Investigating the Causal Links between COVID-19 and Pancreatitis by Bidirectional Mendelian Randomization

Objective: The immune response is a double-edged sword, and COVID-19 shares similarities with pancreatitis in terms of natural immune response, immune storm, and multi-organ involvement. However, whether a causal association between them remained unclear. This study aimed to investigate the potential causal association between COVID-19 and pancreatitis using a bidirectional Mendelian Randomization (MR) approach. Methods: The study analyzed three variables related to COVID-19 (severity, hospitalization, and susceptibility) with a sample size ranging from approximately 1,059,456 to 1,557,411. Additionally, four types of pancreatitis (acute, chronic, alcohol-induced acute, and chronic) were examined, with a sample size ranging from 337,126 to 377,277. Causal associations were estimated using inverse-variance weighted (IVW), median weighted, and MR-Egger methods. Results: The IVW model indicated potential causal associations between genetic susceptibility to severe and hospitalized COVID-19 and a decreased risk of acute pancreatitis (OR = 0.914, p = 0.01; OR = 0.884, p = 0.008) and alcohol-induced chronic pancreatitis (OR = 0.852, p = 0.013; OR = 0.768, p = 0.002), including chronic pancreatitis. Inconsistent associations were observed between IVW and sensitivity analyses in acute and chronic pancreatitis of severe and hospitalized COVID-19. Conversely, no significant associations were found between pancreatitis traits and COVID-19-related variables in reverse MR analysis. No heterogeneity or pleiotropy was found. Conclusions: Host genetic liability to severe and hospitalized COVID-19 was causally associated with declining risk of alcohol-induced chronic pancreatitis, while no significant association was observed for pancreatitis on COVID-19 outcomes. This study has significant implications for unraveling their pathogenesis and guiding clinical management.