The causal role of immune cells in rheumatoid arthritis: a Mendelian randomization study

Abstract

Abstract Objective Rheumatoid arthritis (RA) is a chronic, systemic, and inflammatory disease of unknown etiology, mainly affecting synovial joints, resulting in severe pain, stiffness, limited function, poor quality of life, and work disability. However, the current pathogenesis of RA is not very clear, and autoimmunity may be one of its causes. The complex immune factors that affect the transition between pro-inflammatory and inflammatory phenotypes may play an important role in the homeostasis of the joint environment, but the relationship between the two still needs further confirmation. This study used a comprehensive analysis of two sample Mendelian randomization (MR) to explore the relationship between immune cell characteristics and the risk of RA. Methods Based on publicly available genetic data, the study used Mendelian randomization (MR) comprehensive analysis method to explore the causal relationship between 731 immune cell features and RA risk. To reduce data bias, we used GWAS data from two independent European populations of RA cohorts: the UK Biological Sample Library (Ncase = 1605Ncontrol = 359589) and the FinnGen database (Ncase = 4594Ncontrol = 214196) for MR analysis. Among them, we use the GWAS data of RA in the UK biological sample library as the "discovery queue data", and the GWAS data of RA in the FinnGen database as the "validation queue data". Then, we conduct MR analysis and meta-analysis separately. Use Cochran's Q test and MR Egger intercept test analysis to evaluate the heterogeneity, horizontal pleiotropy, and stability of SNPs in RA. Result We found that a total of 46 SNPs were associated with RA in 731 immune cell features and GWAS data from the UK biological sample library (P < 0.05), while 59 SNPs were associated with RA in the FinnGen database (P < 0.05). Subsequently, we performed meta-analysis on the two sets of data, and if the statistical heterogeneity was significant (I ²༞ 50%), using a random effects model; On the contrary, using a fixed effects model, six SNPs were found to be associated with rheumatoid arthritis (P < 0.05), including: CD39 + secretory CD4 regulatory T cell% secretory CD4 regulatory T cell (P = 0.0001, OR = 0.97, 95% CI: 0.9552–0.985), CD39 + secretory CD4 regulatory T cell% CD4 regulatory T cell (P = 0.0038, OR = 0.97, 95% CI: 0.9502–0.9902), CD39 + CD4 + T cell% T cell (P = 0.0093, OR = 0.98, 95% CI: 0.9652–0.995), CD3 on CD39 + resting CD4 regulatory T cell (P = 0.0411, OR = 0.93, 95% CI: 0.8674–0.9971), CD80 on myeloid Dental Cell (P = 0.0419, OR = 1.06, 95% CI: 1.0021–1.1212), HLA DR on CD33- HLA DR+(P < 0.0001, OR = 1.25, 95% CI: 1.118–1.3975). Conclusion We conducted MR analysis on GWAS data based on large-scale population studies to demonstrate a close relationship between immune cell characteristics and RA from a genetic perspective, which will provide scientific basis for further research on the pathogenesis and clinical treatment of RA.