Epithelioid granulomas, pattern recognition receptors, and phenotypes of Crohn's disease.

INTRODUCTION: Crohn's disease is a chronic inflammatory disorder of the gut. It is assumed that a defective interaction between the bacterial flora of the gut and the innate immune system plays a key role in the pathogenesis of the disease. This may lead to specific histological lesions. The epithelioid granuloma is particularly interesting in this regard as it is also observed in several bacterial infections of the gut. AIMS AND METHODS: We hypothesised that genetic or environmental factors with a known influence on inflammation or immunity would lead to an increased prevalence of granulomas. Therefore, surgical specimens from 161 patients were evaluated for the presence of granulomas. Patients were genotyped for the three single nucleotide polymorphisms in caspase recruitment domain 15 (CARD15)/NOD2 associated with CD and for Asp299Gly in Toll-like receptor 4 (TLR4). RESULTS: The overall prevalence of granulomas was 68.9%. We did not find a significant correlation between granulomas and TLR4 or CARD15 variants. The frequency of granulomas increased with more distal disease (63% small bowel, 72% right colon, 88% left colon, 90% rectum; p=0.01). Granulomas were more frequent in younger patients (odds ratio 0.95 (95% confidence interval 0.92-0.98) p=0.007). CONCLUSION: In this study of 161 well documented CD patients, we found no significant association between CARD15 and TLR4 variants and granulomas. This finding seems to refute our initial hypothesis. However, it may be that additional factors are needed for granuloma development. Granulomas may develop only when specific bacterial components are present. Therefore, future research on granuloma pathogenesis should be orientated towards detection and identification of bacterial components in these lesions.

Tumour necrosis factor-alpha receptor 1 and 2 polymorphisms in inflammatory bowel disease and their association with response to infliximab.

BACKGROUND: The role of tumour necrosis factor-alpha in the pathogenesis of inflammatory bowel disorders is well-known and is underscored by the effectiveness of antitumour necrosis factor-alpha treatment. Tumour necrosis factor-alpha exerts its effect by binding TNFR1 and TNFR2, which genes map to inflammatory bowel disorders susceptibility loci. AIMS AND METHODS: Since TNFR1 and TNFR2 are good candidate genes for inflammatory bowel disorders, we studied the functional TNFR2T587G and the TNFR1A36G mutation in 344 Crohn's disease and 152 ulcerative colitis patients and investigated the relation with disease phenotypes. An association with response to infliximab was evaluated in 166 Crohn's disease patients. RESULTS: The TNFR2 587G allele was more frequent in ulcerative colitis compared with controls (P = 0.03). Both single nucleotide polymorphisms were negatively associated with smoking at diagnosis in Crohn's disease (TNFR1A36G odds ratio: 0.614, 95% confidence interval: 0.452, 0.99 and TNFR2T587G odds ratio: 0.572, 95% confidence interval: 0.820, 0.875). There was a positive association between pancolitis and the TNFR1A36G polymorphism in ulcerative colitis (odds ratio: 5.341, 95% confidence interval: 1.484, 19.39). The biological response to infliximab was lower in patients carrying TNFR1 36G (odds ratio: 0.47, 95% confidence interval: 0.234, 0.946). CONCLUSION: The TNFR2 587G allele was more frequent in ulcerative colitis. Both single nucleotide polymorphisms were negatively associated with smoking in Crohn's disease. A relation between TNFR1A36G and pancolitis was found in ulcerative colitis. There was no clear effect of the polymorphisms on infliximab response although, the TNFR1 minor was associated with a lower response to infliximab.

Genome wide scan in a Flemish inflammatory bowel disease population: support for the IBD4 locus, population heterogeneity, and epistasis.

BACKGROUND AND AIMS: Genome wide scans in inflammatory bowel disease (IBD) have indicated various susceptibility regions with replication of 16cen (IBD1), 12q (IBD2), 6p (IBD3), 14q11 (IBD4), and 3p21. As no linkage was previously found on IBD regions 3, 7, 12, and 16 in Flemish IBD families, a genome wide scan was performed to detect other susceptibility regions in this population. METHODS: A cohort of 149 IBD affected relative pairs, all recruited from the Northern Flemish part of Belgium, were genotyped using microsatellite markers at 12 cM intervals, and analysed by Genehunter non-parametric linkage software. All families were further genotyped for the three main Crohn's disease associated variants in the NOD2/CARD15 gene. RESULTS: Nominal evidence for linkage was observed on chromosomes 1 (D1S197: multipoint non-parametric linkage (NPL) score 2.57, p = 0.004; and at D1S305-D1S252: NPL 2.97, p = 0.001), 4q (D4S406: NPL 1.95, p = 0.03), 6q16 (D6S314: NPL 2.44, p = 0.007), 10p12 (D10S197: NPL 2.05, p = 0.02), 11q22 (D11S35-D11S927: NPL 1.95, p = 0.02) 14q11-12 (D14S80: NPL 2.41, p = 0.008), 20p12 (D20S192: NPL 2.7, p = 0.003), and Xq (DXS990: NPL 1.70, p = 0.04). A total of 51.4% of patients carried at least one NOD2/CARD15 variant. Furthermore, epistasis was observed between susceptibility regions 6q/10p and 20p/10p. CONCLUSION: Genome scanning in a Flemish IBD population found nominal evidence for linkage on 1p, 4q, 10p12, and 14q11, overlapping with other genome scan results, with linkage on 14q11-12 supporting the IBD4 locus. The results further show that epistasis is contributing to the complex model of IBD and indicate that population heterogeneity is not to be underestimated. Finally, NOD2/CARD15 is clearly implicated in the Flemish IBD population.