Plasma proteins and the risk of inflammatory bowel diseases: A two-sample Mendelian randomization study

Dysregulated plasma proteins are therapeutic targets for inflammatory bowel disease (IBD), which is a major global health burden. There is limited causal evidence for these associations. Mendelian randomization (MR) was applied to assess the genetic links between plasma proteins and IBD risk. Genetic instruments for 3282 plasma protein phenotypes were derived from genome-wide association studies (GWAS). Summary statistics from IBD GWAS (overall, Crohn disease [CD] and ulcerative colitis [UC]) were analyzed via inverse-variance weighted (IVW) regression, estimating odds ratios (OR) and 95% confidence intervals (CI). Four proteins showed associations with overall IBD risk: erythrocyte band 7 integral membrane protein (OR = 0.84, 95% CI = 0.77-0.90), Interleukin-1 receptor-like 1 (IL1RL1; OR = 1.07, 1.04-1.10), Interleukin-18 receptor 1 (IL18R1; OR = 1.08, 1.04-1.12), and alcohol dehydrogenase 1 B (ADH1B; OR = 0.85, 0.79-0.91). Subtype analyses revealed CD-specific associations with erythrocyte band 7 (OR = 0.82, 0.76-0.90) and IL1RL1 (OR = 1.10, 1.05-1.14), while UC risk correlated with ADH1B (OR = 0.85, 0.78-0.91) and high-affinity immunoglobulin gamma Fc receptor I (FCGR1A; OR = 0.82, 0.75-0.90). This MR study identified causal associations between specific plasma proteins (erythrocyte band 7, IL1RL1, IL18R1, ADH1B, and FCGR1A) and IBD pathogenesis, with distinct molecular profiles for CD and UC. These findings implicate dysregulated innate immunity and metabolic pathways, offering mechanistic insights into therapeutic development. Further validation of protein-mediated mechanisms is warranted.