ABSTRACT
UNLABELLED: BACKGROUD/PURPOSE: Hirschsprung-associated enterocolitis (HAEC) represents a cause for significant pre- and postoperative morbidity and mortality in Hirschsprung disease (HD). Although multiple studies on HAEC have been performed and several mechanisms have been presumed, the pathogenesis of this condition remains unclear. As changes in colonic mucosal defense are key factors suggested in both Crohn's disease (CD) and HAEC pathogenesis, the aim of the current study was to investigate genetic alterations in the most important susceptibility gene for Crohn's enterocolitis (NOD2) to see whether carriers of polymorphisms within the NOD2 gene are predisposed to the development of HAEC. METHODS: Genotyping for the NOD2 variants in exon 4 (p.Arg702Trp [rs2066844]), exon 8 (p.Gly908Arg [rs2066845]), and exon 11 (p.1007fs [rs2066847]) was performed in 52 white children with HD (41 boys, 11 girls), 152 healthy controls, and 152 children with CD (onset of disease <17 years; mean, 11.8 years). Seventeen patients with HD (32.7%) were carriers of a RET germline mutation, 35 children (67.3%) had short segment disease, and 17 (32.7%) had long segment disease. RESULTS: Ten children (19.2%) with HD were heterozygous carriers of at least one NOD2 variant vs 17 (11.2%) in the healthy control group and 69 (45.4%) in the CD cohort. Hirschsprung-associated enterocolitis was observed in 7 children (13.5%), with 4 having short segment HD and 3 with long segment HD; but none of them were carriers of NOD2 variants. CONCLUSION: Our study shows that NOD2 variants described to be causatively associated with CD do not predispose to the development of HAEC. As data on the molecular basis of HAEC are limited, the distinct mechanisms involved in the pathogenesis of this complication remain unclear.
Subject(s)
Enterocolitis/genetics , Hirschsprung Disease/genetics , Nod2 Signaling Adaptor Protein/genetics , Adolescent , Child , Child, Preschool , Enterocolitis/etiology , Female , Genetic Predisposition to Disease , Genotype , Germ-Line Mutation , Heterozygote , Hirschsprung Disease/complications , Humans , Infant , Male , Mutation , Polymorphism, GeneticABSTRACT
BACKGROUND: Inflammatory bowel disease (IBD) is a polygenetic disorder. Our group previously showed that a variant within the CXCL9 gene is associated with pediatric Crohn's disease. As CXCL9, CXCL10, and CXCL11 are the 3 ligands to the receptor CXCR3, the aim of this study was to investigate the colonic transcriptional activity of the CXCR3 axis and to perform SNP genotyping of a CXCL11 polymorphism in a large pediatric and adult IBD cohort. METHODS: mRNA expression of CXCR3, CXCL9, CXCL10, CXCL11, and IL8 was analyzed in colonic biopsies using real-time PCR. CXCL11 rs6817952 nucleotide substitution was determined in 501 German individuals with IBD (336 CD, 165 UC) including 258 children and 243 adults as well as in 231 controls by a TaqMan SNP genotyping assay. RESULTS: CXCR3 axis genes were significantly overexpressed in inflamed colonic tissue of pediatric CD and UC patients. The prevalence of hetero- and homozygous variants of the rs6817952 genotype was higher in pediatric but not in adult CD patients compared with that in controls (P = 0.04). Moreover, carriers of the hetero- and homozygous genotype variants of rs6817952 were at increased risk for UC in all age groups (P = 0.009). CONCLUSIONS: Our study provides evidence of the significant overexpression of the CXCR3 axis in active IBD, suggesting it has a role in IBD pathogenesis. The rs6817952 A variant is a risk allele for pediatric CD and UC in all age groups. Therapeutic studies will have to show whether the blockade of chemokine receptors such as CXCR3 can modulate intestinal inflammation in a clinical application.
Subject(s)
Inflammatory Bowel Diseases/metabolism , Receptors, CXCR3/analysis , Receptors, CXCR3/metabolism , Adolescent , Adult , Aged , Biopsy , Chemokine CXCL10/analysis , Chemokine CXCL11/analysis , Chemokine CXCL9/analysis , Child , Child, Preschool , Cohort Studies , Colon/metabolism , Female , Gene Expression Regulation , Genetic Predisposition to Disease , Genotype , Germany/epidemiology , Humans , Infant , Inflammatory Bowel Diseases/epidemiology , Inflammatory Bowel Diseases/genetics , Interleukin-8/analysis , Male , Middle Aged , Polymorphism, Single Nucleotide , Prevalence , Receptors, CXCR3/genetics , Risk Factors , Young AdultABSTRACT
BACKGROUND/PURPOSE: Three common mutations of the NOD2/CARD15 gene have been associated with Crohn disease (CD), ileal disease location, and fibrostenotic behavior. The aim of this study was to investigate the effect of these mutations on disease manifestation and the risk of surgery in a cohort of German childhood-onset CD patients. METHODS: Genotyping for the NOD2 mutations p.Arg702Trp, p.Gly908Arg, and p.1007fs was performed in 171 CD children (onset of disease <17 years; mean 11.8 years) and in 253 controls. NOD2 mutation status was correlated with the need for surgery during childhood. RESULTS: Seventy-eight children (45.6%) were carriers of at least 1 NOD2 mutation versus 36 (14.2%) in the control group (P < .0001). NOD2 mutations were highly associated with CD and stricturing behavior (P < .0001), with the p.1007fs mutation also conferring a risk for isolated ileal disease (P = .003). Thirty-two children (18.7%) needed an intestinal resection with a significant association between the need of surgery and NOD2 carrier status. Surgery occurred at an earlier stage of disease in children with p.1007fs mutations. CONCLUSIONS: In children with pediatric-onset CD, the need for surgical therapy younger than 17 years is associated with the NOD2 genotype. Genetic testing therefore may identify children with CD who are at risk.
