Targeted resequencing identifies defective variants of decoy receptor 3 in pediatric-onset inflammatory bowel disease

ArticleinGenes and immunity 14(7) · August 2013with15 Reads
Impact Factor: 2.91 · DOI: 10.1038/gene.2013.43 · Source: PubMed

Genome-wide association studies have implicated common variation at the 20q13 locus in inflammatory bowel disease, particularly for the pediatric Crohn's form. This locus harbors tumor necrosis factor receptor superfamily (TNFRSF6B), encoding a secreted protein, decoy receptor 3 (DcR3), which binds to and neutralizes pro-inflammatory cytokines of the tumor necrosis factor superfamily. We sought to further the evidence of DcR3's role in pediatric IBD by identifying missense mutations with functional significance within TNFRSF6B. We sequenced the exons of the gene in 528 Caucasian pediatric IBD cases and 549 Caucasian healthy controls to establish the frequency of such events in each population. Sequencing revealed that our IBD cohort harbored a greater number of missense variants, yielding an odds ratio of 3.9 (P-value=0.005). Using functional assays, we established that the frequency of mutants defective in secretion from cultured cells was greater in the Crohn's category than in the controls, yielding an odds ratio of 7.1 (P-value=0.004). These results suggest that rare defective variants in TNFRSF6B have a role in the pathogenesis of some cases of IBD and that interventions targeting this group of tumor necrosis factor-family members may benefit patients with IBD.Genes and Immunity advance online publication, 22 August 2013; doi:10.1038/gene.2013.43.

    • "...d 944 con- trols [18,19], a similar rare variant screen focused on TNFRSF6B in pediatric-onset IBD [12] , exome sequencing of TNFAIP3 in 19 primary Sjögren's syndrome patients with lymphoma [31] , and ta..."
      In addition, recently published studies have applied no other method but Sanger sequencing for deep sequencing of extremely specific regions in smaller numbers of samples. These include a search for rare variants across GDF5, a gene harboring a known susceptibility variant for osteoarthritis in 992 cases and 944 con- trols [18,19], a similar rare variant screen focused on TNFRSF6B in pediatric-onset IBD [12] , exome sequencing of TNFAIP3 in 19 primary Sjögren's syndrome patients with lymphoma [31] , and targeted sequencing of the FAM167 and BLK exomes in 191 SLE cases and 96 con- trols [29].
    [Show abstract] [Hide abstract] ABSTRACT: Next-generation DNA sequencing has revolutionized the field of genetics and genomics, providing researchers with the tools to efficiently identify novel rare and low frequency risk variants, which was not practical with previously available methodologies. These methods allow for the sequence capture of a specific locus or small genetic region all the way up to the entire six billion base pairs of the diploid human genome. Rheumatic diseases are a huge burden on the US population, affecting more than 46 million Americans. Those afflicted suffer from one or more of the more than 100 diseases characterized by inflammation and loss of function, mainly of the joints, tendons, ligaments, bones, and muscles. While genetics studies of many of these diseases (for example, systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel disease) have had major successes in defining their genetic architecture, causal alleles and rare variants have still been elusive. This review describes the current high-throughput DNA sequencing methodologies commercially available and their application to rheumatic diseases in both case–control as well as family-based studies.
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  • [Show abstract] [Hide abstract] ABSTRACT: Approaches to understanding the genetic contribution to inflammatory bowel disease (IBD) have continuously evolved from family- and population-based epidemiology, to linkage analysis, and most recently, to genome-wide association studies (GWAS). The next stage in this evolution seems to be the sequencing of the exome, that is, the regions of the human genome which encode proteins. The GWAS approach has been very fruitful in identifying at least 163 loci as being associated with IBD, and now, exome sequencing promises to take our genetic understanding to the next level. In this review we will discuss the possible contributions that can be made by an exome sequencing approach both at the individual patient level to aid with disease diagnosis and future therapies, as well as in advancing knowledge of the pathogenesis of IBD.
    No preview · Article · Oct 2013 · World Journal of Gastroenterology
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  • [Show abstract] [Hide abstract] ABSTRACT: : Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD), ulcerative colitis (UC), and unclassified IBD, is characterized by chronic intestinal inflammation and has a multifactorial etiology with complex interactions between genetic and environmental factors. The genetics of IBD are believed to be common and complex with over 163 associated genetic loci. However, the genetic contribution of the majority of these common loci is small, and the effect sizes are low. Although childhood onset IBD represents only 10% to 25% of all IBD cases, in depth research into the genetic networks of pediatric IBD has revealed exciting new developments and unsuspected pathways. Recent pediatric studies have revealed an increasing spectrum of human monogenic diseases with high effect sizes or penetrance that can present with IBD or IBD-like intestinal inflammation. A substantial proportion of patients with these genetic defects present with very early onset of intestinal inflammation, with onset of IBD at less than 10 years of age. There is also considerable overlap with primary immunodeficiencies and very early onset IBD. This review summarizes the current understanding of the genetics of pediatric IBD with a focus on the very early onset population and discusses the promising results from the effort of finding missing heritability of IBD from studying pediatric population.
    Full-text · Article · Aug 2014 · Inflammatory Bowel Diseases
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