A Systematic Review of Mendelian Randomization Studies on Celiac Disease.

Background and Objective: Mendelian randomization (MR) has become an important tool in epidemiology, used to infer causal relationships diseases. This review aims to consolidate existing MR evidence concerning celiac disease (CeD). Methods: We systematically searched major databases up to May 2024, adhering to PRISMA guidelines. Only MR studies explicitly investigating CeD were included. We assessed the quality of each study based on the strength, independence, and exclusivity of the instrumental variables used. Results: From an initial pool of 207 articles, 35 met our inclusion criteria. These studies frequently addressed the relationship between CeD and autoimmune diseases like inflammatory bowel disease (IBD) and explored connections with gut microbiota, various cancers, and metabolic disorders. Significant findings highlight a robust bi-directional association between IBD and CeD and complex interactions with gut microbiota. Notably, many associations reported were near the threshold of clinical significance. Conclusion: This systematic review highlights the dual nature of current MR evidence on CeD. On one hand, we observe consistent associations between CeD, IBDs, and gut microbiota. On the other, there is a plethora of weaker associations that raise critical questions about their clinical and research significance. This work lays a solid foundation for deeper investigations into these weaker links, particularly in relation to lymphomas and psychiatric conditions. It calls for an expanded use of MR and other methodologies to explore under-researched areas.