基于孟德尔随机化探讨免疫细胞与散发型克雅氏病的因果关系

A Mendelian Randomization Study on the Causal Relationship between Immune Cells and Sporadic Creutzfeldt-Jakob Disease

摘要: 目的：采用两样本孟德尔随机化(MR)方法研究731种免疫细胞表型与散发型克雅氏病(sporadic Creutzfeld-Jacob disease, sCJD)发病风险的因果效应。方法：在全基因组关联研究数据库(genome wide association study, GWAS)中筛选符合条件的731种免疫细胞表型及散发型克雅氏病的因果关系。共纳入了四种类型的免疫特征(MFI, RC, AC和MP)。综合敏感性分析用于验证结果的异质性和水平多向性。结果：IVW结果显示免疫细胞与免疫细胞发病风险存在因果效应，其中四种免疫表型对散发型克雅氏病的保护作用：CD24+ CD27+ %lymphocyte (OR = 0.925, 95% CI: 0.863~0.991, P = 0.027)、CX3CR1 on monocyte (OR = 0.924, 95% CI: 0.859~0.994, P = 0.034)、SSC-A on myeloid DC (OR = 0.857, 95% CI: 0.740~0.993, P = 0.040)、Unsw mem AC (OR = 0.844, 95% CI: 0.718~0.992, P = 0.040)。六种免疫表型对散发型克雅氏病的危害作用：CD28− CD8dim %T cell (OR = 1.099, 95% CI: 1.012~1.195, P = 0.025)、CD40 on CD14− CD16+ monocyte (OR = 1.062, 95% CI: 1.000~1.129, P = 0.050)、CD62L− myeloid DC %DC (OR = 1.092, 95% CI: 1.009~1.183, P = 0.013)、Mo MDSC AC (OR = 1.123, 95% CI: 1.036~1.217, P = 0.005)、SSC-A on CD4+ (OR = 1.147, 95% CI: 1.035~1.271, P = 0.028)、SSC-A on NK (OR = 1.116, 95% CI: 1.010~1.232, P = 0.031)。结论：我们的研究通过基因手段证明了免疫细胞与散发型克雅氏病之间的密切联系，从而为今后的临床研究与预防提供了指导。

Abstract: Objective: This paper aims to investigate the causal effects of 731 immune cell phenotypes and the risk of sporadic Creutzfeld-Jacob disease (sCJD) using a two-sample Mendelian randomization (MR) approach. Methods: Eligible 731 immune cell phenotypes were screened for causal association with sporadic Creutzfeldt-Jakob disease (sCJD) in the genome wide association study (GWAS) database. A total of four types of immune profiles (MFI, RC, AC and MP) were included. Integrated sensitivity analysis was used to validate the heterogeneity and horizontal multidirectionality of the results. Results: IVW results showed a causal effect of immune cells and risk of immune cell pathogenesis, with four immune phenotypes protective against disseminated Creutzfeldt-Jakob disease: CD24+ CD27+ %lymphocyte (OR = 0.925, 95% CI: 0.863~0.991, P = 0.027), CX3CR1 on monocyte (OR = 0.924, 95% CI: 0.859~0.994, P = 0.034), SSC-A on myeloid DC (OR = 0.857, 95% CI: 0.740~0.993, P = 0.040), Unsw mem AC (OR = 0.844, 95% CI: 0.718~0.992, P = 0.040). The hazardous effects of six immunophenotypes on disseminated Creutzfeldt-Jakob disease: CD28− CD8dim %T cell (OR = 1.099, 95% CI: 1.012~1.195, P = 0.025), CD40 on CD14− CD16+ monocyte (OR = 1.062, 95% CI: 1.000~1.129, P = 0.050), CD62L− myeloid DC %DC (OR = 1.092, 95% CI: 1.009~1.183, P = 0.013), Mo MDSC AC (OR = 1.123, 95% CI: 1.036~1.217, P = 0.005), SSC-A on CD4+ (OR = 1.147, 95% CI: 1.035~1.271, P = 0.028), SSC-A on NK (OR = 1.116, 95% CI: 1.010~1.232, P = 0.031). Conclusion: Our study demonstrated a close association between immune cells and disseminated Creutzfeldt-Jakob disease by genetic means, thus providing guidance for future clinical research and prevention.