Glucocorticoid resistance in Crohn's disease and ulcerative colitis: an association study investigating GR and FKBP5 gene polymorphisms.

The aim of this study is to investigate the role of single-nucleotide polymorphisms (SNPs) of the glucocorticoid receptor (GR) and of the related co-chaperone FKBP5 genes in the development of glucocorticoid (GC) resistance in Crohn's disease (CD) and ulcerative colitis (UC) patients. We have developed a high-resolution DNA melting method that allows simultaneous identification of GR (BclI, N363S and ER22/23EK) and FKBP5 (rs3800373, rs1360780 and rs4713916) polymorphisms. Genotype frequencies were determined in 100 consecutive CD and 100 UC patients under GCs therapy (50 responders and 50 resisters). The variation of FKBP5 polymorphism rs4713916 (G/A), in the putative promoter region of FKBP5, is significantly associated with resistance to GC treatment in CD (responder=17% versus resister=35%; P=0.0043). No significant differences were found in UC patients. If these preliminary findings will be confirmed, the combination of GR and FKBP5 mutational analyses could help to identify subgroups of CD patients with higher chances to benefit from GC treatment.

The -A2518G polymorphism of monocyte chemoattractant protein-1 is associated with Crohn's disease.

OBJECTIVES: The -A2518G variation in monocyte chemoattractant protein (MCP)-1 gene promoter has been associated with autoimmune diseases. Our aim was to investigate the gene polymorphism and MCP-1 plasma levels in patients with inflammatory bowel disease (IBD). METHODS: Family-based and case-control association analyses of the -A2518G polymorphism (rs1024611) were performed in 1,936 subjects (770 patients with Crohn's disease (CD), 316 patients with ulcerative colitis (UC), 302 healthy relatives (151 CD trios), and 548 healthy controls (HCs)). Extensive gene sequencing was also undertaken, and a further six single-nucleotide polymorphisms (SNPs) were genotyped in 435 CD patients and 189 HCs. MCP-1 protein plasma levels in 234 CD patients, 117 UC patients, and 108 HCs were assessed by an immunosorbent assay. RESULTS: Five SNPs in strong linkage disequilibrium (D'>0.85) were associated with CD, with the strongest signal found at the -A2518G SNP. The frequency of the G allele was significantly lower in CD patients (22.1%), compared with HCs (29.8%), both at case-control (P=6 x 10(-6)) and at transmission disequilibrium test analyses (T/U 41/88; P=4 x 10(-4)). No difference in alleles (26.1%) and genotype frequencies were found in UC patients. MCP-1 plasma levels in CD and UC patients were similar to those in HCs (P=0.38), irrespective of disease activity, or MCP-1 genotypes. However, 30 CD (13%) and 20 UC patients (17%) with extensive colonic involvement had plasma levels significantly higher than HCs (P=0.02). CONCLUSIONS: The -A2518G polymorphism seems to be associated with CD but does not influence MCP-1 plasma levels, which in contrast are increased in UC and CD with extensive colonic involvement.

Anti-Saccharomyces cerevisiae mannan antibodies in inflammatory bowel disease: comparison of different assays and correlation with clinical features.

BACKGROUND: Anti-Saccharomyces cerevisiae mannan antibodies have been proposed as a new serological marker associated with Crohn's disease. However, their clinical value is still unclear; furthermore, a standardization of anti-S. cerevisiae mannan measurements is lacking. AIM: In this study, we aimed to assess the correlation between anti-S. cerevisiae mannan detection and specific clinical features in Crohn's disease and ulcerative colitis. Moreover, we tested the concordance of four different anti-S. cerevisiae mannan assays. MATERIALS AND METHODS: Serum samples from 196 patients with Crohn's disease, 197 patients with ulcerative colitis and 100 unrelated healthy controls were tested for anti-S. cerevisiae mannan with a standard enzyme-linked immunosorbent assay method (Lille) by one of the authors (VP). Subsequently, 60 randomly selected serum samples (27 Crohn's disease, 28 ulcerative colitis and five healthy controls) were tested for anti-S. cerevisiae mannan with three different commercial kits. RESULTS: With the Lille assay, anti-S. cerevisiae mannan were detected in 100 of 196 patients with Crohn's disease (51%; P < 0.0001 vs. controls), 32 of 197 patients with ulcerative colitis (16%; P < 0.02 vs. controls), and six of 100 controls (6%). No correlation between presence of anti-S. cerevisiae mannan and specific clinical features was found in both ulcerative colitis and Crohn's disease patients. The percentages of anti-S. cerevisiae mannan detected with four different assays ranged from 28 (Bouty) up to 43% (Inova), but these differences did not reach statistical significance. The concordance rate of anti-S. cerevisiae mannan detection in the four assays was very low (11 concordant results of 60 samples, 18.3%) (k = 0.15). No improvement of the concordance rate was obtained by modifying the suggested cut-off values (k = 0.20). CONCLUSION: In this study, we confirm that anti-S. cerevisiae mannan are significantly more frequent in Crohn's disease patients compared with ulcerative colitis patients (P < 0.0001) and controls. However, no correlation with clinical features was found in both ulcerative colitis and Crohn's disease. The low prevalence of anti-S. cerevisiae mannan, at least in our population, and the low concordance rate between different assays, makes the clinical role of this marker questionable.