Causal Effects of AL Amyloidosis on Autoimmune Diseases and the Role of Inflammatory Cytokines: Insights from Mendelian Randomization

Background This study aims to investigate the causal effect of amyloid light-chain (AL) amyloidosis on autoimmune diseases (ADs), with a focus on identifying inflammatory cytokines as potential mediators from a genetic perspective. Methods Instrumental variables strongly associated with AL amyloidosis were identified from the largest available genetic cohort. Two-sample Mendelian randomization (MR) analyses were conducted to assess causal associations, followed by rigorous sensitivity analyses and validation in independent cohorts. Protein-protein interaction (PPI) analyses were applied to explore cytokine networks mediating the observed associations. Results AL amyloidosis was associated with an increased risk of celiac disease and overall AD risk but exhibited a protective effect against inflammatory bowel disease (IBD) and ulcerative colitis (UC). Protein quantitative trait locus (pQTL) analysis quantified inflammatory cytokine changes across these conditions, and the results were visualized. Conclusions Genetically predicted AL amyloidosis increases the risk of celiac disease and overall autoimmune disease susceptibility while reducing the risk of IBD and UC. These associations may involve inflammatory cytokines such as IL-6, CCL3, and BAFF, suggesting a potential mechanistic pathway worthy of further investigation.