Causal relationship between circulating immune cells and inflammatory bowel disease: A Mendelian randomization analysis

Abstract

Inflammatory bowel disease (IBD) is an immune-mediated inflammation of the gastrointestinal tract that includes Crohn disease and ulcerative colitis (UC). Although IBD is associated with elevated levels of innate and adaptive immunity, the relationship between circulating immune cells and IBD remains largely unknown. Therefore, we conducted a bidirectional 2-sample Mendelian randomization (MR) study to determine their causal relationship. Genome-wide association study summary statistics were extracted from publicly available databases regarding immune cell phenotypes and IBD traits (including IBD, Crohn disease, and UC). MR analysis was conducted using 5 MR methods, with inverse-variance-weighted (IVW) as the primary analysis method. False discovery rate correction (FDR) was used to reduce the likelihood of type 1 errors. We also conducted MR-Egger-intercept tests to evaluate horizontal pleiotropy. After FDR adjustment of the P values for the IVW method, the results indicated no causal relationship between immune cell phenotypes and IBD or UC, but 4 immune characteristics were causally associated with Crohn disease. The percentage of human leukocyte antigen DR+ CD4+ T cells in lymphocytes was positively associated with the development of Crohn disease (odd ratio [OR], 1.13; 95% confidence interval [CI], 1.07–1.21; P < .001; P FDR = 0.019), whereas the percentage of IgD− CD27− B cells in lymphocytes (OR, 0.85; 95% CI, 0.79–0.92; P < .001; P FDR = 0.014), CD28 on CD39+ secreting CD4 regulatory T cells (OR, 0.92; 95% CI, 0.89–0.96; P < .001; P FDR = 0.019), and the percentage of naïve CD4+ T cells in all CD4+ T cells (OR, 0.90; 95% CI, 0.85–0.95; P < .001; P FDR = 0.027) were negatively related to the risk of Crohn disease. MR analysis of the above 4 immune cell phenotypes revealed no horizontal pleiotropy. In the reverse MR analysis, Crohn disease was not causally associated with any of these immune cell phenotypes. The findings provide insight into the relationship between immune cells and IBD pathogenesis, and may serve as a basis for developing novel immunotherapies.