A Link Between Cellular Recycling & Crohn’s Disease (IRGM)

IRGM (immunity-related GTPase family M protein) is a cog in the machinery of the immune system that regulates autophagy. Autophagy (from the Greek for self-eating) is the regulated process by which a cell breaks down dysfunctional or foreign components. The cell can then recycle useful chemical components for further purposes [R].

IRGM can be activated by three signals (that we know of): starvation (lack of energy), interferons (antiviral and antimicrobial response proteins), and contact with bacteria or bacterial products [R, R].

During a bacterial infection, some white blood cells ingest and break down the invaders using the process of autophagy. Researchers believe that IRGM is required for the cell to trigger autophagy in response to microbes [R, R, R].

Without IRGM, cells would be more susceptible to damage and bacterial infection. On the other hand, overexpression of IRGM can trigger cell death by damaging the mitochondria [R].

IRGM is activated by starvation, interferons, or contact with bacterial products. In turn, it triggers the process of autophagy.

Well-regulated autophagy is important for the maintenance of the intestinal lining, which forms the major barrier between bacteria in the gut and our bloodstreams. As such, IRGM is a major player in our gut health [R, R].

What is Crohn’s Disease?

IBD is a group of autoimmune diseases characterized by inflammation and sores in the gut lining, which can result in diarrhea, abdominal pain, fatigue, fever, rectal bleeding, nutritional deficiencies, and weight loss. The definition of IBD includes both ulcerative colitis and Crohn’s disease [R].

Crohn’s disease differs from ulcerative colitis in that it is centered higher in the digestive tract (typically in the small intestine, though it can occur anywhere between the mouth and anus) and may damage broader swaths of tissue [R, R].

IRGM & Crohn’s Disease

IRGM is relatively well-studied as a genetic risk factor for Crohn’s disease [R, R].

The level of expression of IRGM is highly variable from tissue to tissue, and there is some confusion about whether high or low IRGM may increase the risk of Crohn’s. On the one hand, autophagy plays an important role in maintaining the intestinal barrier and preventing bacterial infection; on the other, IRGM overexpression may cause cell death in the lining of the gut [R, R].

Genetic association studies can provide some clues about whether high or low gut IRGM could be harmful. In cell studies, risk alleles have been associated with both higher and lower IRGM expression, depending on the cell type. In human studies, however, risk alleles have been associated with increased IRGM in the gut tissues specifically [R].

A possible mechanism for IRGM and Crohn’s disease may be that very high IRGM triggers cell death in the intestinal lining. However, some researchers have also found evidence of IRGM deficiency in models of IBD [R, R].

IRGM mutations are linked with Crohn’s disease, but researchers disagree about whether very high or very low IRGM is more likely to cause IBD.

Interactions With Other Gut Inflammation Genes

IRGM is known to interact with and possibly regulate other genes that have been implicated in Crohn’s disease. The most conspicuous among these are TNF and NOD2 [R, R].

If you have detrimental mutations in IRGM, check out these other genes as well.

Multiple IRGM variants have been associated with increased rates of Crohn’s disease. These include:

• The ‘T’ allele of rs1000113 [R]
• The ‘G’ allele of rs7714584 [R]
• The ‘G’ allele of rs11747270 [R]
• The ‘C’ allele of rs13361189 [R]
• The ‘G’ allele of rs11741861 [R]
• The ‘T’ allele of rs10065172 [R]

In each of these cases, the rare allele is the one associated with disease. Little research has been done into how these alleles change the expression or activity of IRGM, though one study found significantly increased IRGM expression in the gut of Crohn’s disease patients with one copy of the risky ‘T’ allele at rs10065172 compared to those with no copies. However, the relationship between the ‘TT’ homozygous genotype and IRGM expression was less clear [R].

A more consistent finding has been that risk alleles in IRGM increase the expression of TNF-alpha, a strong proinflammatory cytokine which is dramatically increased in Crohn’s disease patients. Oddly, increased TNF expression has been linked with IRGM deficiency in some human cell studies, throwing another wrench in the research [R].

It is also possible that different IRGM risk alleles have different effects on expression, with some causing overexpression and some causing deficiency. Additional research is required.

At least six common IRGM variants have been significantly associated with Crohn’s disease. The precise mechanism of effect of these variants remains unclear.

SNP Summary and Table

IRGM rs1000113

• ‘C’ = Not associated with Crohn’s disease
• ‘T’ = Associated with Crohn’s disease
• About 36% of all people worldwide have at least one copy of the ‘T’ allele.
• The ‘T’ allele is significantly less common in people of European (20%) and South Asian (22%) descent and significantly more common in people of East Asian descent (63%).

IRGM rs7714584

• ‘A’ = Not associated with Crohn’s disease
• ‘G’ = Associated with Crohn’s disease
• About half of all people worldwide have at least one copy of the ‘G’ allele, but frequencies vary widely between ethnic groups.
• The ‘GG’ genotype is most common in people of East Asian (21%) and African (27%) descent.

IRGM rs11747270

• ‘A’ = Not associated with Crohn’s disease
• ‘G’ = Associated with Crohn’s disease
• Allele frequencies for this SNP are closely linked to those for rs7714584.

IRGM rs13361189

• ‘T’ = Not associated with Crohn’s disease
• ‘C’ = Associated with Crohn’s disease
• Allele frequencies for this SNP are closely linked to those for rs7714584.

IRGM rs11741861

• ‘A’ = Not associated with Crohn’s disease
• ‘G’ = Associated with Crohn’s disease
• Only about a quarter of all people worldwide have at least one copy of the ‘G’ allele.
• The ‘G’ allele is much more common in people of East Asian descent (63%).

IRGM rs10065172

• ‘C’ = Not associated with Crohn’s disease
• ‘T’ = Associated with Crohn’s disease
• Allele frequencies for this SNP are closely linked to those for rs7714584.