The inflammatory bowel disease, Crohn＇s disease and ulcerative colitis, are polygenic disorders with important environmental interactions. To date, the most widely adopted approach to identifying ...susceptibility genes in complex diseases has involved genome wide linkage studies followed by studies of positional candidate genes in loci of interest. This review encompasses data from studies into novel candidate genes implicated in the pathogenesis of inflammatory bowel disease. Novel techniques to identify candidate genes-genome wide association studies, yeast-two hybrid screening, microarray gene expression studies and proteomic profiling, are also reviewed and their potential role in unravelling the pathogenesis of inflammatory bowel disease are discussed.
Objective. Crohn's disease (CD) is a chronic inflammatory bowel disorder caused by environmental and genetic factors. Mutations in the CARD15 gene have been associated with CD. No previous ...case-control CARD15 study has been performed in the Swedish population.
Material and methods. The study comprised of 321 individuals: 178 with CD and 143 healthy controls (HCs), all from Stockholm County. All were genotyped for the three main CD-associated CARD15 variants (R702W, G908R and 1007fs) and phenotypic associations were investigated.
Results. The allele frequencies of the R702W variant (4.5% CD versus 0.7% HC, p=0.008, OR = 6.8) and the G908R variant (2.0% CD versus 0% HC, p=0.045) were more common in CD patients than in controls. No significant difference in1007fs variant allele frequency was found between CD patients and controls (2.0% CD versus 1.7% HC, p = 0.8, OR = 1.1). Carriage of CARD15 variants was more common in the CD patients than in controls (15.2% CD versus 4.2% HC, p = 0.001, OR = 4.1, population attributable risk (PAR) = 11.4%). Genotype-phenotype analysis demonstrated that CARD15 variants were associated with ileal disease (p=0.0006, OR = 9.3, CI = 2.2-34) and protective for colonic CD (p = 0.01, OR = 0.18). An association between CARD15 variants and ileal CD (p=0.004, OR = 6.6) was confirmed by multivariate analyses.
Conclusions. The CARD15 variants R702W and G908R, but not 1007fs, are associated with susceptibility to CD in Stockholm County. Genotype-phenotype analysis shows an association with ileal CD. The contribution of these CARD15 mutations in Swedish CD patients overall is low in relation to studies elsewhere in Central Europe and North America, but is consistent with emerging data from elsewhere in Scandinavia and in Northern Europe.
Background:
The Fc receptors II and III (FcgR2a, and FcgR3a) play a crucial role in the regulation of the immune response. The FcgR2a*519GG and FcgR3a*559CC genotypes have been associated with ...several autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, nephritis, and possibly to type I diabetes, and celiac disease. In a large multicenter, two‐stage study of 6570 people, we tested whether the FcgR2a and FcgR3a genes were also involved in inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC).
Methods:
We genotyped the FcgR2a*A519G and FcgR3a*A559C functional variants in 4205 IBD patients in six well‐phenotyped Caucasian IBD cohorts and 2365 ethnically matched controls recruited from the Netherlands, Spain, and New Zealand.
Results:
In the initial Dutch study we found a significant association of FcgR2a genotypes with IBD (P‐genotype = 0.02); while the FcgR2a*519GG was more common in controls (23%) than in IBD patients (18%; odds ratio OR = 0.75; 95% confidence interval CI 0.61–0.92; P = 0.004). This association was corroborated by a combined analysis across all the study populations (Mantel–Haenszel MH OR = 0.84; 0.74–0.95; P = 0.005) in the next stage. The Fcgr2a*GG genotype was associated with both UC (MH‐OR = 0.84; 0.72–0.97; P = 0.01) and CD (MH‐OR = 0.84; 0.73–0.97; P = 0.01), suggesting that this genotype confers a protective effect against IBD. There was no association of FcgR3a*A559C genotypes with IBD, CD, or UC in any of the three studied populations.
Conclusions:
The FcgR2a*519G functional variant was associated with IBD and reduced susceptibility to UC and to CD in Caucasians. There was no association between FcgR3a*5A559C and IBD, CD or UC. (Inflamm Bowel Dis 2010)
Objective. Recent data have controversially suggested that variants of the organic cation transport genes SLC22A4 (OCTN1) and SLC22A5 (OCTN2) are responsible for the contribution of IBD5 to disease ...susceptibility in Crohn's disease (CD). The objective of this study was to assess the contribution of the SLC22A4 variant (1672C→T) and SLC22A5 variant (−207G→C) together with three IBD5 haplotype markers in the previously uninvestigated Swedish CD population. Material and methods. The study comprised 178 CD patients and 143 healthy controls (HC). Genotyping for IBD5 single nucleotide polymorphisms (SNPs) IGR2096a_1, IGR2198a_1, IGR2230a_1, SLC22A4 1672C→T and SLC22A5 −207G→C was carried out using the TaqMan® system. Associations with disease susceptibility and disease phenotype were investigated. Results. Strong linkage disequilibrium was observed between the investigated SNPs (D prime >0.92). IGR2096a_1 allelic frequency and homozygosity rates were associated with CD (44% CD versus 33.8% HC, p =0.008, OR =1.55 and 20% CD versus 12% HC, p =0.04, OR =1.93, respectively). Variant allelic frequency of SLC22A4, 1672C→T (44% versus 36%, p =0.03, OR =1.4) and homozygosity for the SLC22A4, SLC22A5 TC haplotype (1672C→T, −207G→C) (21.3% versus 12%, p =0.03, OR =1.78, population attributable risk (PAR) =11%) were associated with CD. There was no association between the allelic frequency of SLC22A5 and CD (46.6% CD versus 41.5% HC, p =0.82). The association of the TC haplotype with CD was not independent of the SNPs representing the extended IBD5 linkage interval. Conclusions. The IBD5 locus is associated with CD in the Swedish population. The strongest association is with the marker SNP IGR2096a_1, lying p-telomeric to SLC22A4 and SLC22A5. The effect of the TC haplotype was not an independent determinant in this population.
Causes of inflammatory bowel diseases are not well understood and the most prominent forms, Crohn’s disease (CD) and ulcerative colitis (UC), are sometimes hard to distinguish. Glycosylation of IgG ...has been associated with CD and UC. IgG Fc-glycosylation affects IgG effector functions. We evaluated changes in IgG Fc-glycosylation associated with UC and CD, as well as with disease characteristics in different patient groups.
We analyzed 3441 plasma samples obtained from 2 independent cohorts of patients with CD (874 patients from Italy and 391 from the United States) or UC (1056 from Italy and 253 from the US and healthy individuals controls; 427 in Italy and 440 from the United States). IgG Fc-glycosylation (tryptic glycopeptides) was analyzed by liquid chromatography coupled to mass spectrometry. We analyzed associations between disease status (UC vs controls, CD vs controls, and UC vs CD) and glycopeptide traits, and associations between clinical characteristics and glycopeptide traits, using a logistic regression model with age and sex included as covariates.
Patients with CD or UC had lower levels of IgG galactosylation than controls. For example, the odds ratio (OR) for IgG1 galactosylation in patients with CD was 0.59 (95% confidence interval CI, 0.51–0.69) and for patients with UC was 0.81 (95% CI, 0.71–0.92). Fucosylation of IgG was increased in patients with CD vs controls (for IgG1: OR, 1.27; 95% CI, 1.12–1.44), but decreased in patients with UC vs controls (for IgG23: OR, 0.72; 95% CI, 0.63–0.82). Decreased galactosylation associated with more severe CD or UC, including the need for surgery in patients with UC vs controls (for IgG1: OR, 0.69; 95% CI, 0.54–0.89) and in patients with CD vs controls (for IgG23: OR, 0.78; 95% CI, 0.66–0.91).
In a retrospective analysis of plasma samples from patients with CD or UC, we associated levels of IgG Fc-glycosylation with disease (compared to controls) and its clinical features. These findings could increase our understanding of mechanisms of CD and UC pathogenesis and be used to develop diagnostics or guide treatment.
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Epigenetic alterations may provide important insights into gene-environment interaction in inflammatory bowel disease (IBD). Here we observe epigenome-wide DNA methylation differences in 240 ...newly-diagnosed IBD cases and 190 controls. These include 439 differentially methylated positions (DMPs) and 5 differentially methylated regions (DMRs), which we study in detail using whole genome bisulphite sequencing. We replicate the top DMP (RPS6KA2) and DMRs (VMP1, ITGB2 and TXK) in an independent cohort. Using paired genetic and epigenetic data, we delineate methylation quantitative trait loci; VMP1/microRNA-21 methylation associates with two polymorphisms in linkage disequilibrium with a known IBD susceptibility variant. Separated cell data shows that IBD-associated hypermethylation within the TXK promoter region negatively correlates with gene expression in whole-blood and CD8
T cells, but not other cell types. Thus, site-specific DNA methylation changes in IBD relate to underlying genotype and associate with cell-specific alteration in gene expression.
Preclinical ulcerative colitis is poorly defined. We aimed to characterize the preclinical systemic inflammation in ulcerative colitis, using a comprehensive set of proteins.
We obtained plasma ...samples biobanked from individuals who developed ulcerative colitis later in life (n = 72) and matched healthy controls (n = 140) within a population-based screening cohort. We measured 92 proteins related to inflammation using a proximity extension assay. The biologic relevance of these findings was validated in an inception cohort of patients with ulcerative colitis (n = 101) and healthy controls (n = 50). To examine the influence of genetic and environmental factors on these markers, a cohort of healthy twin siblings of patients with ulcerative colitis (n = 41) and matched healthy controls (n = 37) were explored.
Six proteins (MMP10, CXCL9, CCL11, SLAMF1, CXCL11 and MCP-1) were up-regulated (P < .05) in preclinical ulcerative colitis compared with controls based on both univariate and multivariable models. Ingenuity Pathway Analyses identified several potential key regulators, including interleukin-1β, tumor necrosis factor, interferon-gamma, oncostatin M, nuclear factor-κB, interleukin-6, and interleukin-4. For validation, we built a multivariable model to predict disease in the inception cohort. The model discriminated treatment-naïve patients with ulcerative colitis from controls with leave-one-out cross-validation (area under the curve = 0.92). Consistently, MMP10, CXCL9, CXCL11, and MCP-1, but not CCL11 and SLAMF1, were significantly up-regulated among the healthy twin siblings, even though their relative abundances seemed higher in incident ulcerative colitis.
A set of inflammatory proteins are up-regulated several years before a diagnosis of ulcerative colitis. These proteins were highly predictive of an ulcerative colitis diagnosis, and some seemed to be up-regulated already at exposure to genetic and environmental risk factors.
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To characterize the preclinical inflammation in ulcerative colitis, we explored systemic inflammatory markers in a population-based cohort of healthy individuals. A 6-protein signature could separate individuals who later developed disease.
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