Elucidating Causal Associations Between Immune Cells, Circulating Inflammatory Proteins, and Chronic Inflammatory Demyelinating Polyneuropathy: A Two‐Sample Two‐Step Mendelian Randomization Study

BACKGROUND AND AIMS: Immune cells and circulating inflammatory proteins play crucial roles in chronic inflammatory demyelinating polyneuropathy (CIDP) pathogenesis. However, the causal associations between these factors and CIDP remain unclear. Herein, we aimed to explore these associations using a two-sample, two-step Mendelian randomization (MR) approach. METHODS: Two-sample MR analysis was conducted using genome-wide association studies data to assess links between immune cells, inflammatory proteins, and CIDP. Data on 731 immune cell traits were obtained from a cohort of 3757 Sardinians, 91 inflammatory proteins from 14 824 Europeans across 11 cohorts, and CIDP data from 456 348 Europeans in the UK Biobank. Fixed-effect inverse variance weighted and Bayesian-weighted MR methods were used, along with a two-step MR to assess mediation effects. Sensitivity analyses were performed to check for horizontal pleiotropy and heterogeneity. RESULTS: Twenty-five immune cell traits were found to be significantly associated with CIDP. Of these, 17 immunophenotypes increased CIDP risk, whereas 8 were protective. Among inflammatory proteins, cystatin D (CST5) and interleukin-18 (IL-18) were linked to CIDP risk. Although not statistically significant, CST5 appeared to partially mediate the association between CD8+ NKT %T cells and CIDP (OR, 1.006; 95% CI, 1.00-1.02), accounting for approximately 3% of the mediation effect. INTERPRETATION: Our findings highlight several novel immune cell and inflammatory protein interactions implicated in CIDP. These results present new immune targets for future CIDP therapies.