IRGM variants and susceptibility to inflammatory bowel disease in the German population

PLoS One. 2013;8(1):e54338. doi: 10.1371/journal.pone.0054338. Epub 2013 Jan 24.

Abstract

Background & aims: Genome-wide association studies identified the autophagy gene IRGM 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.

Methodology/principal findings: 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 IRGM 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 NOD2, IL23R and ATG16L1 were performed. Our analysis revealed an association of the IRGM 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 IRGM SNPs. In UC, several IRGM 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 IRGM and ATG16L1 (p<0.05), which, however, did not remain significant after Bonferroni correction.

Conclusions/significance: Our results confirm IRGM as susceptibility gene for CD in the German population, supporting a role for the autophagy genes IRGM and ATG16L1 in the pathogenesis of CD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Autophagy-Related Proteins
  • Carrier Proteins / genetics
  • Case-Control Studies
  • Colitis, Ulcerative / epidemiology
  • Colitis, Ulcerative / genetics*
  • Crohn Disease / epidemiology
  • Crohn Disease / genetics*
  • Epistasis, Genetic
  • European Continental Ancestry Group
  • Female
  • GTP-Binding Proteins / genetics*
  • Gene Frequency
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Germany / epidemiology
  • Haplotypes
  • Humans
  • Linkage Disequilibrium
  • Male
  • Middle Aged
  • Phenotype
  • Polymorphism, Single Nucleotide*

Substances

  • ATG16L1 protein, human
  • Autophagy-Related Proteins
  • Carrier Proteins
  • GTP-Binding Proteins
  • IRGM protein, human

Grant support

JG was supported by a grant from the Broad Medical Foundation (IBD-0126R2). J. Seiderer and JD were supported by grants from the Ludwig-Maximilians-University Munich (FöFoLe Nr. 422; Habilitationsstipendium, LMUExcellent to J. Seiderer and Promotionsstipendium to JD); J. Seiderer was also supported by the Else Kröner-Fresenius-Stiftung (81/08//EKMS08/01). S. Brand was supported by grants from the German Research Foundation (BR 1912/6-1), the Else Kröner-Fresenius-Stiftung (Else Kröner Exzellenzstipendium 2010; 2010_EKES.32), and by grants of Ludwig-Maximilians-University Munich (Excellence Initiative, Investment Funds 2008 and FöFoLe program). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.