Causal mediation of plasma metabolomics in pancreatitis: A Mendelian randomization study

Pancreatitis frequently leads to hospital stay for digestive system disorders and is in high demand for treatment. To identify possible treatment targets, we utilized Mendelian randomization (MR) to investigate the potential causal effects of metabolites on the outcomes of pancreatitis and examined the intermediary roles of risk factors associated with pancreatitis. We gathered GWAS data on 1091 plasma metabolites and 319 metabolite ratios, along with risk factors and phenotypes associated with pancreatitis and its subtypes. Risk factors included H, T2DM, body mass index (BMI), HLP, cholelithiasis, and Inflammatory bowel disease (IBD). Phenotypic outcomes encompassed acute pancreatitis (AP), chronic pancreatitis, alcohol-induced acute pancreatitis, and alcohol-induced chronic pancreatitis. To test the robustness of the findings, we estimated causality using inverse-variance-weighted MR complemented by sensitivity analyses. Additionally, we performed reverse MR analysis to explore potential reverse causality. This study identified 53 plasma metabolites and 22 metabolite ratios predicted by genetics that were significantly associated with pancreatitis (P < .05). Additionally, 54 metabolite ratios and 193 metabolites were associated with pancreatitis risk factors, with 86 and 27 metabolites, respectively, showing significant associations. The MR analysis confirmed that BMI, IBD, and HLP as pancreatitis risk factors (P < .05). It was also revealed that BMI and IBD mediate the relationship between certain metabolite levels and pancreatitis. The identified metabolites and their ratios have the potential to serve as circulating biomarkers with promising applications in CP screening and prevention strategies.