TMEM258 modulates immune infiltration networks underlying co-susceptibility to Crohn disease and acute pancreatitis

Crohn disease (CD) is an immune-mediated chronic inflammatory disease of the gastrointestinal tract. In addition to common intestinal symptoms such as abdominal pain and diarrhea, it may be combined with extraintestinal manifestations in the joints, skin, and biliopancreatic tract. Previous studies have reported a causal association between inflammatory bowel disease and acute pancreatitis (AP), but the underlying pathogenesis remains unclear. It is clinically important to investigate the genetic co-morbidity between CD and AP for the diagnosis and management of extraintestinal manifestations. Bibliometric analysis was utilized to explore the CD-AP relationship. A two-sample Mendelian Randomization (MR) approach assessed the causality. Clinical data from 23 patients with a documented history of CD at 3 major gastroenterology centers were examined. Expression quantitative trait loci data including 5421 cis-expression quantitative trait loci genes from blood samples of 31,684 individuals across 37 cohorts identified variant-associated genes. Transmembrane protein 258 (TMEM258) was further investigated through bulk and single-cell RNA sequencing. Its expression was quantified via RT-PCR in intestinal samples from a dextran sulfate sodium-induced acute colitis mouse model. Immune cell infiltration analysis was performed to evaluate the immune correlations. Mediators between CD and AP were identified from 731 candidate immune cells by two-step MR and mediation analysis. Persistent literature reports have noted associations between inflammatory bowel disease and AP. Our two-sample MR analysis revealed a potential causal relationship between CD and AP (odds ratio = 1.043; 95% CI: 1.011-1.075; P = .008). In 23 patients with CD and AP co-morbidity, late-onset AP predominantly occurs in CD patients with the L1B2 phenotype compared to early-onset AP. DHX58, KLRG1, MARK3, and TMEM258 were causal biomarkers in both conditions. TMEM258 mediates the immune response in this comorbidity and is highly expressed in mesenchymal cells within the inflamed intestinal tissues of CD patients. TMEM258 expression positively correlated to M1 macrophages and plasma cells, and negatively correlated to neutrophils and naïve CD8+ T cells. CD28+ double negative T cells and naïve CD8+ T cells mediate the predictive effect of CD on the onset of AP. Through MR and multi-omics analyses, our study demonstrates that TMEM258 is a shared susceptibility gene for CD and AP, increasing the risk of AP in CD by reducing T cell infiltration.