Causal relationship between immune cell-mediated circulating inflammatory proteins and rheumatoid arthritis

Abstract

BACKGROUND: Studies have shown that circulating inflammatory proteins and immune cells are associated with rheumatoid arthritis, but the causal relationship is unclear. OBJECTIVE: To explore the causal relationships between circulating inflammatory proteins and rheumatoid arthritis mediated by immune cells. METHODS: We downloaded data on circulating inflammatory proteins and immune cell phenotypes from the GWAS Catalog database (a publicly accessible database jointly established and maintained by the National Human Genome Research Institute and the European Bioinformatics Institute), and genome-wide association study data for rheumatoid arthritis from the FinnGen database (a genomics project resulting from collaboration between Finnish research institutions, biobanks, and international industry partners, also publicly accessible). Two-step Mendelian randomization analyses were performed: inverse variance weighting was used to assess the causal effects of 91 circulating inflammatory proteins and 731 immune cell phenotypes on rheumatoid arthritis risk, supplemented by MR-Egger, weighted median, weighted mode, simple mode, and sensitivity analyses. The mediating role of identified immune cells in the relationship between circulating inflammatory proteins and rheumatoid arthritis was evaluated. RESULTS AND CONCLUSION: Inverse variance weighting analysis showed that four circulating inflammatory proteins were significantly associated with rheumatoid arthritis risk, of which one was a risk factor and three were protective factors. Forty-six immune cell phenotypes were significantly associated with rheumatoid arthritis, of which 20 were risk factors and 26 were protective factors. Reverse Mendelian randomization analysis found no causal association between rheumatoid arthritis and the four identified circulating inflammatory proteins. Sensitivity analyses revealed no significant heterogeneity or horizontal pleiotropy. Further mediation analysis showed that CD19 on IgD- CD38br partially mediated the causal effect of interleukin-18 (β=0.064, OR=1.066, P=0.044) on rheumatoid arthritis, with a mediation effect of 0.004, a mediation proportion of 5.7%, and a direct effect of 0.060. The results reveal causal associations between circulating inflammatory proteins and immune cells with rheumatoid arthritis, and identify that CD19 on IgD- CD38br partially mediates the causal relationship between interleukin-18 and rheumatoid arthritis. For the Chinese biomedical research field, reference can be made to the integrated analysis framework of international multi-omics platforms and cross-ethnic cohort data to construct a combined database of epigenomics, proteomics, and metabolomics specific to the Chinese population, revealing the molecular regulatory networks underlying complex diseases, and facilitating disease subtyping and early diagnostic biomarker development. By learning from transnational collaborative research mechanisms, establish natural population cohorts of multiple ethnicities and regions in China, systematically analyze the impact of environmental exposure and gene interactions on health, and provide scientific evidence for formulating localized disease prevention strategies.

1. Introduction

Rheumatoid arthritis is a chronic inflammatory autoimmune disease characterized by symmetric synovial inflammation, progressive bone and cartilage erosion, and autoantibody formation [1]. Its global incidence ranges from 0.24% to 1% [2], and it affects women two to three times more often than men [3]. The main clinical manifestations include joint pain, stiffness, swelling, deformity, and dysfunction. As the disease progresses, severe joint tissue damage occurs, significantly increasing the risk of disability and complications such as infection, lymphoma, osteoporosis, and cardiovascular disease [4]. The pathogenesis of rheumatoid arthritis remains unclear, but it is generally believed to involve genetic susceptibility, environmental factors, and abnormal immune responses [5]. Currently, clinical treatments include nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, biologics, and surgical options [6], but treatment outcomes vary among individuals [3]. Therefore, deeply exploring the pathological roots of rheumatoid arthritis and continuously optimizing treatment strategies are of immeasurable value for improving patient prognosis and quality of life.

Circulating inflammatory proteins are core mediators of the immune response, widely distributed throughout the body via the circulatory system, forming dynamic regulatory networks with tissue microenvironments and metabolic networks to maintain homeostasis. Pathological activation of the immune system can lead to