<em>IRGM</em> Variants and Susceptibility to Inflammatory Bowel Disease in the German Population

<div><h3>Background & Aims</h3><p>Genome-wide association studies identified the autophagy gene <em>IRGM</em> to be strongly associated with Crohn's disease (CD) but its impact in ulcerative colitis (UC), its phenotypic effects and potential epistatic interactions with other IBD susceptibility genes are less clear which we therefore analyzed in this study.</p> <h3>Methodology/Principal Findings</h3><p>Genomic DNA from 2060 individuals including 817 CD patients, 283 UC patients, and 961 healthy, unrelated controls (all of Caucasian origin) was analyzed for six <em>IRGM</em> single nucleotide polymorphisms (SNPs) (rs13371189, rs10065172 = p.Leu105Leu, rs4958847, rs1000113, rs11747270, rs931058). In all patients, a detailed genotype-phenotype analysis and testing for epistasis with the three major CD susceptibility genes <em>NOD2</em>, <em>IL23R</em> and <em>ATG16L1</em> were performed.</p> <p>Our analysis revealed an association of the <em>IRGM</em> SNPs rs13371189 (p = 0.02, OR 1.31 [95% CI 1.05–1.65]), rs10065172 = p.Leu105Leu (p = 0.016, OR 1.33 [95% CI 1.06–1.66]) and rs1000113 (p = 0.047, OR 1.27 [95% CI 1.01–1.61]) with CD susceptibility. There was linkage disequilibrium between these three <em>IRGM</em> SNPs. In UC, several <em>IRGM</em> haplotypes were weakly associated with UC susceptibility (p<0.05). Genotype-phenotype analysis revealed no significant associations with a specific IBD phenotype or ileal CD involvement. There was evidence for weak gene-gene-interaction between several SNPs of the autophagy genes <em>IRGM</em> and <em>ATG16L1</em> (p<0.05), which, however, did not remain significant after Bonferroni correction.</p> <h3>Conclusions/Significance</h3><p>Our results confirm <em>IRGM</em> as susceptibility gene for CD in the German population, supporting a role for the autophagy genes <em>IRGM</em> and <em>ATG16L1</em> in the pathogenesis of CD.</p> </div>