三甲胺N-氧化物及其前体与胰腺疾病易感性的效应分析

Effect analysis of trimethylamine N-oxide and its precursors on susceptibility to pancreatic diseases

目的基于孟德尔随机化(MR)方法探究三甲胺N-氧化物(TMAO)及其前体(甜菜碱、肉碱和胆碱)与胰腺疾病之间的因果关系。方法收集TMAO、甜菜碱、肉碱、胆碱、急性胰腺炎(AP)、慢性胰腺炎(CP)、胰腺癌(PC)和循环免疫细胞(白细胞、淋巴细胞、单核细胞、中性粒细胞、嗜酸粒细胞和嗜碱粒细胞)特征的全基因组关联研究数据。根据加强流行病学观察研究报告(STROBE)-MR指南,严格筛选可用的遗传变异〔单核苷酸多态性(SNP)〕,使用逆方差加权(IVW)、MR-Egger回归法和加权中位数法评估暴露(TMAO及其前体)与结局(胰腺疾病及循环免疫细胞特征)之间的因果关系。用基于MR-Egger回归法、MR-PRESSO、Cochrane''sQ检验和留一法的敏感性分析评估结果的可靠性。结果共纳入36个与TMAO及其前体相关的SNP,其中5个与TMAO相关,13个与甜菜碱相关,12个与肉碱相关,6个与胆碱相关。①MR分析显示,TMAO可能增加AP发病风险〔优势比(OR)=1.100,95%可信区间(95%CI)为1.008~1.200,P=0.032〕,胆碱可能降低酒精性急性胰腺炎(AAP)发病风险(OR=0.743,95%CI为0.585~0.944,P=0.015)。MR-Egger回归法和加权中位数分析得到因果效应与IVW结果一致。没有证据支持TMAO及其前体与CP和PC风险之间的因果关系。敏感性分析显示,MR分析的SNP不存在异质性,存在多效性的可能性较低。留一法分析确定剔除任一SNP后,其余SNP对结果的影响效应区间与整体效应区间相似,提示MR结果的鲁棒性。②血浆TMAO水平与循环单核细胞计数升高存在正向因果关系(OR=1.017,95%CI为1.000*~1.034,P=0.048,*代表数据由1.0001保留3位小数所得)。MR-Egger回归法和加权中位数分析得到因果效应与IVW结果一致。敏感性分析显示,MR分析的SNP不存在异质性和多效性。留一法分析确定剔除任一SNP后,其余SNP对结果的影响效应区间与整体效应区间相似,提示MR结果的鲁棒性。结论TMAO、胆碱可能改变AP发病风险,TMAO可能有助于AP时循环单核细胞计数的升高。

Objective To investigate the causal relationship between trimethylamine N-oxide(TMAO)and its precursors(betaine,carnitine,and choline)and pancreatic diseases based on the Mendelian randomization(MR)method.Methods Genome-wide association study data of TMAO,betaine,carnitine,choline,acute pancreatitis(AP),chronic pancreatitis(CP),pancreatic cancer(PC),and circulating immune cell characteristics(white blood cell,lymphocyte,monocyte,neutrophil,eosinophil and basophil)were collected.According to the Strengthening the Reporting of Observational Studies in Epidemiology(STROBE)-MR reporting guidelines,the available genetic variants[single nucleotide polymorphism(SNP)]were strictly screened.The causal relationship between exposure(TMAO and its precursors)and outcomes(pancreatic diseases and circulating immune cell characteristics)was evaluated using inverse variance weighting(IVW),MR-Egger regression and weighted median.The reliability of the results was evaluated by sensitivity analysis based on MR-Egger regression,MR-PRESSO,Cochrane's Q test and leave-one-out method.Results A total of 36 SNP associated with TMAO and its precursors were included.Five of these were associated with TMAO,13 with betaine,12 with carnitine,and 6 with choline.①MR analysis showed that TMAO may increase the risk of AP[odds ratio(OR)=1.100,95%confidence interval(95%CI)was 1.008-1.200,P=0.032],and choline may reduce the risk of alcoholic acute pancreatitis(AAP;OR=0.743,95%CI was 0.585-0.944,P=0.015).The analysis results of MR-Egger regression and weighted median were consistent with the IVW results.There is no evidence to support a causal relationship between TMAO and its precursors and the risk of CP and PC.Sensitivity analysis indicated that SNP analyzed by MR showed no heterogeneity and low pleiotropy.The leave-one-out method analysis determined that after excluding any SNP,the effect intervals of the remaining SNP on the results were similar to the overall effect intervals,which suggested the robustness of MR results.②There was a positive causal relationship between plasma TMAO level and circulating monocyte count(OR=1.017,95%CI was 1.000*-1.034,P=0.048,*represented that the data was obtained by correcting to 3 decimal places from 1.0001).The causal effect obtained by MR-Egger regression and weighted median analysis was consistent with the results of IVW.Sensitivity analysis illustrated SNP analyzed by MR showed no heterogeneity and pleiotropy.The leave-one-out method analysis determined that after excluding any SNP,the effect intervals of the remaining SNP on the results were similar to the overall effect intervals,which suggested the robustness of MR results.Conclusion TMAO and choline may change the risk of AP,and TMAO may contribute to the increase of circulating monocyte count in AP.