rs4958847 — IRGM

Intronic IRGM variant raising risk for Crohn's disease — particularly ileal disease and fistulizing complications

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IRGM rs4958847 — Autophagy Failure at the Gut Frontier

The human gut is in a constant negotiation with bacteria. Most organisms are kept out by the epithelial barrier, but some — including adherent-invasive Escherichia coli (AIEC) — breach the lining and invade cells directly. The body's main weapon against these intracellular invaders is [autophagy | A cellular recycling process that wraps damaged organelles and intracellular pathogens in double-membrane vesicles called autophagosomes and delivers them to lysosomes for destruction], a process in which IRGM (Immunity-Related GTPase Family M)11 IRGM (Immunity-Related GTPase Family M)
Encodes a GTPase that controls mitochondrial dynamics and serves as a master regulator of selective autophagy, specifically xenophagy (pathogen clearance) and mitophagy (damaged mitochondria elimination) plays a central coordinating role. rs4958847 is a common intronic variant in IRGM, raising the risk for Crohn's disease — particularly the ileal subtype and its most severe complications.

The Evidence

The IRGM locus was first replicated as a Crohn's disease susceptibility gene22 first replicated as a Crohn's disease susceptibility gene
Parkes et al. 2007 — Nature Genetics 39(7):830-2; genome-wide replication study, combined P=2.1×10⁻¹⁰ in a multi-locus replication analysis. rs4958847 specifically was established as a risk variant through a body of subsequent replication and meta-analysis work.

The most definitive quantification comes from a 2013 meta-analysis of 25 studies33 2013 meta-analysis of 25 studies
Lu et al. 2013 — PLoS One; 20,590 IBD cases and 27,670 controls which found rs4958847 A allele OR=1.18 (95% CI 1.08–1.29, P=0.0002) for CD, surviving Bonferroni correction. A separate pooled analysis by Palomino-Morales et al. 200944 Palomino-Morales et al. 2009
Genes Immun 10(4):356-64; 557 CD, 425 UC patients and 672 controls found rs4958847 A allele OR=1.31 (P=2.78×10⁻¹⁷) for CD.

The effect size is larger in phenotype-restricted analyses. In a New Zealand Caucasian cohort55 New Zealand Caucasian cohort
Roberts et al. 2008 — Genes Immun; 507 CD patients, 475 UC, 576 controls specifically analysing ileal disease, rs4958847 A allele OR reached 1.77 (95% CI 1.22–2.56, P=0.0022), confirming that the risk is concentrated in the ileal subtype. An Italian study by Latiano et al. 200966 Latiano et al. 2009
Am J Gastroenterol; 823 CD patients including 265 paediatric cases and 578 controls found the A allele was associated with fistulizing behavior (OR=1.54, P=0.037) and perianal fistulas (OR=1.55, P=0.045), extending the signal to severe disease complications.

A 2012 surgical outcomes study77 2012 surgical outcomes study
Sehgal et al. — Dis Colon Rectum; 66 ileocolonic CD patients who underwent ileocolectomy found rs4958847 to be the most significant predictor of surgical recurrence: A-allele carriers required reoperation on average every 6.87 years versus 11.43 years for GG individuals (P=0.007), suggesting the variant marks not just susceptibility but ongoing disease severity post-surgery.

Practical Implications

For A-allele carriers with established or suspected Crohn's disease, monitoring for ileal disease patterns and fistulizing complications is more relevant than for non-carriers. Anti-TNF biologics are an established treatment for fistulizing CD — the complication subtype most strongly linked to rs4958847.

Genotype Interpretations

What each possible genotype means for this variant.

GG Typical IRGM Normal

Common genotype — standard IRGM autophagy function

You carry two copies of the common G allele at rs4958847. This is the lower-risk genotype at this IRGM locus. Globally approximately 54% of people carry this genotype; in European populations the frequency is higher (~76%), reflecting the lower A-allele frequency in that ancestry. Your genetic risk for Crohn's disease from this locus is at or below the population average.

AG One Risk Allele Intermediate

One IRGM risk allele — modestly elevated Crohn's disease risk

rs4958847 is an intronic variant in IRGM, located on chromosome 5q33.1.

The association is strongest for ileal disease and fistulizing complications. The A-allele frequency is substantially higher in African (47%) and East Asian (54%) than European (13%) populations, meaning the population-attributable risk differs by ancestry.

AA Two Risk Alleles High Risk

Two IRGM risk alleles — meaningfully elevated Crohn's disease and fistula risk

The surgical recurrence data (Sehgal et al. 2012 — A-allele carriers reoperated every 6.87 vs 11.43 years in GG individuals) suggests the A allele marks ongoing biological susceptibility, not merely disease initiation.