Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility

Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation.Large-scale sequence-based analyses identify novel risk variants and susceptibility genes for Crohn's disease, and implicate mesenchymal cell-mediated intestinal homeostasis in disease etiology.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes.

GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach

The IBD international genetics consortium provides further evidence for linkage to IBD4 and shows gene-environment interaction

BACKGROUND AND AIMS: The inflammatory bowel diseases (IBDs) Crohn's disease (CD) and ulcerative colitis are complex disorders with an important genetic determinant. One gene associated with CD has been identified: NOD2/CARD15. Two independent genome-wide scans found significant evidence (logarithm of odds [LOD] 3.6) and suggestive evidence (LOD 2.8) for linkage on locus 14q11-12, also known as the IBD4 locus. To further characterize this locus, we assessed gene-environment interaction (IBD4 x smoking) and phenotypic heterogeneity in a large cohort of IBD-affected sibling pairs as part of an ongoing international collaborative effort. PATIENTS AND METHODS: A total of 733 IBD families, comprising 892 affected sibling pairs, were genotyped for microsatellites D14S261, D14S283, D14S972, and D14S275, spanning the IBD4 locus. Information on gender, ethnicity, age at onset, smoking at diagnosis, extraintestinal manifestations, and disease location was available. RESULTS: A significant distortion in the mean allele sharing (MAS) between affected siblings was observed for CD patients only at each of the four markers (54.6%, 52.8%, 50.4%, and 53.3%, respectively). Maximum linkage for CD was observed at marker D14S261 (multipoint nonparametric linkage score 2.36; P </= 0.01; MAS 54.6%). MAS was higher in CD families in which all siblings or at least one sibling smoked compared with nonsmoking CD families (MAS, 58.90%, 57.50%, and 52.80%, respectively). CONCLUSIONS: The IBD International Genetics Consortium replicated the IBD4 locus on chromosome 14q for CD and also showed evidence for a gene-environment interaction at this locus. Further studies are needed to explore the mechanism by which smoking influences IBD4

Genetic variants in the region harbouring IL2/IL21 associated with ulcerative colitis.

Item does not contain fulltextOBJECTIVES: Genetic susceptibility is known to play a large part in the predisposition to the inflammatory bowel diseases (IBDs) known as Crohn's disease (CD) and ulcerative colitis (UC). The IL2/IL21 locus on 4q27 is known to be a common risk locus for inflammatory disease (shown in coeliac disease, type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus and psoriasis), while the roles that interleukin 2 (IL2) and IL21 play in the immune response also make them attractive candidates for IBD. The objective of this study was to test for association between the IL2/IL21 locus and the IBDs. METHODS: The four single nucleotide polymorphisms (SNPs) in the IL2/IL21 locus most associated with coeliac disease were genotyped in 1590 subjects with IBD and 929 controls from The Netherlands, and then replicated in a North American cohort (2387 cases and 1266 controls) and an Italian cohort (805 cases and 421 controls), yielding a total of 4782 cases (3194 UC, 1588 CD) and 2616 controls. Allelic association testing and a pooled analysis using a Cochran-Mantel-Haenszel test were performed. RESULTS: All four SNPs were strongly associated with UC in all three cohorts and reached genome-wide significance in the pooled analysis (rs13151961 p = 1.35 x 10(-10), rs13119723 p = 8.60 x 10(-8), rs6840978 p = 3.0 7x 10(-8), rs6822844 p = 2.77 x 10(-9)). A moderate association with CD was also found in the pooled analysis (p value range 0.0016-9.86 x 10(-5)). CONCLUSIONS: A strong association for the IL2/IL21 locus with UC was found, which also confirms it as a general susceptibility locus for inflammatory disease

Síndrome ascítica em frangos de corte: uma revisão sobre a fisiologia, avaliação e perspectivas Ascitic syndrome in broiler chickens: a review about physiology, evaluation and perspectives

Os programas de melhoramento genético de frangos de corte que buscam máxima velocidade de ganho de peso, alta eficiência alimentar, alta viabilidade, maior rendimento de carcaça e menor deposição de gordura podem desencadear algumas síndromes fisiológicas, dentre as quais destacam-se o estresse calórico, a morte súbita e a ascite. A ascite se enquadra no conceito das síndromes multifatoriais, uma vez que sua manifestação ocorre quando certos fatores genéticos e ambientais atuam em conjunto determinando o processo. As limitações anatômica e fisiológica da circulação sanguínea nos pulmões provocam a síndrome de hipertensão pulmonar (PHS); esta pode provocar grande acúmulo de fluido na cavidade abdominal, quadro este denominado de ascite. Ocorre redução da eficiência da circulação sangüínea, levando as aves à morte por hipóxia, predominantemente no período entre 30 e 40 dias de idade. Uma vez desencadeado o processo ascítico, a ave dificilmente é aproveitada no abate já que a mesma restringe o consumo de alimento, ganhando menos peso. Adicionalmente, a carcaça apresenta aumento do volume da cavidade abdominal e conseqüente congestão dos órgãos internos. A descrição da fisiologia, medidas de avaliação e perspectivas são apresentadas neste trabalho.<br>Poultry genetic breeding programs which look for maximum weight gain, improved feed conversion, high viability, high carcass yield and low fat deposition may cause some physiologic syndromes, for example caloric stress, sudden death and ascites. Ascites is framed in concept of the multifactorial syndromes, once its manifestation happens when certain genetic and environment factors act together, determining the process. Anatomical and physiological limitations in blood circulation in the lungs give rise to pulmonary hypertension syndrome (PHS), producing great fluid accumulation in abdominal cavity, which is denominated ascites. Ascites causes reduction of blood circulation efficiency, leading broilers to death due to hypoxia, mainly between 30 and 40 days of age. Ascitic broilers have reduced body weight gain as a consequence of feed restriction. Additionally, there is increased abdominal cavity volume and internal organ congestion. Ascites is discussed through this manuscript based on physiological description, evaluation measures and perspectives