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


RESULTS
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
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.
Department of Medicine II - Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
Jürgen
J
Glas
Julia
J
Seiderer
Stephanie
S
Bues
Johannes
J
Stallhofer
Christoph
C
Fries
Torsten
T
Olszak
Eleni
E
Tsekeri
Martin
M
Wetzke
Florian
F
Beigel
Christian
C
Steib
Matthias
M
Friedrich
Burkhard
B
Göke
Julia
J
Diegelmann
Darina
D
Czamara
Stephan
S
Brand
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics; D016022:Case-Control Studies; D003093:Colitis, Ulcerative / Q000453:epidemiology / Q000235:genetics*; D003424:Crohn Disease / Q000453:epidemiology / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005858:Germany / Q000453:epidemiology; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D044465:White People
C518959:ATG16L1 protein, human; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D019204:GTP-Binding Proteins; C513539:IRGM protein, human