孟德尔随机化探讨三甲胺N-氧化物及其前体与静脉血栓栓塞的因果关系

Mendelian Randomization Exploring the Causality of Trimethylamine N-oxide and Its Precursors with Venous Thromboembolism

目的越来越多的研究关注三甲胺N-氧化物(TMAO)及其前体与静脉血栓栓塞(VTE)的关系,但在已发表的研究中,二者之间的联系尚不清楚。因此,现采用两样本孟德尔随机化(MR)来探讨TMAO及其前体与VTE[包括深静脉血栓(DVT)和肺栓塞]风险的因果关系。方法TMAO及其前体、DVT和肺栓塞的汇总统计数据来自多个全基因组关联研究。主要分析采用逆方差加权法,其他四种敏感性分析方法作为补充(MR-Egger、MR多效性残差和异常值检验、最大似然比法和加权中值法)。最后,使用Bonferroni进行校正,其校正标准为P=0.0125(0.05/4=0.0125),当P值在0.0125和0.05之间时,考虑TMAO和VTE存在潜在的相关性。结果基因预测显示:TMAO浓度每增加1个单位,DVT的相对风险就会增加0.08%(OR=1.0008,95%CI 1.0004~1.0012,P=0.0013),胆碱浓度每增加1个单位,则DVT的相对风险可能会增加0.06%(OR=1.0006,95%CI 1.0001~1.0012,P=0.0420)。结论该MR研究支持TMAO和胆碱对DVT的潜在因果效应,表明降低TMAO和胆碱的水平可能降低DVT风险。

Objective Recently,although more and more researchers have focused on the relationship of trimethylamine N-oxide(TMAO)and its precursors with venous thromboembolism(VTE),the association between them in previous studies remains unclear.Therefore,a two-sample Mendelian randomization(MR)was used to explore a causal association of TMAO and its precursors with VTE risk,including deep vein thrombosis(DVT)and pulmonary embolism.Methods In this study,summary statistics of TMAO and its precursors,DVT,and pulmonary embolism were obtained from several extensive genome-wide association studies.Our primary analyses were conducted by inverse-variance weighting method,complementary with the other four sensitivity analysis(MR-Egger,MR pleiotropy residual sum and outlier test,Maximum likelihood,and weighted median).Finally,the Bonferroni corrected significance level with P=0.0125(0.05 divided by 4 risk factors)was used,and a potential association was considered when the P-value was between 0.0125 and 0.05.Results Gene prediction reported that for every 1 unit increase in TMAO concentrations,the relative risk of DVT increased by 0.08%(OR=1.0008,95%CI 1.0004~1.0012,P=0.0013)and for every 1 unit increase in choline concentrations,the relative risk of DVT may increase by 0.06%(OR=1.0006,95%CI 1.0001~1.0012,P=0.0420).Conclusion This MR analysis supports a potential causal effect of TMAO and choline on DVT,suggesting lowering their levels may reduce DVT risk.