两样本孟德尔随机化分析循环代谢产物与吉兰-巴雷综合征的因果关系

Analysis of the causal relationship between circulating metabolites and Guillain-Barré syndrome by two sample Mendelian randomization

目的采用两样本孟德尔随机化(MR)探讨417种循环代谢产物与吉兰-巴雷综合征(GBS)风险的因果关系。方法通过MRC IEU OpenGWAS项目获得3个循环代谢产物全基因组关联研究(GWAS)数据,分别为“met-a”“met-c”和“met-d”。GBS相关的单核苷酸多态性位点(SNPs)数据来源于芬兰生物银行数据库,表型代码为“finn-b-G6_GUILBAR”。将来自GWAS的与循环代谢产物密切相关的遗传变异数据(SNPs)作为工具变量(IVs),与来自芬兰的GBS GWAS数据进行双样本MR分析,主要采用随机效应模型的逆方差加权(IVW)方法,根据效应指标优势比(OR)和95%CI评估结果。使用留一法、异质性检验、水平基因多效性检验验证结果的稳定性和可靠性。结果共5种循环代谢产物具有与GBS因果关系的提示性证据。其中,肌酐(OR=2.924,95%CI:1.194~7.163,P=0.019)、谷氨酰胺(OR=1.902,95%CI:1.007~3.592,P=0.048)、异戊酰基肉碱(OR=140.767,95%CI:3.510~5645.336,P=0.009)的循环水平与GBS风险较高有关。相反,基因预测葡萄糖(OR=0.308,95%CI:0.010~0.981,P=0.046)、X-11491(OR=0.069,95%CI:0.007~0.707,P=0.024)的循环水平与GBS风险呈负相关。结论肌酐、谷氨酰胺、异戊酰基肉碱、葡萄糖、X-11491可能与GBS有因果关系。

Objective To investigate the causal relationship between 417 circulating metabolites and the risk of Guillain-Barrésyndrome(GBS)using two sample Mendelian randomization(MR)analysis method.Methods Three genome-wide association studies(GWAS)of circulating metabolites were obtained through the MRC IEU OpenGWAS project,namely“met-a”,“met-c”,and“met-d”.The data on single nucleotide polymorphism sites(SNPs)related to GBS was sourced from the FinnGen Consortia database,with the phenotype code“finn-b-G6_GUILBAR”.Genetic variation data(SNPs)closely related to circulating metabolites from GWAS was used as instrumental variables(IVs)and a two-sample MR analysis with GBS GWAS data from Finland was conducted.The inverse variance weighted(IVW)method of the random effects model was mainly used,and the results were evaluated based on the odds ratio(OR)and 95%CI of the effect indicators.The leave-one-out method,heterogeneity test,and horizontal gene pleiotropy test were used to verify the stability and reliability of the results.Results There was suggestive evidence for a causal relationship between 5 circulating metabolites and GBS.Among them,the circulating level of creatinine(OR=2.924,95%CI:1.194-7.163,P=0.019),glutamine(OR=1.902,95%CI:1.007-3.592,P=0.048)and isovaleryl carnitine(OR=140.767,95%CI:3.510-5645.336,P=0.009)were associated with a higher risk of GBS.On the contrary,genetic predicted the circulating level of glucose(OR=0.308,95%CI:0.010-0.981,P=0.046)and X-11491(OR=0.069,95%CI:0.007-0.707,P=0.024)were negatively correlated with the risk of GBS.Conclusion Creatinine,glutamine,isovaleryl carnitine,glucose and X-11491 may have causal relationships with GBS.