ATG16L1 Rs2241880/T300A Increases Susceptibility to Perianal Crohn's Disease: An Updated Meta-analysis on Inflammatory Bowel Disease Risk and Clinical Outcomes

Background: ATG16L1 plays a fundamental role in the degradative intracellular pathway known as autophagy, being a mediator of inflammation and microbial homeostasis. The variant rs2241880 can diminish these capabilities, potentially contributing to inflammatory bowel disease (IBD) pathogenesis.

Objectives: To perform an updated meta-analysis on the association between ATG16L1 rs2241880 and IBD susceptibility by exploring the impact of age, ethnicity, and geography. Moreover, to investigate the association between rs2241880 and clinical features.

Methods: Literature searches up until September 2022 across 7 electronic public databases were performed for all case-control studies on ATG16L1 rs2241880 and IBD. Pooled odds ratios (OR ) and 95% CI were calculated under the random effects model.

Results: Our analyses included a total of 30,606 IBD patients, comprising 21,270 Crohn's disease (CD) and 9336 ulcerative colitis (UC) patients, and 33,329 controls. ATG16L1 rs2241880 was significantly associated with CD susceptibility, where the A allele was protective (OR : 0.74, 95% CI: 0.72-0.77, p-value: <0.001), while the G allele was a risk factor (OR : 1.23, 95% CI: 1.09-1.39, p-value: 0.001), depending on the minor allele frequencies observed in this multi-ancestry study sample. rs2241880 was predominantly relevant in Caucasians from North America and Europe, and in Latin American populations. Importantly, CD patients harbouring the G allele were significantly more predisposed to perianal disease (OR : 1.21, 95% CI: 1.07-1.38, p-value: 0.003).

Conclusions: ATG16L1 rs2241880 (G allele) is a consistent risk factor for IBD in Caucasian cohorts and influences clinical outcomes. As its role in non-Caucasian populations remains ambiguous, further studies in under-reported populations are necessary.