Identification of ATG16L1 and IRGM1 as Crohns Disease Susceptibility Genes

The genetic loci for both ATG16L1 and IRGM1 were linked to Crohn's disease by genome-wide association studies in which genetic variations between Crohn's disease patients and controls were analyzed using gene chips containing ~10,000

known single nucleotide polymorphisms (SNPs) across the human genome (The Wellcome Trust Case Control Consortium 2007; Rioux et al. 2007; Hampe et al. 2007; Parkes et al. 2007; McCarroll et al. 2008; Barrett et al. 2008). For ATG16L1, the genetic linkage is stronger for patients that primarily have ileal disease, which is not necessarily true for the other susceptibility loci. This genetic linkage is attributed to a single SNP (rs2241880) that leads to a threonine to alanine amino acid substitution in a region of the Atg16L1 protein without a known function. The rs2241880 SNP is very common and can be found in as many as 50% of healthy individuals depending on the population examined (The Wellcome Trust Case Control Consortium 2007; Rioux et al. 2007; Hampe et al. 2007). Homozygosity for the risk allele of ATG16L1 alone confers a twofold increase in risk of ileal Crohn's disease, while homozygosity for the risk allele of ATG16L1, NOD2, and a third susceptibility locus, IBD5, can confer a combined 20-fold increase in risk for Crohn's disease in the same population examined (Prescott et al. 2007). This finding exemplifies the intricate interplay between the various susceptibility loci, and indicates that future studies need to examine how these genes relate to each other in their function, especially in the context of the intestine. Notwithstanding these genetic factors, the environment clearly contributes to Crohn's disease (Jess et al. 2005).

In contrast to ATG16L1, the association between IRGM1 and Crohn's disease is attributed to several noncoding SNPs (The Wellcome Trust Case Control Consortium 2007; Parkes et al. 2007) associated with a 20 kb deletion 2.7 kb upstream of the IRGM1 transcriptional start site (McCarroll et al. 2008). Significantly different levels of IRGM1 transcripts can be detected when comparing cells with sequence variations at this locus, indicating that the deleted sequence has a role in transcriptional regulation (McCarroll et al. 2008). However, whether the deletion leads to an increase or a decrease in transcription is highly dependent on the cell line analyzed, underlying the importance of studies with primary cells to complement these foun-dational genetic studies. It is worth mentioning that, unlike the ATG16L1 polymorphism which is strictly associated with Crohn's disease (Fisher et al. 2008), the IRGM1 deletion shows increased frequency in both patients with Crohn's disease and ulcerative colitis (McCarroll et al. 2008), a pathologically distinct form of inflammatory bowel disease. In the North American population that was studied, 10% of healthy individuals carried this particular polymorphism of the IRGM1 locus compared to 15% and 14% of patients with Crohn's disease and ulcerative colitis, respectively (McCarroll et al. 2008). It will be interesting to see if the combination of the ATG16L1 and IRGM1 risk alleles act synergistically and confer a greater risk than one locus alone. Given that more than 30 loci have been linked to Crohn's disease susceptibility (Barrett et al. 2008), it will be essential to determine which loci act via a role in autophagy or other IRGM1 or ATG16L1 -dependent processes.

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