Assessing the causal relationship between immune traits and systemic lupus erythematosus by bi-directional Mendelian randomization analysis

Abstract

Previous studies have observed relationships between immune cells and systemic lupus erythematosus (SLE), but their causal links remain undetermined. Based on the public available genome-wide association studies (GWAS) summary statistics, we conducted two-sample Mendelian randomization (MR) to evaluate the associations between 731 immune phenotypes and SLE pairs. Pairwise pleiotropy analysis was performed to identify pleiotropic genes for significant immunophenotype-SLE pairs. A comprehensive gene function analysis was undertaken to explore the mechanisms of immune cells in SLE. By using the instrumental variables extracted from GWAS data, we observed that increased levels of five immune phenotypes were causally associated with SLE risk (FDR < 0.05), that were CD20 on IgD⁺ CD38^- naïve, BAFF-R on IgD⁺ CD38^dim, CD39⁺ secreting Treg AC, CD14^- CD16⁺ monocyte AC, and HLA DR on CD14⁺ monocyte. Pairwise gene-based analyses identified a total of 38 pleiotropic genes for 5 significant pairs identified and gene set enrichment analysis revealed the involvement of the identified pleiotropic genes in complex pathways (i.e., systemic lupus erythematosus, an integral component of luminal side of endoplasmic reticulum membrane, C-type lectin receptor signaling pathway and regulation of hormone secretion). This study demonstrates that the immune response influences the progression of SLE in a complex pattern. These findings greatly improve our understanding of the interaction between immune response and SLE risk and also aid in the design of therapeutic strategies from an immunological perspective.

Keywords: Immune cells; Immunophenotypes; Mendelian Randomization; Pleiotropy; Systemic lupus erythematosus.