Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease

Rivas, Manuel A.; Beaudoin, Mélissa; Gardet, Agnès; Stevens, Christine; Sharma, Yashoda; Zhang, Clarence K.; Boucher, Gabrielle; Ripke, Stephan; Ellinghaus, David; Burtt, Noél P.; Fennell, Tim; Kirby, Andrew; Latiano, Anna; Goyette, Philippe; Green, Todd; Halfvarson, Jonas; Haritunians, Talin; Korn, Joshua M.; Kuruvilla, Finny G.; Lagacé, Caroline; Neale, Benjamin M.; Lo, Ken Sin; Schumm, L. Philip; Törkvist, Leif; Dubinsky, Marla; Brant, Steven R.; Silverberg, Mark S.; Duerr, Richard H.; Altshuler, David; Gabriel, Stacey; Lettre, Guillaume; Franke, André; D’Amato, Mauro; McGovern, Dermot P.; Cho, Judy H.; Rioux, John D.; Xavier, Ramnik J.; Daly, Mark J.

doi:10.1038/ng.952

Cited by 694 publications

(560 citation statements)

References 47 publications

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“…4 However, this susceptibility has been associated with mutations at multiple chromosomal loci making the relationship between genetics and IBD-susceptibility complex. 4,[8][9][10] To date, the greatest documented risk of IBD susceptibility occurs in individuals with a homozygous polymorphism in the NOD2 gene, which encodes a bacterial peptidoglycan receptor associated with activity of the nuclear factor kappa-B (NF-kB) transcriptional pathway. 11 Other genes reported to affect susceptibility to IBD, include CARD9, IL23R and MUC19 which encode proteins associated with innate immune signaling, cytokine signaling and mucin production, respectively.…”

Section: Inflammatory Bowel Disease (Ibd)mentioning

confidence: 99%

Hydroxylases as therapeutic targets in inflammatory bowel disease

Cummins

Doherty

Taylor

2013

Laboratory Investigation

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Inflammatory bowel disease (IBD) is a common and debilitating clinical disorder comprising ulcerative colitis and Crohn's disease. IBD occurs when inappropriate immunological activity in the intestinal mucosa results in epithelial barrier dysfunction leading to exposure of the mucosal immune system to luminal antigenic material. This in turn results in the cycles of inflammation and further barrier dysfunction which underlie disease progression. Although significant therapeutic advances have been made over the last decade, current immunosuppressive and anti-inflammatory treatments for IBD have significant limitations due to lack of treatment response in some patients and adverse effects, including increased risk of infection and malignancy. Recent studies using experimental models of IBD have identified that intracellular hydroxylases, a group of enzymes responsible for oxygen sensing and activation of adaptive transcriptional responses to hypoxia may represent a new class of therapeutic targets in IBD. Hydroxylase inhibitors are effective in ameliorating symptoms of colitis at least in part through the promotion of intestinal epithelial barrier function. The mechanism of this protection is due to activation of hypoxia-sensitive transcription factors, including the hypoxiainducible factor (HIF) and nuclear factor kappa-B (NF-kB), which activate specific epithelial barrier-protective transcriptional programs. In this review, the mechanism(s) of action and the therapeutic potential of small molecule hydroxylase inhibitors for the treatment of IBD will be discussed.

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Section: Inflammatory Bowel Disease (Ibd)mentioning

confidence: 99%

Hydroxylases as therapeutic targets in inflammatory bowel disease

Cummins

Doherty

Taylor

2013

Laboratory Investigation

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“…A number of successful candidate gene sequencing studies discovered associations of multiple rare coding variants with complex phenotypes (23)(24)(25)(26)(27)(28)(29)(30)(31)(32). Ongoing whole-exome sequencing studies attempt an unbiased search for genes harboring multiple rare variants collectively associated with complex traits (33).…”

Section: Introductionmentioning

confidence: 99%

Inferring causality and functional significance of human coding DNA variants

Sunyaev

2012

Human Molecular Genetics

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Sequencing technology enables the complete characterization of human genetic variation. Statistical genetics studies identify numerous loci linked to or associated with phenotypes of direct medical interest. The major remaining challenge is to characterize functionally significant alleles that are causally implicated in the genetic basis of human traits. Here, I review three sources of evidence for the functional significance of human DNA variants in protein-coding genes. These include (i) statistical genetics considerations such as co-segregation with the phenotype, allele frequency in unaffected controls and recurrence; (ii) in vitro functional assays and model organism experiments; and (iii) computational methods for predicting the functional effect of amino acid substitutions. In spite of many successes of recent studies, functional characterization of human allelic variants remains problematic.

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“…1A). Fine mapping of the loci reveals multiple missense, intronic, and intergenic single-nucleotide polymorphisms (SNPs) linked to increased disease susceptibility within the C1ORF106 locus (6,(9)(10)(11)(12). C1ORF106 is highly expressed in epithelial-rich tissues in both human and mouse, particularly in the gastrointestinal tract, as well as in other tissues with key roles in barrier function, such as skin (Fig.…”

Section: Resultsmentioning

confidence: 99%

Inflammatory Bowel Disease Susceptibility Gene C1ORF106 Regulates Intestinal Epithelial Permeability

Manzanillo¹,

Mouchess²,

Ota³

et al. 2018

ImmunoHorizons

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Intestinal epithelial cells form a physical barrier that is tightly regulated to control intestinal permeability. Proinflammatory cytokines, such as TNF-α, increase epithelial permeability through disruption of epithelial junctions. The regulation of the epithelial barrier in inflammatory gastrointestinal disease remains to be fully characterized. In this article, we show that the human inflammatory bowel disease genetic susceptibility gene C1ORF106 plays a key role in regulating gut epithelial permeability. C1ORF106 directly interacts with cytohesins to maintain functional epithelial cell junctions. C1orf106-deficient mice are hypersensitive to TNF-α–induced increase in epithelial permeability, and this is associated with increased diarrhea. This study identifies C1ORF106 as an epithelial cell junction protein, and the loss of C1ORF106 augments TNF-α–induced intestinal epithelial leakage and diarrhea that may play a critical role in the development of inflammatory bowel disease.

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Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease

Cited by 694 publications

References 47 publications

Hydroxylases as therapeutic targets in inflammatory bowel disease

Hydroxylases as therapeutic targets in inflammatory bowel disease

Inferring causality and functional significance of human coding DNA variants

Inflammatory Bowel Disease Susceptibility Gene C1ORF106 Regulates Intestinal Epithelial Permeability

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