rs2241880 — ATG16L1 T300A

ATG16L1 T300A — Autophagy, Gut Health, and Crohn's Disease Risk

The ATG16L1 gene provides instructions for making a protein essential to autophagy, the cellular recycling system that clears out damaged components and invading bacteria. The T300A variant¹¹ The T300A variant
This threonine-to-alanine substitution at position 300 is one of the most replicated genetic risk factors for Crohn's disease, first identified in genome-wide association studies in 2007 and subsequently confirmed in dozens of independent cohorts worldwide. In the gut, ATG16L1 plays a critical role in Paneth cells, specialized epithelial cells that secrete antimicrobial peptides and maintain the intestinal barrier. The T300A variant impairs this function, allowing bacteria to persist when they would normally be destroyed.

The Mechanism

The T300A variant sits near a caspase-3 cleavage site²² The T300A variant sits near a caspase-3 cleavage site
Amino acids 296-299 form a caspase cleavage motif, and the T300A substitution significantly increases the protein's susceptibility to caspase-3-mediated degradation during cellular stress. When cells experience metabolic stress, death receptor activation, or starvation, caspase-3 degrades the T300A variant more rapidly than wild-type ATG16L1, resulting in diminished autophagy. This leaves epithelial cells less able to clear invading bacteria like Salmonella and Yersinia enterocolitica. Studies in human epithelial cells show the T300A variant has markedly decreased efficiency³³ the T300A variant has markedly decreased efficiency
The ala300-containing variant showed decreased capture of internalized Salmonella within autophagosomes compared to the wildtype thr300-containing variant in capturing bacteria within autophagosomes. The variant also disrupts the WD40 domain's ability to interact with proteins like TMEM59, further impairing unconventional autophagy pathways.

The Evidence

Multiple meta-analyses confirm the T300A association with Crohn's disease⁴⁴ Multiple meta-analyses confirm the T300A association with Crohn's disease
Meta-analysis of 30,606 IBD patients found the G allele was a risk factor (OR 1.23, 95% CI: 1.09-1.39, p=0.001) while the A allele was protective (OR 0.74, 95% CI: 0.72-0.77, p<0.001). The association is strongest in Caucasian populations from North America, Europe, and Latin America, with minimal to no association observed in Asian populations. CD patients carrying the G allele are significantly more predisposed to perianal disease⁵⁵ CD patients carrying the G allele are significantly more predisposed to perianal disease
OR 1.21, 95% CI: 1.07-1.38, p=0.003, one of the more severe and treatment-resistant manifestations of Crohn's. A 2025 meta-analysis found the G allele increases CD risk worldwide⁶⁶ A 2025 meta-analysis found the G allele increases CD risk worldwide
OR 1.33, 95% CI: 1.29-1.37, with GG homozygotes showing higher risk than AG heterozygotes. The variant also alters gut microbiota composition—studies in knock-in mice show increased Bacteroides ovatus and elevated Th17 and Th1 immune cells⁷⁷ studies in knock-in mice show increased Bacteroides ovatus and elevated Th17 and Th1 immune cells
Changes occur before disease onset, suggesting T300A contributes to dysbiosis and immune infiltration prior to symptoms.

Practical Implications

This variant doesn't cause Crohn's disease on its own—it's a susceptibility factor that increases risk in the presence of environmental triggers like smoking, certain infections, or dietary patterns that stress the gut. For those with the GG genotype (about 19% of Europeans), maintaining gut barrier integrity becomes especially important. This means prioritizing dietary fiber, fermented foods, and avoiding pro-inflammatory processed foods and excessive antibiotic use. Regular monitoring for early signs of inflammatory bowel disease (persistent diarrhea, abdominal pain, blood in stool) allows for earlier intervention. The variant's impact on bacterial clearance also suggests that individuals with GG may benefit from strategies that support innate immunity and gut microbial diversity.

Interactions

ATG16L1 T300A interacts with other Crohn's disease susceptibility genes through multiple pathways. Multidimensionality reduction analysis shows interaction between ATG16L1, IBD5 (rs6596075), and IL23R (rs10889677) risk alleles⁸⁸ Multidimensionality reduction analysis shows interaction between ATG16L1, IBD5 (rs6596075), and IL23R (rs10889677) risk alleles
MDR analysis suggested an interaction between IBD5, ATG16L1, and IL23R risk alleles, with combined carriage of multiple risk variants substantially increasing CD risk. NOD2 (rs17221417) is particularly important— NOD2 recruits ATG16L1 to sites of bacterial entry⁹⁹ NOD2 recruits ATG16L1 to sites of bacterial entry, so NOD2 mutations combined with ATG16L1 T300A produce a synergistic defect in bacterial autophagy. Individuals homozygous for risk alleles at ATG16L1, IBD5, and NOD2 face approximately 20-fold higher CD risk¹⁰¹⁰ Individuals homozygous for risk alleles at ATG16L1, IBD5, and NOD2 face approximately 20-fold higher CD risk
CI ~9-49 compared to those carrying none of these variants. IL23R variants also show statistical interaction, as IL23R regulates the Th17 immune response that becomes dysregulated when ATG16L1-mediated bacterial clearance fails.