Inflammation status modulates the effect of host genetic variation on intestinal gene expression in inflammatory bowel disease.

More than 240 genetic risk loci have been associated with inflammatory bowel disease (IBD), but little is known about how they contribute to disease development in involved tissue. Here, we hypothesized that host genetic variation affects gene expression in an inflammation-dependent way, and investigated 299 snap-frozen intestinal biopsies from inflamed and non-inflamed mucosa from 171 IBD patients. RNA-sequencing was performed, and genotypes were determined using whole exome sequencing and genome wide genotyping.

Whole exome sequencing analyses reveal gene-microbiota interactions in the context of IBD.

Objective: Both the gut microbiome and host genetics are known to play significant roles in the pathogenesis of IBD. However, the interaction between these two factors and its implications in the aetiology of IBD remain underexplored. Here, we report on the influence of host genetics on the gut microbiome in IBD.

The genetic background of inflammatory bowel disease: from correlation to causality.

Recent studies have greatly improved our insight into the genetic background of inflammatory bowel disease (IBD). New high-throughput technologies and large-scale international collaborations have contributed to the identification of 200 independent genetic risk loci for IBD. However, in most of these loci, it is unclear which gene conveys the risk for IBD.

Drug Repositioning in Inflammatory Bowel Disease Based on Genetic Information.

Background: Currently, 200 genetic risk loci have been identified for inflammatory bowel disease (IBD). Although these findings have significantly advanced our insight into IBD biology, there has been little progress in translating this knowledge toward clinical practice, like more cost-efficient drug development. Our aim was to use genetic knowledge to identify drugs that warrant further investigation in IBD treatment.

Down the line from genome-wide association studies in inflammatory bowel disease: the resulting clinical benefits and the outlook for the future.

Inflammatory bowel disease (IBD), consisting of Crohn's disease and ulcerative colitis, is a chronic inflammatory disease of the gut. The etiology of IBD is complex, involving genetic as well as environmental factors. Genetic studies have identified 163 genetic risk loci for IBD, which have led to new insights into the biological mechanisms of the disease.

Performance of the Montreal classification for inflammatory bowel diseases.

Aim: To validate the Montreal classification system for Crohn's disease (CD) and ulcerative colitis (UC) within the Netherlands.

Methods: A selection of 20 de-identified medical records with an appropriate representation of the inflammatory bowel disease (IBD) sub phenotypes were scored by 30 observers with different professions (gastroenterologist specialist in IBD, gastroenterologist in training and IBD-nurses) and experience level with IBD patient care. Patients were classified according to the Montreal classification.

Multi-ethnic studies in complex traits.

The successes of genome-wide association (GWA) studies have mainly come from studies performed in populations of European descent. Since complex traits are characterized by marked genetic heterogeneity, the findings so far may provide an incomplete picture of the genetic architecture of complex traits. However, the recent GWA studies performed on East Asian populations now allow us to globally assess the heterogeneity of association signals between populations of European ancestry and East Asians, and the possible obstacles for multi-ethnic GWA studies.

HNF4α and CDH1 are associated with ulcerative colitis in a Dutch cohort.

Background: Inflammatory bowel diseases (IBDs), consisting of ulcerative colitis (UC) and Crohn's disease (CD), are complex disorders with multiple genes contributing to disease pathogenesis. A recent genome-wide association scan identified three novel susceptibility loci for UC: HNF4α, CDH1, and LAMB1. We performed an analysis of these three loci in an independent cohort.

Wnt signaling and Dupuytren's disease.

Background: Dupuytren's disease is a benign fibromatosis of the hands and fingers that leads to flexion contractures. We hypothesized that multiple genetic and environmental factors influence susceptibility to this disease and sought to identify susceptibility genes to better understand its pathogenesis.

Methods: We conducted a genomewide association study of 960 Dutch persons with Dupuytren's disease and 3117 controls (the discovery set) to test for association between the disease and genetic markers.

A meta-analysis of genome-wide association scans identifies IL18RAP, PTPN2, TAGAP, and PUS10 as shared risk loci for Crohn's disease and celiac disease.

Crohn's disease (CD) and celiac disease (CelD) are chronic intestinal inflammatory diseases, involving genetic and environmental factors in their pathogenesis. The two diseases can co-occur within families, and studies suggest that CelD patients have a higher risk to develop CD than the general population. These observations suggest that CD and CelD may share common genetic risk loci.

Association of FcgR2a, but not FcgR3a, with inflammatory bowel diseases across three Caucasian populations.

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).

Analysis of SNPs with an effect on gene expression identifies UBE2L3 and BCL3 as potential new risk genes for Crohn's disease.

Genome-wide association studies (GWAS) for Crohn's disease (CD) have identified loci explaining approximately 20% of the total genetic risk of CD. Part of the other genetic risk loci is probably partly hidden among signals discarded by the multiple testing correction needed in the analysis of GWAS data. Strategies for finding these hidden loci require large replication cohorts and are costly to perform.

Genetic association analysis of the functional c.714T>G polymorphism and mucosal expression of dectin-1 in inflammatory bowel disease.

Background: Dectin-1 is a pattern recognition receptor (PRR) expressed by myeloid cells that specifically recognizes beta-1,3 glucan, a polysaccharide and major component of the fungal cell wall. Upon activation, dectin-1 signaling converges, similar to NOD2, on the adaptor molecule CARD9 which is associated with inflammatory bowel disease (IBD). An early stop codon polymorphism (c.

[The genetic basis of inflammatory bowel disease unravelled by genetic association studies].

Crohn's disease and ulcerative colitis are chronic inflammatory bowel diseases characterized by recurring active inflammation of the digestive tract. Ulcerative colitis and Crohn's disease are complex diseases involving genetic as well as environmental factors. Since the introduction of genome-wide association studies, enormous progress has been made in recent years in unravelling the genetic basis of these diseases.

Genetic analysis in a Dutch study sample identifies more ulcerative colitis susceptibility loci and shows their additive role in disease risk.

Objectives: Genetic susceptibility is known to make a major contribution to the pathogenesis of ulcerative colitis (UC). Recently, three studies, including a genome-wide association study (GWAS), reported novel UC risk loci.

Methods: The top-20 single-nucleotide polymorphisms (SNPs) from the first UC-GWAS were genotyped, as part of the study's replication phase, in 561 UC cases and 728 controls from our Dutch UC study sample.

Inflammatory bowel disease and celiac disease: overlaps in the pathology and genetics, and their potential drug targets.

Inflammatory bowel disease, which covers Crohn's disease and ulcerative colitis, and celiac disease are both inflammatory diseases of the intestinal tract. In both diseases an antigen activates several inflammatory pathways, which cause extensive damage to the intestinal mucosa and lead to increased permeability of the intestinal epithelium. The causative antigen in inflammatory bowel disease is the microflora in the intestinal lumen, facilitated by an impaired innate immune system that is unable to halt the invasion of microbes into the lamina propria.