Two-stage genome-wide methylation profiling in childhood-onset Crohn's Disease implicates epigenetic alterations at the VMP1/MIR21 and HLA loci.

Background: As a result of technological and analytical advances, genome-wide characterization of key epigenetic alterations is now feasible in complex diseases. We hypothesized that this may provide important insights into gene-environmental interactions in Crohn's disease (CD) and is especially pertinent to early onset disease.

Methods: The Illumina 450K platform was applied to assess epigenome-wide methylation profiles in circulating leukocyte DNA in discovery and replication pediatric CD cohorts and controls.

Genome-wide methylation profiling in Crohn's disease identifies altered epigenetic regulation of key host defense mechanisms including the Th17 pathway.

Background: Germline variation in the 71 Crohn's disease (CD) loci implicated by genome-wide association studies (GWAS) only accounts for approximately 25% of estimated heritability. The contribution of epigenetic alterations to disease pathogenesis is emerging as a research priority.

Materials And Methods: The methylation status of 27,578 CpG sites across the genome was analyzed using the Illumina Human Methylation27 assay in DNA extracted from whole blood samples from 40 adult females (21 ileal CD, 19 healthy controls) and 16 girls with childhood-onset CD, all nonsmokers.

TLE1 modifies the effects of NOD2 in the pathogenesis of Crohn's disease.

Background & Aims: The mechanisms by which specific mutations in NOD2/CARD15 increase the risk for Crohn's disease (CD) are unclear. We identified proteins that interact with NOD2 and investigated them by expression, genetic, and functional analyses.

Methods: By using a yeast 2-hybrid screen of an intestinal epithelial library, we identified proteins that interact with NOD2 and confirmed the interactions in mammalian cells using co-immunoprecipitation.

Fecal calprotectin complements routine laboratory investigations in diagnosing childhood inflammatory bowel disease.

Background: We aimed to study fecal calprotectin in Scottish children with inflammatory bowel disease (IBD) and compare its diagnostic accuracy with blood parameters.

Methods: Stool samples from 48 Scottish children (29 males, 19 females) had calprotectin measured at IBD diagnosis. The median age at diagnosis was 11.

Analysis of germline GLI1 variation implicates hedgehog signalling in the regulation of intestinal inflammatory pathways.

Background: Ulcerative colitis (UC) and Crohn's disease (CD) are polygenic chronic inflammatory bowel diseases (IBD) of high prevalence that are associated with considerable morbidity. The hedgehog (HH) signalling pathway, which includes the transcription factor glioma-associated oncogene homolog 1 (GLI1), plays vital roles in gastrointestinal tract development, homeostasis, and malignancy. We identified a germline variation in GLI1 (within the IBD2 linkage region, 12q13) in patients with IBD.

Definition of phenotypic characteristics of childhood-onset inflammatory bowel disease.

Background & Aims: Childhood-onset inflammatory bowel disease (IBD) might be etiologically different from adult-onset IBD. We analyzed disease phenotypes and progression of childhood-onset disease and compared them with characteristics of adult-onset disease in patients in Scotland.

Methods: Anatomic locations and behaviors were assessed in 416 patients with childhood-onset (276 Crohn's disease [CD], 99 ulcerative colitis [UC], 41 IBD type unclassified [IBDU] diagnosed before seventeenth birthday) and 1297 patients with adult-onset (596 CD, 701 UC) IBD using the Montreal classification.

Investigation of NOD1/CARD4 variation in inflammatory bowel disease using a haplotype-tagging strategy.

Both NOD1/CARD4 and NOD2/CARD15 are intracellular pattern-recognition receptors involved in the innate immune response. Germline NOD2/CARD15 variation has a definite effect on susceptibility to Crohn's disease (CD) and phenotype, although this contribution is weak in Scotland and Scandinavia. The NOD1/CARD4 gene lies within the putative inflammatory bowel disease (IBD) locus at 7p14.

Smoking habit and load influence age at diagnosis and disease extent in ulcerative colitis.

Introduction: Cigarette smoking affects susceptibility to ulcerative colitis (UC), but its effects on age at diagnosis, disease extent, and need for surgery are less well defined. We examined these parameters in a detailed retrospective analysis of a large cohort of well-characterized UC patients.

Methods: 499 UC patients (254 male, median age 34.

Does cigarette smoking influence the phenotype of Crohn's disease? Analysis using the Montreal classification.

Objectives: The clinical subclassification of Crohn's disease by phenotype has recently been reevaluated. We have investigated the relationships between smoking habit, age at diagnosis, disease location, and progression to stricturing or penetrating complications using the Montreal classification.

Methods: 408 patients (157 male, median age 29.

Genotype-phenotype analysis in childhood-onset Crohn's disease: NOD2/CARD15 variants consistently predict phenotypic characteristics of severe disease.

Introduction: The incidence of early-onset CD in Scotland is among the highest worldwide. Three single nucleotide polymorphisms (SNPs) R702W, G908R and Leu1007finsC in the NOD2/CARD15 gene predispose to adult CD. We investigated the contribution of these variants to disease susceptibility and phenotype in the Scottish early-onset IBD population.

Sero-reactivity to microbial components in Crohn's disease is associated with disease severity and progression, but not NOD2/CARD15 genotype.

Background And Aims: Antibodies directed against the porin protein C of Escherichia coli (anti-OmpC) and Pseudomonas fluorescens (anti-I2) have recently been described in Crohn's disease (CD). Those directed against Saccharomyces cerevisiae (ASCA) and the perinuclear component of neutrophils (pANCA) have been more widely studied and may be of diagnostic importance. We aimed to assess the frequency of anti-OmpC, anti-I2, ASCA, and pANCA, in an independent Scottish CD cohort, establish phenotypic associations, and compare with a U.

Incidence of juvenile-onset Crohn's disease in Scotland: association with northern latitude and affluence.

Background & Aims: The incidence of Crohn's disease in Scottish children has increased steadily over 30 years. Many studies have investigated genetic influence or possible links with childhood events. We aimed to study sociodemographic and/or geographic distribution of juvenile=onset Crohn's disease in Scotland.

Disease location, anti-Saccharomyces cerevisiae antibody, and NOD2/CARD15 genotype influence the progression of disease behavior in Crohn's disease.

Background: Crohn's disease (CD) is characterized by heterogeneity of phenotype. The Vienna classification can be used to classify CD, and recent data illustrate that behavior evolves over the course of the disease. Clinical and biological influences on disease progression remain unclear.