血清代谢物与肝细胞癌之间的因果关系:孟德尔随机化研究  

Causal relationship between serum metabolites and hepatocellular carcinoma:a Mendelian randomization study

作　　者：陈景瑞 刘邵文 张玉良 周金[3] 刘宝群 崔子林[4] Chen Jingrui;Liu Shaowen;Zhang Yuliang;Zhou Jin;Liu Baoqun;Cui Zilin(The First Central Clinical School,Tianjin Medical University,Tianjin 300192,China;Clinical School of Paediatrics,Tianjin Medical University,Tianjin 300192,China;Department of General Surgery,Affiliated Hospital of Inner Mongolia Minzu University,Tongliao 028000,China;Department of Hepatobiliary Surgery,Tianjin First Central Hospital,Tianjin 300192,China)

机构地区：[1]天津医科大学一中心临床学院,天津300192 [2]天津医科大学儿童临床学院,天津300192 [3]内蒙古民族大学附属医院普外科,通辽028000 [4]天津市第一中心医院肝胆外科,天津300192

出　　处：《中华肝胆外科杂志》2024年第12期903-907,共5页Chinese Journal of Hepatobiliary Surgery

基　　金：国家自然科学基金(82372194)。

摘　　要：目的通过孟德尔随机化(MR)研究阐明血清代谢物和肝细胞癌之间的因果关系。方法通过代谢物组学全基因组关联研究(GWAS)服务器获取血清代谢物GWAS数据作为暴露组,研究样本包括来自2项欧洲人口研究的7824名成人,从IEU Open GWAS prodect获取肝细胞癌GWAS数据作为结局组,包括总样本197611例,评价486种血清代谢物与肝细胞癌的关系。以逆方差加权(IVW)为主要分析方法,MR-Egger回归法、加权中位数法、简单模式法和加权模式法为补充分析方法。敏感性分析采用Cochran''sQ检验、MR-Egger回归的截距项、留一分析和MR-PRESSO。反向MR和MR-steiger检验用于排除反向因果关系的影响。使用MetaboAnalyst 5.0进行代谢组学通路分析。结果MR最终确定了6种与肝细胞癌有潜在因果关系的代谢物:甘露糖(OR=0.38,95%CI:0.16~0.92,P=0.032)、γ-谷氨酰酪氨酸(OR=3.34,95%CI:1.14~9.83,P=0.028)、甘油-3-磷酸(OR=0.17,95%CI:0.04~0.70,P=0.014)、2-亚油酰甘油磷酸胆碱(OR=0.33,95%CI:0.13~0.98,P=0.028)、1-硬脂酰甘油磷酰乙醇胺(OR=2.44,95%CI:1.05~5.65,P=0.038)和棕榈酰鞘磷脂(OR=5.62,95%CI:1.56~20.18,P=0.008)。6种代谢物的敏感性分析均显示稳健,异质性检验均不存在异常变量,且均未发现基因多效性。反向MR和Steiger检验都不支持代谢物与肝细胞癌之间存在反向因果关系。代谢通路分析结果显示,醚类脂质代谢通路可能与肝细胞癌的发展有关(P=0.002)。结论6种血清代谢物(甘露糖、γ-谷氨酰酪氨酸、甘油-3-磷酸、2-亚油酰甘油磷酸胆碱、1-硬脂酰甘油磷酰乙醇胺和棕榈酰鞘磷脂)与肝细胞癌存在因果关系。ObjectiveTo elucidate the causal relationship between serum metabolites and hepatocellular carcinoma(HCC)by the Mendelian randomization.MethodsThe serum metabolite genome-wide association study(GWAS)data from the Metabolomics GWAS server was selected as the exposure group.The study sample includes 7824 adults from two European population studies.The GWAS data of HCC was obtained from the IEU Open GWAS project as the outcome group,including a total sample of 197611 cases,to evaluate the relationship between 486 serum metabolites and HCC.The inverse variance weighting method(IVW)was used as the primary analysis method.Supplementary analysis methods included MR-Egger,weighted median,simple mode,and weighted mode.Sensitivity analyses were conducted using Cochran's Q test,MR-Egger intercept test,leave-one-out analysis,and MR-PRESSO.Reverse MR and MR-Steiger tests were employed to exclude the influence of reverse causality.Metabolomic pathway analysis was performed using MetaboAnalyst 5.0.ResultsThe MR results finally identified six metabolites with potential causal relationships with HCC:mannose(OR=0.38,95%CI:0.16-0.92,P=0.032),γ-glutamyltyrosine(OR=3.34,95%CI:1.14-9.83,P=0.028),glycerol-3-phosphate(OR=0.17,95%CI:0.04-0.70,P=0.014),2-linoleoylglycerophosphocholine(OR=0.33,95%CI:0.13-0.98,P=0.028),1-stearoylglycerophosphoethanolamine(OR=2.44,95%CI:1.05-5.65,P=0.038),and palmitoyl sphingomyelin(OR=5.62,95%CI:1.56-20.18,P=0.008).Sensitivity analyses for the six metabolites showed robustness,with no abnormal variables in the heterogeneity tests,and no evidence of genetic pleio-tropy was observed.Both reverse MR and Steiger tests did not support the existence of reverse causality between the metabolites and HCC.Metabolic pathway analysis indicated that ether lipid metabolism is closely related to the occurrence of HCC(P=0.002).ConclusionSix serum metabolites(mannose,γ-glutamyltyrosine,glycerol-3-phosphate,2-linoleoylglycerophosphocholine,1-stearoylglycerophosphoethanolamine,and palmitoyl sphingomyelin)have causal relatio

关 键 词：癌 肝细胞 代谢物 孟德尔随机化 因果关系 

分 类 号：R28[医药卫生—中药学]