[Show abstract][Hide abstract] ABSTRACT: Background:
Serrated epithelial change (SEC) is a histological finding in long standing colitis that may be associated with dysplasia. Our primary aim was to determine the incidence of dysplasia and colorectal cancer (CRC) in inflammatory bowel disease (IBD) patients with SEC. Secondary aims were to determine the rate of location concordance between SEC and dysplasia/CRC and to identify other risk factors associated with dysplasia in IBD patients with SEC.
A retrospective, descriptive, observational study was performed by searching the Pathology Data System at a single tertiary referral center for a histologic finding of "serrated epithelial change." The patient's first pathology specimen with SEC was designated the index SEC. All subsequent pathology reports were evaluated for the occurrence and location of dysplasia or CRC. Univariable and multivariable logistic regression were performed to identify predictors of dysplasia.
There were 187 patients with confirmed IBD and one or more histologic findings of SEC without prior dysplasia. Mean IBD duration was 16 years, and median follow-up time was 28 months. The rate of high-grade dysplasia or CRC was 17 per 1000 patient-years. Thirty-nine of 187 patients (21%) had synchronous or metachronous dysplasia or CRC. Location concordance was 68%. Multivariable analysis found SEC on follow-up examinations, older age at IBD diagnosis, male gender, and a first degree relative with CRC were associated with dysplasia in IBD patients with SEC.
This uncontrolled study describes a high frequency of dysplasia in patients with a histologic finding of SEC. SEC seen on successive scopes further increased the risk of dysplasia. Further controlled studies are needed to determine if SEC is a pre-cancerous lesion in IBD patients and if SEC can be endoscopically identified.
Full-text · Article · Dec 2015 · Gastrointestinal endoscopy
[Show abstract][Hide abstract] ABSTRACT: Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases.
[Show abstract][Hide abstract] ABSTRACT: Background:
Rare variants (<1%) likely contribute significantly to risk for common diseases such as inflammatory bowel disease (IBD) in specific patient subsets, such as those with high familiality. They are, however, extraordinarily challenging to identify.
To discover candidate rare variants associated with IBD, we performed whole-exome sequencing on 6 members of a pediatric-onset IBD family with multiple affected individuals. To determine whether the variants discovered in this family are also associated with nonfamilial IBD, we investigated their influence on disease in 2 large case-control (CC) series.
We identified 2 rare variants, rs142430606 and rs200958270, both in the established IBD-susceptibility gene IL17REL, carried by all 4 affected family members and their obligate carrier parents. We then demonstrated that both variants are associated with sporadic ulcerative colitis (UC) in 2 independent data sets. For UC in CC 1: rs142430606 (odds ratio [OR] = 2.99, Padj = 0.028; minor allele frequency [MAF]cases = 0.0063, MAFcontrols = 0.0021); rs200958270 (OR = 2.61, Padj = 0.082; MAFcases = 0.0045, MAFcontrols = 0.0017). For UC in CC 2: rs142430606 (OR = 1.94, P = 0.0056; MAFcases = 0.0071, MAFcontrols = 0.0045); rs200958270 (OR = 2.08, P = 0.0028; MAFcases = 0.0071, MAFcontrols = 0.0042).
We discover in a family and replicate in 2 CC data sets 2 rare susceptibility variants for IBD, both in IL17REL. Our results illustrate that whole-exome sequencing performed on disease-enriched families to guide association testing can be an efficient strategy for the discovery of rare disease-associated variants. We speculate that rare variants identified in families and confirmed in the general population may be important modifiers of disease risk for patients with a family history, and that genetic testing of these variants may be warranted in this patient subset.
No preview · Article · Oct 2015 · Inflammatory Bowel Diseases
[Show abstract][Hide abstract] ABSTRACT: Background:
There has been considerable progress in identifying IBD susceptibility genes but little progress in examining the role of genetic variation in the development of the extra-intestinal manifestations (EIMs) of IBD. This study identified clinical, serologic, and genetic factors associated with ocular-EIMs (O-EIMs) in IBD.
We performed a retrospective case-control study of IBD patients comparing those with and without O-EIMs using the Cedars-Sinai IBD Research Repository (MIRIAD) and the NIDDK IBD Genetics Consortium Repository. Genotyping was performed using Illumina whole genome platforms.
124 cases and 3328 controls with available clinical data were identified. 103 cases and 2808 controls had genetic data available. Erythema nodosum and peripheral arthritis particularly were common in patients with O-EIMs (p = 2.77x10(-13) and p = 2.58x10(-13), respectively) with increasing odds ratios for O-EIMs with each additional non-ocular-EIM (for ≥ EIMs, OR 14.72). Nominal association with O-EIMs was observed at several known IBD susceptibility single nuclear polymorphisms (SNPs). One locus, containing RBM19, achieved genome-wide level of significance for association with O-EIMs.
In IBD, O-EIMs co-occur with musculoskeletal and skin manifestations and, in this study, are nominally associated with known IBD susceptibility SNPs. Additional cohorts are needed to verify these results and identify additional genes.
No preview · Article · Oct 2015 · Journal of Crohn s and Colitis
[Show abstract][Hide abstract] ABSTRACT: Defects in intestinal innate defense systems predispose patients to inflammatory bowel disease (IBD). Reactive oxygen species (ROS) generated by nicotinamide-adenine dinucleotide phosphate (NADPH) oxidases in the mucosal barrier maintain gut homeostasis and defend against pathogenic attack. We hypothesized that molecular genetic defects in intestinal NADPH oxidases might be present in children with IBD.
After targeted exome sequencing of epithelial NADPH oxidases NOX1 and DUOX2 on 209 children with very early onset inflammatory bowel disease (VEOIBD), the identified mutations were validated using Sanger Sequencing. A structural analysis of NOX1 and DUOX2 variants was performed by homology in silico modeling. The functional characterization included ROS generation in model cell lines and in in vivo transduced murine crypts, protein expression, intracellular localization, and cell-based infection studies with the enteric pathogens Campylobacter jejuni and enteropathogenic Escherichia coli.
We identified missense mutations in NOX1 (c.988G>A, p.Pro330Ser; c.967G>A, p.Asp360Asn) and DUOX2 (c.4474G>A, p.Arg1211Cys; c.3631C>T, p.Arg1492Cys) in 5 of 209 VEOIBD patients. The NOX1 p.Asp360Asn variant was replicated in a male Ashkenazi Jewish ulcerative colitis cohort. All NOX1 and DUOX2 variants showed reduced ROS production compared with wild-type enzymes. Despite appropriate cellular localization and comparable pathogen-stimulated translocation of altered oxidases, cells harboring NOX1 or DUOX2 variants had defective host resistance to infection with C. jejuni.
This study identifies the first inactivating missense variants in NOX1 and DUOX2 associated with VEOIBD. Defective ROS production from intestinal epithelial cells constitutes a risk factor for developing VEOIBD.
[Show abstract][Hide abstract] ABSTRACT: Dendritic cells (DC) mediate intestinal immune tolerance. Despite striking differences between the colon and the ileum both in function and bacterial load, few studies distinguish between properties of immune cells in these compartments. Furthermore, information of gut DC in humans is scarce. We aimed to characterise human colonic versus ileal DC.
Human DC from paired colonic and ileal samples were characterised by flow cytometry, electron microscopy or used to stimulate T cell responses in a mixed leucocyte reaction.
A lower proportion of colonic DC produced pro-inflammatory cytokines (tumour necrosis factor-α and interleukin (IL)-1β) compared with their ileal counterparts and exhibited an enhanced ability to generate CD4(+)FoxP3(+)IL-10(+) (regulatory) T cells. There were enhanced proportions of CD103(+)Sirpα(-) DC in the colon, with increased proportions of CD103(+)Sirpα(+) DC in the ileum. A greater proportion of colonic DC subsets analysed expressed the lymph-node-homing marker CCR7, alongside enhanced endocytic capacity, which was most striking in CD103(+)Sirpα(+) DC. Expression of the inhibitory receptor ILT3 was enhanced on colonic DC. Interestingly, endocytic capacity was associated with CD103(+) DC, in particular CD103(+)Sirpα(+) DC. However, expression of ILT3 was associated with CD103(-) DC. Colonic and ileal DC differentially expressed skin-homing marker CCR4 and small-bowel-homing marker CCR9, respectively, and this corresponded to their ability to imprint these homing markers on T cells.
The regulatory properties of colonic DC may represent an evolutionary adaptation to the greater bacterial load in the colon. The colon and the ileum should be regarded as separate entities, each comprising DC with distinct roles in mucosal immunity and imprinting.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
[Show abstract][Hide abstract] ABSTRACT: Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles. To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1∗01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD.
[Show abstract][Hide abstract] ABSTRACT: Prom1/CD133 has been identified in colorectal, hepatocellular, and pancreatic cancer as a cancer stem cell marker and has been used as such to predict colon cancer recurrence in humans. Its potential molecular function as well as its role as a marker of intestinal regeneration is still not fully known. We evaluated the role of Prom1 in intestinal regeneration in inflammatory bowel disease (IBD), determined the function of Prom1, and characterized the effect of a lack of Prom1 on intestinal tumor formation in animal models. Our results suggest that Apc mutations lead to an increase in Prom1 expressing cells in the intestinal crypt stem cell compartment and in early intestinal adenomas. Also, Prom1 knockout mice are more susceptible to intestinal tumor formation. We conclude that Prom1 likely plays a role in regulating intestinal homeostasis and that these results clearly illustrate the role of Prom1 in intestinal regeneration. We further conclude that Prom1 may provide a novel therapeutic target for patients with gastrointestinal conditions such as IBD, short bowel syndrome, and colorectal cancer.
Full-text · Article · Nov 2014 · Frontiers in Oncology
[Show abstract][Hide abstract] ABSTRACT: Background In the northern hemisphere, the incidence of inflammatory bowel diseases (IBD) has a north-south gradient, suggesting a link between ultraviolet (UV) exposure or vitamin D status and the pathogenesis of IBD. Aim To test the association of UV exposure with the rates and severity of IBD hospitalisation. Methods We conducted a retrospective nationwide analysis of 649 932 Crohn's disease (CD), 384 267 ulcerative colitis (UC), and 288 894 297 non-IBD hospitalisations in the US between 1998 and 2010. Mean UV exposure was assigned to each hospitalisation using surface measures from the National Oceanic and Atmospheric Administration. Relative rates across UV exposures were estimated for IBD hospitalisations, prolonged hospitalisations, bowel surgeries and deaths. Results Among IBD patients, lower UV exposures had increased hospitalisation rates for CD (217.8 vs. 182.5 per 100 000 overall hospitalisations with low and very high UV, respectively; P trend <0.001) and UC (123.2 vs. 113.8 per 100 000; P trend = 0.033). Low UV groups had greater relative rates of prolonged hospitalisations [CD: 1.13, 95% confidence interval (CI) 1.07-1.19; UC: 1.21, 95% CI 1.13-1.30], bowel surgeries (CD: 1.24, 95% CI 1.16-1.32; UC: 1.21, 95% CI 1.09-1.33), and CD deaths (CD: 1.76, 95% CI 1.14-2.71; UC: 1.24, 95% CI 0.92-1.67). Among non-IBD patients, low UV was associated with prolonged hospitalisations (1.09; 95% CI 1.07-1.11) and deaths (1.13; 95% CI 1.09-1.17), but not bowel surgeries (1.01; 95% CI 0.99-1.03). Conclusions Lower ultraviolet exposure is associated with greater rates of hospitalisation, prolonged hospitalisation and the need for bowel surgery in IBD. This trend for bowel surgery was not seen with non-IBD encounters.
No preview · Article · Jun 2014 · Alimentary Pharmacology & Therapeutics