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Genetics of inflammatory bowel disease from multifactorial to monogenic forms.

ABSTRACT: Inflammatory bowel disease (IBD) is a group of chronic multifactorial disorders. According to a recent study, the number of IBD association loci is increased to 201, of which 37 and 27 loci contribute specifically to the development of Crohn's disease and ulcerative colitis respectively. Some IBD associated genes are involved in innate immunity, in the autophagy and in the inflammatory response such as NOD2, ATG16L1 and IL23R, while other are implicated in immune mediated disease (STAT3) and in susceptibility to mycobacterium infection (IL12B). In case of early onset of IBD (VEO-IBD) within the 6(th) year of age, the disease may be caused by mutations in genes responsible for severe monogenic disorders such as the primary immunodeficiency diseases. In this review we discuss how these monogenic disorders through different immune mechanisms can similarly be responsible of VEO-IBD phenotype. Moreover we would highlight how the identification of pathogenic genes by Next Generation Sequencing technologies can allow to obtain a rapid diagnosis and to apply specific therapies.

SUBMITTER: Bianco AM

PROVIDER: S-EPMC4649114 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Genetics of inflammatory bowel disease from multifactorial to monogenic forms.

Bianco Anna Monica AM Girardelli Martina M Tommasini Alberto A

World journal of gastroenterology 20151101 43

Inflammatory bowel disease (IBD) is a group of chronic multifactorial disorders. According to a recent study, the number of IBD association loci is increased to 201, of which 37 and 27 loci contribute specifically to the development of Crohn's disease and ulcerative colitis respectively. Some IBD associated genes are involved in innate immunity, in the autophagy and in the inflammatory response such as NOD2, ATG16L1 and IL23R, while other are implicated in immune mediated disease (STAT3) and in ...[more]

PMID: 26604638

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Project description:Inflammatory bowel diseases (IBDs) are complex, multifactorial disorders that comprise Crohn's disease (CD) and ulcerative colitis (UC). Genome-wide association studies have identified approximately 100 loci that are significantly associated with IBD. These loci implicate a diverse array of genes and pathophysiologic mechanisms, including microbe recognition, lymphocyte activation, cytokine signaling, and intestinal epithelial defense. Consistent with epidemiologic predictions, many IBD-associated loci demonstrate genome-wide significant associations to both CD and UC, notably, genes whose products function in the interleukin-23 pathway, and transcription factors, including NK2 transcription factor related, locus 3 (NKX2-3), SMAD3, STAT3, ZMIZ1, and c-REL. Although CD and UC are both associated with genomic regions that implicate products of genes involved in leukocyte trafficking, there is evidence for association patterns that are distinct between CD and UC. CD-predominant associations include NOD2 and genes that regulate autophagy. In UC, the predominant association signal is on chromosome 6p21, in the major histocompatibility complex region, near HLA class II genes. UC-predominant loci have also implicated genes mediating epithelial defense function. There is a striking overlap of loci between diseases, which could provide comparative insight into mechanisms of disease pathogenesis. Genes that encode factors that function in the interleukin-23 pathway have been associated with a number of chronic inflammatory diseases, notably psoriasis and ankylosing spondylitis. Distinct genetic associations indicate that the colitis associated with primary sclerosing cholangitis is pathophysiologically distinct from UC that is not associated with primary sclerosing cholangitis. As many as 14 susceptibility loci are shared between IBD and celiac disease, indicating significant overlap in pathophysiology. Future genetic studies will be directed toward identifying uncommon variations with potentially greater statistical effects, defining population differences, and more completely accounting for familial transmission of disease.

Project description:Human genetics and host-associated microbial communities have been associated independently with a wide range of chronic diseases. One of the strongest associations in each case is inflammatory bowel disease (IBD), but disease risk cannot be explained fully by either factor individually. Recent findings point to interactions between host genetics and microbial exposures as important contributors to disease risk in IBD. These include evidence of the partial heritability of the gut microbiota and the conferral of gut mucosal inflammation by microbiome transplant even when the dysbiosis was initially genetically derived. Although there have been several tests for association of individual genetic loci with bacterial taxa, there has been no direct comparison of complex genome-microbiome associations in large cohorts of patients with an immunity-related disease.We obtained 16S ribosomal RNA (rRNA) gene sequences from intestinal biopsies as well as host genotype via Immunochip in three independent cohorts totaling 474 individuals. We tested for correlation between relative abundance of bacterial taxa and number of minor alleles at known IBD risk loci, including fine mapping of multiple risk alleles in the Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) gene exon. We identified host polymorphisms whose associations with bacterial taxa were conserved across two or more cohorts, and we tested related genes for enrichment of host functional pathways.We identified and confirmed in two cohorts a significant association between NOD2 risk allele count and increased relative abundance of Enterobacteriaceae, with directionality of the effect conserved in the third cohort. Forty-eight additional IBD-related SNPs have directionality of their associations with bacterial taxa significantly conserved across two or three cohorts, implicating genes enriched for regulation of innate immune response, the JAK-STAT cascade, and other immunity-related pathways.These results suggest complex interactions between genetically altered host functional pathways and the structure of the microbiome. Our findings demonstrate the ability to uncover novel associations from paired genome-microbiome data, and they suggest a complex link between host genetics and microbial dysbiosis in subjects with IBD across independent cohorts.

Project description:In this review, we provide an update on genome-wide association studies (GWAS) in inflammatory bowel disease (IBD). In addition, we summarize progress in defining the functional consequences of associated alleles for coding and noncoding genetic variation. In the small minority of loci where major association signals correspond to nonsynonymous variation, we summarize studies defining their functional effects and implications for therapeutic targeting. Importantly, the large majority of GWAS-associated loci involve noncoding variation, many of which modulate levels of gene expression. Recent expression quantitative trait loci (eQTL) studies have established that the expression of most human genes is regulated by noncoding genetic variations. Significant advances in defining the epigenetic landscape have demonstrated that IBD GWAS signals are highly enriched within cell-specific active enhancer marks. Studies in European ancestry populations have dominated the landscape of IBD genetics studies, but increasingly, studies in Asian and African-American populations are being reported. Common variation accounts for only a modest fraction of the predicted heritability and the role of rare genetic variation of higher effects (ie, odds ratios markedly deviating from 1) is increasingly being identified through sequencing efforts. These sequencing studies have been particularly productive in more severe very early onset cases. A major challenge in IBD genetics will be harnessing the vast array of genetic discovery for clinical utility through emerging precision medical initiatives. In this article, we discuss the rapidly evolving area of direct-to-consumer genetic testing and the current utility of clinical exome sequencing, especially in very early onset, severe IBD cases. We summarize recent progress in the pharmacogenetics of IBD with respect to partitioning patient responses to anti-TNF and thiopurine therapies. Highly collaborative studies across research centers and across subspecialties and disciplines will be required to fully realize the promise of genetic discovery in IBD.

Dataset Information

Genetics of inflammatory bowel disease from multifactorial to monogenic forms.

Publications

Genetics of inflammatory bowel disease from multifactorial to monogenic forms.

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