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The high incidence of Scottish Crohn's disease (CD) is not explained by the common three NOD2/CARD15 variants. We aimed to identify population-specific NOD2/CARD15 coding variants. A total of 1478 (320 inflammatory bowel disease patients <16 years, 343 adult CD patients, 542 parents and 273 controls). All NOD2/CARD15 exons were sequenced in 24 CD patients. Sequencing identified 18 single-nucleotide polymorphisms (SNPs) including 4 non-synonymous coding SNPs altering the structure of the Leucine-rich region—two were well established (1007-/C and 908G/R). Two other variants, valine955isoleucine (955V/I) and methionine863valine (863M/V), were genotyped in all subjects. 863M/V carriage was not significantly higher in CD patients vs controls (1.35 vs 0.37%, P=0.27). 955V/I carriage was no higher in CD or ulcerative colitis patients (12.8 and 15.8%, respectively) compared to controls (16.2%). Transmission disequilibrium test analysis was negative. 955V/I carriage was higher in indeterminate colitis patients (n=29) compared to controls (41.4 vs 16.2%, P=0.001, OR=3.6 (1.6–8.2)). Population-specific NOD2/CARD15 exonic variants do not account for the high-CD prevalence in Scotland.Genes and Immunity (2008) 9, 556–560; doi:10.1038/gene.2008.44; published online 19 June 2008 [ABSTRACT FROM AUTHOR]

Background and aims: The OCTN1 (SLC22A4 1672C→T) and OCTN2 (SLC22A5 -207G→C) variants within the IBD5 locus have been associated with susceptibility to adult onset Crohn's disease (CD), but their contribution in children has not been examined. Methods: These OCTN1/2 variants and IBD5 marker single nucleotide polymorphisms (SNPs) (IGR2096a•1, IGR2198a•1, and IGR2230a•1) were examined in 299 Scottish children (200 with CD, 74 with ulcerative colitis (UC), and 25 with indeterminate colitis (IC)), together with 502 parents (for transmission disequilibrium testing) and 256 controls. Results: All SNPs were in strong linkage disequilibrium (D' >0.94). TDT analysis showed association of the OCTN1 variant with inflammatory bowel disease (IBD) (p = 0.01) and CD (p = 0.04). Allele frequencies of the OCTN1/2 variants were significantly higher in IBD/CD cases (p<0.04). The homozygous mutant OCTN1/2 haplotype was increased in IBD (24.3% v 16.1%, p=0.02) and UC (28.2% v 16.1%, p=0.02) compared with controls. The OCTN1/2 variants were not independent of the background IBD5 risk haplotype in conferring disease susceptibility. Unifactorial analysis in CD patients showed that carriage of the TC haplotype was associated with lower weight, height, and BMI centile (<9th centile) at diagnosis (weight: 87.9% v 67.3% (p=0.002), odds ratio (OR)= 3.52 (95% confidence interval, 1.51 to 8.22); height: 84.1% v 68.4%(p<0.05), OR=2.44 (1.00 to 5.99); BMI: 79.6% v 61.1% (p=0.02), OR=2.49 (1.14 to 5.44)), and lower weight centile at follow up (87.5% v 64.6% (p=0.03), OR=3.83 (1.03 to 14.24)). Multifactorial binary logistic regression analysis confirmed association of the TC haplotype with lower weight centile at diagnosis (p=0.02, OR= 3.41 (1.20 to 9.66)). Conclusions: These data implicate variants within the IBD5 haplotype, as determinants of disease susceptibility and growth indices in early onset IBD. The OCTN1/2 variants remain potential positional candidate genes, but require further analysis. [ABSTRACT FROM AUTHOR]

Introduction: Recent data have suggested that specific haplotypic variants of the DLG5 gene on chromosome 10q23 may be associated with susceptibility to inflammatory bowel disease (IBD) in Germany. Haplotype D, notably characterised by the presence of a G→A substitution at nucleotide 113, was associated with susceptibility to Crohn's disease (CD) whereas an extended haplotype A conferred protection. Aims: Association of DLG5 haplotypic variants with disease susceptibility, genotype-phenotype relationships, and epistasis with CARD 15 was investigated in the Scottish population. Patients and methods: A total of 374 CD, 305 ulcerative colitis (UC), and 294 healthy controls (HC) were studied. Genotyping for the variants rs1248696 (113A, representing haplotype D) and the single nucleotide polymorphism tag rs2289311 (representing haplotype A) were typed using the Taqman system. Results: On analysis of the DLG5 variant 113A, there were no associations with IBD when allelic frequency (11.4% IBD v 13.2% HC; p=0.30) and carrier frequency (19.2% IBD v 24.6% HC; p =0.069) were analysed. No associations were observed between 11 3A variant allelic frequency (p=0.37), carrier frequency (p =0.057), and CD. In fact, 113A heterozygosity rates were lower in CD (16%) and IBD (16.9%) than in HC (23%) (p =0.029 and p = 0.033, respectively). No associations between DIGS and UC were observed. Haplotype A was not protective and there was no evidence of epistasis between DLG5 and CARD15. Conclusions: The present data contrast strongly with previous data from Germany. DLG5 113A is not associated with disease susceptibility and haplotype A does not confer resistance. Further work is required to evaluate the significance of DLG5 in other populations from geographically diverse regions. [ABSTRACT FROM AUTHOR]

Anti- Saccharomyces cerevisiae antibodies (ASCAs) have been proposed as serological markers, which may differentiate Crohn's disease (CD) from ulcerative colitis (UC) and predict disease phenotype. Their importance in pathogenesis is unproven. We investigated the relationship between ASCAs, disease phenotype and NOD2/CARD15 genotype in CD and whether ASCAs were related to antibodies to other fungal proteins. Serum from 228 patients [143 CD, 75 UC, 10 with indeterminate colitis (IC)] and 78 healthy controls (HC) were assayed for ASCA. Antibodies (IgA, IgG) to other fungal proteins ( Fusarium species ATC20334, Mycoprotein) were measured in the same samples using an in-house enzyme-linked immunosorbent assay (ELISA) assay. ASCAs were present in 57% of CD, 19% of UC, 30% of IC and 8% of HCs. ASCA-positive status was a predictor for CD with sensitivity of 57%, specificity of 87%, positive predictive value of 78% and negative predictive value of 68%. ASCA was associated with proximal (gastroduodenal and small bowel involvement) rather than purely colonic disease ( P < 0·001) and with a more severe disease phenotype and requirement for surgery over a median follow-up time of 9 years ( P < 0·0001). No associations with NOD2/CARD15 mutations were seen. There was no association between ASCA and antibodies to MP (IgA or IgG). These data implicate ASCA as a specific marker of disease location and progression in CD, emphasizing the heterogeneity within IBD. [ABSTRACT FROM AUTHOR]

In this article, Stevens et al. present a series of findings that demonstrate vimentin, an intermediate filament protein, to be a key regulator of nucleodde-binding oligomerization domain containing 2 (NOD2) function. Genetic variants of the vimentin gene are associated with Crohn's disease, supporting a role for this protein in disease pathogenesis. [ABSTRACT FROM AUTHOR]

The multidrug resistance gene (MDR1) gene encodes a transmembrane efflux pump which is highly expressed on intestinal epithelial cells. The ulcerative colitis (UC) like phenotype in mdrla-deficient mice and the position of the gene within chromosome 7q22, together with recent genetic studies implicate this as a strong candidate gene for inflammatory bowel's disease. The MDR1 SNP C3435T at exon 26 correlates strongly with MDR1 expression and has been shown to be associated with increased susceptibility to UC. Authors tested whether this SNP is associated with UC and performed further genotype-phenotype analysis in a large well characterised Caucasian cohort. These data suggest that the MDR1 gene encodes determinants of disease susceptibility and behaviour UC.