摘要
目的 利用孟德尔随机化(MR)探究循环炎症蛋白与肝癌之间的因果关系.方法 91种循环炎症蛋白的全基因组关联研究(GWAS)数据来源于GWAS目录,研究对象来自11个队列的14 824名欧洲血统参与者.肝癌的汇总统计数据来源于GWAS数据库,总样本197 611例.通过双样本MR分析评估91种循环炎症蛋白与肝癌的因果关系.其中,逆方差加权法、加权中值法、Mr-Egger 回归法、简易模式法和加权模式法为主要分析方法,并且使用优势比(OR)评估二者之间的因果关系.同时使用Cochran's Q检验、Mr-PRESSO、MR-Egger回归法的截距项和留一分析法进行敏感性分析.反向MR和Steiger用来排除反向因果关系的影响.结果 在91种循环炎症蛋白中,C-C基序趋化因子 20 水平(OR=1.28,95％CI:1.01～1.62)、CD40L 受体水平(OR=1.31,95％CI:1.00～1.28)、成纤维细胞生长因子21水平(OR=1.47,95％CI:1.18～1.83)、神经胶质细胞系衍生神经营养因子水平(OR=1.29,95％CI:1.08～1.54)、白细胞介素(IL)-13 水平(OR=1.24,95％CI:1.02～1.50)、IL-20 水平(OR=1.78,95％CI:1.30～2.44)、IL-20 受体亚基 α 水平(OR=1.43,95％CI:1.06～1.93)和基质金属蛋白酶-10水平(OR=1.21,95％CI:1.04～1.39)与肝癌的发生存在正向因果关系;IL-1α 水平(OR=0.83,95％CI:0.71～0.96)、IL-24 水平(OR=0.68,95％CI:0.47～0.99)、白血病抑制因子水平(OR=0.77,95％CI:0.60～0.98)和干细胞因子水平(OR=0.87,95％CI:0.78～0.97)与肝癌的发生存在负向因果关系.12种循环炎症蛋白的异质性检验均不存在异常变量,敏感性分析均显示稳健,且均未发现基因多效性,反向MR和Steiger检验都不支持炎症蛋白与肝癌之间存在反向因果关系.结论 C-C基序趋化因子20、CD40L受体、成纤维细胞生长因子21、神经胶质细胞系衍生神经营养因子、IL-13、IL-20、IL-20受体亚基α、基质金属蛋白酶-10、IL-1α、IL-24、白血病抑制因子和干细胞因子可能与肝癌发生发展存在因果关系.
Abstract
Objective To study the relationship between circulating inflammatory proteins and liver cancer by Mendelian randomization.Methods Data from the genome-wide association study(GWAS)of 91 circulating inflammatory proteins were sourced from the GWAS Catalog,involving 14 824 participants of European ancestry from 11 cohorts.Summary statistics for liver cancer were obtained from the GWAS data-base,encompassing a total sample of 197 611 cases,a two-sample Mendelian randomization analysis was conducted to evaluate the relationship between 91 circulating inflammatory proteins and liver cancer.Among them,inverse variance weighting,weighted median method,MR-Egger,simple mode,and weighted mode were the main analysis methods.Using odds ratio(OR)values to evaluate the causal relationship between them.Cochran Q-test,MR-PRESSO,MR-Egger intercept,and"leave-one-out"analyses were used for sen-sitivity analysis.Reverse MR,MR-Steiger tests were employed to rule out the influence of reverse causality.Results Among the circulating 91 inflammatory proteins,C-C motif chemokine 20(OR=1.28,95％CI:1.01-1.62),CD40 receptor(OR=1.31,95％CI:1.00-1.28),fibroblast growth factor 21(OR=1.47,95％CI:1.18-1.83),glial cell line-derived neurotrophic factor(OR=1.29,95％CI:1.08-1.54),interleukin-13(IL-13)(OR=1.24,95％CI:1.02-1.50),IL-20 levels(OR=1.78,95％CI:1.30-2.44),IL-20 receptor subunit alpha(OR=1.43,95％CI:1.06-1.93),and matrix metalloprotei-nase-10(OR=1.21,95％CI:1.04-1.39)have positive causal relationship with the occurrence of liver cancer.And IL-1 alpha(OR=0.83,95％CI:0.71-0.96),IL-24(OR=0.68,95％CI:0.47-0.99),leukemia inhibitory factor(OR=0.77,95％CI:0.60-0.98)and stem cell factor(OR=0.87,95％CI:0.78-0.97)showed negative causal relationship with the occurrence of liver cancer.Heterogeneity tests for all 12 circulating inflammatory proteins revealed no outliers.Sensitivity analyses consistently demonstrated robustness,with no evidence of pleiotropy observed.Neither reverse MR nor MR-Steiger tests supported the existence of a reverse causal relationship between inflammatory proteins and liver cancer.Conclusion The C-C motif chemokine 20,CD40L receptor,fibroblast growth factor 21,glial cell line-derived neurotrophic factor,IL-13,IL-20,IL-20 receptor subunit alpha,MMP-10,IL-1 alpha,IL-24,leukemia inhibitory factor,and stem cell factor may be causally related to the development of liver cancer.
维普
万方数据