streptococcus thermophilus的丰度与胰腺癌发生的OR及95%CI分别为1.34(1.06~1.68)、1.28(1.01~1.63);尿素循环、大肠杆菌不饱和脂肪酸合成、N10-甲酰四氢叶酸合成三条代谢通路的富集度与胰腺癌发生的OR及95%CI分别为0.71(0.51~0.99)、0.73(0.57~0.93)、0.72(0.54~0.96);L-蛋氨酸合成、尿囊素降解为甘氧酸Ⅲ、泛醌醇-8合成三条代谢通路的富集度与胰腺癌发生的OR及95%CI分别为1.40(1.02~1.91)、1.18(1.00~1.38)、1.42(1.15~1.76)。此外,通过留一法的验证,确认结果稳定,并未发现对研究结果产生强烈影响的特定工具变量。此外,敏感性分析排除了异质性和基因水平多效性对因果效应估计的潜在干扰。结论:普氏菌和嗜热链球菌与胰腺癌的发生有潜在的因果关系;尿素循环、大肠杆菌不饱和脂肪酸合成、N10-甲酰四氢叶酸合成三条代谢通路的富集可降低胰腺癌的发生风险,L-蛋氨酸合成、尿囊素降解为甘氧酸Ⅲ、泛醌醇-8合成三条代谢通路的富集可增加胰腺癌发生风险。

Objective:To investigate the causal relationship between gut microbiota and its metabolic pathways and pancreatic cancer by performing two-sample Mendelian randomization analysis.Methods:GWAS data of gut microbiota and its metabolic pathways was obtained from The Dutch Microbiome Project and pancreatic cancer GWAS comes from The FinnGen Biobank.Independent genetic loci significantly correlated with the relative abundance of gut microbiota and the enrichment of bacterial path‑ways were extracted as instrumental variables according to P<1×10^(-5),and F>10.We performed the inverse variance weighting method for the main analysis,and the effect size was determined by the OR and 95%CI.In the sensitivity analysis,multiple methods such as the leave-one-out method,Cochran's Q test,MR-Egger method,and MR-PRESSO were employed to ensure the stability and reliability of the analysis results.Results:The OR and 95%CI of Prevotella copri and Streptococcus thermophilus were 1.34(1.06‑1.68)and 1.28(1.01‑1.63),respectively.The OR and 95%CI of the three metabolic pathways of urea cycle,unsaturated fatty acid synthesis and N10-formyltetrahydrofolate synthesis were 0.71(0.51‑0.99),0.73(0.57‑0.93)and 0.72(0.54‑0.96),respectively.The OR and 95%CI of L-methionine synthesis,allantoin degradation to glyoxylⅢand ubiquinol 8 synthesis were 1.40(1.02‑1.91),1.18(1.00‑1.38)and 1.42(1.15‑1.76),respectively.The leave-one-out analysis showed stable results,with no instrumental variables that had a strong influence on the results.In addition,the sensitivity analysis also excluded the influence of heterogeneity and horizontal gene pleiotropy on the estimation of causal effect.Conclusion:Prevotella copri and Streptococcus thermophilus have potential causal relationship with pancreatic cancer.Enrichment of three metabolic pathways of urea cycle,Escoli unsaturated fatty acid synthesis and N10-formyltetrahydrofolate synthesis can reduce the risk of pancreatic cancer,while enrichment of three metabolic pathways of L-methionine synthesis,allantoin degradation to glyoxylⅢand panquinol-8 synthesis can increase the risk of pancreatic cancer.