rs13361189 — IRGM −4299T>C

The Autophagy Guardian — When Gut Immunity Falters

Your cells have a sophisticated waste disposal and defense system called autophagy — literally "self-eating" — that wraps up cellular debris, damaged organelles, and invading bacteria in membranous sacks and destroys them. IRGM (Immunity-Related GTPase M) acts as a master regulator of this process, especially in the gut, where it coordinates your intestinal cells' response to the trillions of bacteria living in your digestive tract.

The rs13361189 variant sits in a regulatory region 4,299 base pairs upstream of the IRGM gene¹¹ 4,299 base pairs upstream of the IRGM gene
This promoter position affects gene transcription, and it's in perfect linkage disequilibrium²² perfect linkage disequilibrium
Two variants are always inherited together with a 20-kilobase deletion that fundamentally alters how much IRGM your cells produce. This isn't just an academic curiosity — it's one of the strongest genetic risk factors for Crohn's disease, a chronic inflammatory bowel condition that affects millions worldwide.

The Mechanism

IRGM is a GTP-binding protein that functions as a platform for assembling the core autophagy machinery. When a bacterial cell enters your intestinal epithelium — either a pathogen breaching the barrier or a commensal bacterium that's wandered where it shouldn't — IRGM springs into action. It physically interacts with NOD2 and ATG16L1³³ physically interacts with NOD2 and ATG16L1
Two other major Crohn's disease risk genes, creating a molecular complex, recruiting the autophagy initiation proteins ULK1 and BECN1 to the invasion site.

IRGM also regulates mitochondrial dynamics⁴⁴ regulates mitochondrial dynamics
It controls mitochondrial fission, which is necessary for autophagy, demonstrating differential affinity for the mitochondrial lipid cardiolipin and affecting mitochondrial fission — a process that turns out to be essential for autophagic control of intracellular bacteria like Mycobacterium tuberculosis.

The rs13361189 C allele (the risk variant) reduces IRGM expression by approximately 30-50%⁵⁵ reduces IRGM expression by approximately 30-50%
Measured in whole blood and terminal ileum tissue in carriers. This reduction compromises the cell's ability to quickly wrap invading bacteria in autophagosomes, allowing bacterial persistence and triggering chronic inflammation as the immune system struggles to clear an infection it can't eliminate.

Intriguingly, the same variant also upregulates ZNF300P1⁶⁶ upregulates ZNF300P1
A long non-coding RNA adjacent to IRGM on chromosome 5, a long non-coding RNA that appears to further dysregulate the autophagy pathway, creating a cascade of altered gene expression affecting inflammation and immune response.

The Evidence

The association between IRGM variants and Crohn's disease emerged from genome-wide association studies⁷⁷ genome-wide association studies
GWAS scan millions of genetic variants across thousands of people that identified rs13361189 as one of the strongest signals outside the MHC region, with a combined p-value of 2.1 × 10⁻¹⁰ — extraordinarily robust by genomic standards.

A meta-analysis of seven case-control studies⁸⁸ meta-analysis of seven case-control studies
Including 3,093 Crohn's patients and 3,227 controls confirmed that the C allele increases Crohn's disease risk with a relative risk of 1.25 (95% CI: 1.04-1.50, P=0.016). In the dominant model (CT + CC versus TT), the relative risk is 1.21 (95% CI: 1.03-1.42, P=0.018). While these effect sizes might seem modest, they're clinically meaningful for a complex polygenic disease.

The population genetics tell a fascinating story: the C (risk) allele frequency is approximately 8% in Europeans but jumps to 44% in Africans and 43% in East Asians. Yet Crohn's disease remains primarily a disease of European ancestry populations, suggesting gene-environment or gene-gene interactions⁹⁹ gene-environment or gene-gene interactions
The variant alone isn't sufficient — other factors must be present are required for disease manifestation.

Functional studies have demonstrated that IRGM-deficient cells show impaired autophagy¹⁰¹⁰ IRGM-deficient cells show impaired autophagy
Measured by accumulation of LC3-II and p62, autophagy markers and extended survival of intracellular bacteria including Mycobacterium tuberculosis, Salmonella, and adherent-invasive E. coli (AIEC) — a strain commonly found in Crohn's disease patients.

Perhaps most compelling, rs13361189 minor allele carriers show altered expression¹¹¹¹ rs13361189 minor allele carriers show altered expression
Of dozens of inflammation and autophagy genes beyond just IRGM of multiple genes regulating inflammation and autophagy in both blood and intestinal tissue, including reduced expression of genes involved in bacterial sensing (TLRs) and inflammatory regulation (cytokines), creating a systemic defect in immune homeostasis.

Practical Actions

If you carry one or two C alleles at rs13361189, your autophagy system is working at reduced capacity, particularly in your gut. This has implications beyond Crohn's disease risk — it affects how your body handles gut bacteria, clears cellular debris, and maintains the intestinal barrier.

Autophagy enhancement becomes a priority. Vitamin D is a potent autophagy inducer¹²¹² Vitamin D is a potent autophagy inducer
Through the VDR receptor, it upregulates autophagy genes and specifically promotes intestinal autophagy while modulating gut microbiota. Maintaining adequate vitamin D levels (25-hydroxyvitamin D above 30 ng/mL, ideally 40-60 ng/mL) is particularly important for IRGM variant carriers.

Dietary strategies can support autophagy and reduce inflammatory triggers. A recent randomized controlled trial of fasting-mimicking diet¹³¹³ randomized controlled trial of fasting-mimicking diet
Five consecutive days per month of 700-1,100 calories in Crohn's patients showed that about two-thirds experienced improvement in symptoms, likely through autophagy induction and reduced inflammatory signaling. Even without formal fasting protocols, reducing ultra-processed foods, limiting red and processed meat, and emphasizing fiber from diverse plant sources can help maintain gut microbiome balance.

Butyrate-producing bacteria deserve special attention. People with IRGM variants show reduced abundance of Roseburia and Faecalibacterium¹⁴¹⁴ reduced abundance of Roseburia and Faecalibacterium
Key butyrate producers that support colonocyte health, bacteria that produce the short-chain fatty acid butyrate. Butyrate not only nourishes colonocytes but also induces autophagy through AMPK activation¹⁵¹⁵ induces autophagy through AMPK activation
AMPK inhibits mTOR, the master autophagy suppressor, partially compensating for reduced IRGM function. Resistant starch (found in cooked and cooled potatoes, rice, and legumes), inulin (from Jerusalem artichokes, chicory, garlic), and other fermentable fibers feed these beneficial bacteria.

Monitoring is important for C allele carriers, especially if you have digestive symptoms. Fecal calprotectin¹⁶¹⁶ Fecal calprotectin
A protein released by inflamed intestinal cells, measured in stool is a non-invasive marker of intestinal inflammation that's more specific than blood tests like CRP or ESR. If you have chronic digestive issues — particularly abdominal pain, diarrhea, or unexplained weight loss — request fecal calprotectin testing. Elevated levels (>150 μg/g) warrant gastroenterology referral and possible colonoscopy.

Omega-3 fatty acids (EPA and DHA) support both autophagy and anti-inflammatory signaling. While the evidence is mixed for omega-3s in established Crohn's disease, they may help maintain gut barrier function and reduce low-grade inflammation in at-risk individuals.

Interactions

IRGM doesn't work in isolation — it's part of an interconnected autophagy network¹⁷¹⁷ interconnected autophagy network
Including NOD2 (rs2066844, rs2066845, rs2066847) and ATG16L1 (rs2241880) that includes NOD2 and ATG16L1, two other major Crohn's disease susceptibility genes. NOD2 recognizes bacterial cell wall fragments (muramyl-dipeptide) and recruits ATG16L1 to the bacterial entry site at the plasma membrane, initiating autophagosome formation. IRGM promotes ubiquitination of the complex and assembly of the core autophagy machinery.

When you carry risk variants in multiple autophagy genes — such as IRGM rs13361189 plus NOD2 frameshift mutations (rs2066847) or ATG16L1 T300A (rs2241880) — the combined effect on Crohn's risk is multiplicative¹⁸¹⁸ combined effect on Crohn's risk is multiplicative
Each additional risk allele substantially increases disease susceptibility, not merely additive. A genetic interaction has been documented between rs13361189 and ATG16L1 rs2241880, with compound carriers showing markedly reduced bacterial clearance in functional studies.

The IRGM variant also affects response to certain treatments. While the data is limited, some studies suggest that ATG16L1 variants predict response to anti-TNF biologics¹⁹¹⁹ ATG16L1 variants predict response to anti-TNF biologics
IRGM variants may show similar patterns like adalimumab in Crohn's disease patients, though similar associations for IRGM variants specifically have not been as well characterized.

Beyond Crohn's disease, IRGM variants modify tuberculosis susceptibility²⁰²⁰ modify tuberculosis susceptibility
The same autophagy defect impairs clearance of Mycobacterium tuberculosis, with some studies showing protective effects against active TB progression in rs13361189 C carriers (OR 0.72, 95% CI 0.51-1.01 in Chinese populations), possibly due to altered cytokine responses. The variant also associates with altered risk for other infections where autophagy plays a role in pathogen control.