A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease

Ogura, Yasunori; Bonen, Denise K.; Inohara, Naohiro; Nicolae, Dan L.; Chen, Felicia F.; Ramos, Richard; Britton, Heidi; Moran, Thomas J.; Karaliuskas, Reda; Duerr, Richard H.; Achkar, Jean–Paul; Brant, Steven R.; Bayless, Theodore M.; Kirschner, Barbara S.; Hanauer, Stephen B.; Núñez, Gabriel; Cho, Judy H.

doi:10.1038/35079114

Cited by 4,528 publications

(3,171 citation statements)

References 21 publications

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“…In addition, the recent identification of CARD15, a gene involved in NFkB activation as a susceptibility gene for CD, emphasizes the important role of the innate immune system in the pathogenesis of CD. 22,23 Although the data from the present study did not reveal a significant association with the IL-12 p40 TaqI polymorphism, this does not necessarily exclude a role for the IL-12 gene in the susceptibility to CD. The relatively small sample size in combination with the rare frequency of the variant allele may not have been powerful enough to detect such an association.…”

Section: Discussioncontrasting

confidence: 83%

A TaqI polymorphism in the 3′UTR of the IL-12 p40 gene correlates with increased IL-12 secretion

et al. 2002

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Interleukin-12 (IL-12) is a key cytokine for the induction of Th1 immune responses. We evaluated whether a TaqI polymorphism in the 3 0 UTR of the IL-12 p40 gene affects secretion of IL-12 in vitro, and whether this polymorphism is associated with susceptibility to Crohn's disease (CD). IL-12 p40 and p70 secretion by monocytes in relation to genotype was determined in 63 healthy donors. Genotype and allele frequencies of the TaqI polymorphism in 150 CD patients were compared with 145 ethnically matched healthy controls (HC). No significant association was found between genotype and IL-12 p40 secretion after stimulation of monocytes with SAC+IFNg. In contrast, increasing IL-12 p70 secretion was found across the categories of noncarriers, heterozygotes and homozygotes for the variant allele (median values 7 SEM: 147 7 27, 282 7 51 and 482 7 34 pg/ ml, respectively; Po0.005). The allele and genotype frequencies of this polymorphism in patients with CD did not differ statistically significantly from HC. The presence of a TaqI polymorphism in the IL12 p40 3 0 UTR correlates with increased in vitro IL-12 p70, but not p40 secretion. While this polymorphism does not appear to be correlated with susceptibility to CD in the limited population of patients tested here, it could influence the occurrence of the disease in certain subsets of patients.

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Section: Discussioncontrasting

confidence: 83%

A TaqI polymorphism in the 3′UTR of the IL-12 p40 gene correlates with increased IL-12 secretion

et al. 2002

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“…[1][2][3][4] The incidence of IBD is relatively higher in Caucasian than in Asian populations; however, the incidence in Asia is increasing. 5,6 Of the two types of IBD, the genetic contribution to disease risk has been documented more extensively and clearly for CD [7][8][9][10][11][12][13][14][15][16][17] than for UC. [18][19][20][21] So far, linkage and genome-wide association studies have identified more than 30 CD-susceptibility loci in Caucasian populations.…”

Section: Introductionmentioning

confidence: 99%

No association between TNFSF15 and IL23R with ulcerative colitis in Koreans

et al. 2011

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Recent genome-wide association studies have shown that some Crohn's disease (CD)-associated loci also contribute to ulcerative colitis (UC) susceptibility. To understand the genetic relationship between the two forms of inflammatory bowel disease, we investigated the well-established CD-susceptibility genes TNFSF15 (tumor necrosis factor ligand superfamily, member 15) and IL23R in Korean patients with UC. Eight TNFSF15 and five IL23R single-nucleotide polymorphisms were genotyped in 654 patients with UC and in 601 healthy controls. There was no association between TNFSF15 or IL23R variants and UC in Korean individuals, in contrast to previous reports of a shared association of the IL23R gene with both CD and UC in Caucasian individuals. Our data suggest that neither TNFSF15 nor IL23R variants contribute to UC susceptibility in Koreans.

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“…An allele of murine TLR4, Lpsd, was first noted to decrease the severity of experimental colitis induced by dextran sulfate sodium (DSS), 6 and more recently, TLR4 À/À and MyD88 À/À mice have been shown to have more severe DSS-induced colitis than their wild-type littermates. [7][8][9] In addition, mutations in CARD15/NOD2 have been associated with susceptibility to human CD [10][11][12] and shown to affect nuclear factor-kB (NF-kB) activation, interleukin (IL)-1b processing, and resistance to intestinal Listeria monocytogenes infection in mice. 13,14 Within the TLR family of PRR, there are 10 different transmembrane receptors (TLR1-10) that are found either on the extracellular surface of cells (TLR1, 2 and 4) or within intracellular compartments such as endosomes (TLR3 and 7-9).…”

Section: Introductionmentioning

confidence: 99%

The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases

et al. 2007

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The intestinal flora has long been thought to play a role either in initiating or in exacerbating the inflammatory bowel diseases (IBD). Host defenses, such as those mediated by the Toll-like receptors (TLR), are critical to the host/pathogen interaction and have been implicated in IBD pathophysiology. To explore the association of genetic variation in TLR pathways with susceptibility to IBD, we performed a replication study and pooled analyses of the putative IBD risk alleles in NFKB1 and TLR4, and we performed a haplotype-based screen for association to IBD in the TLR genes and a selection of their adaptor and signaling molecules. Our genotyping of 1539 cases of IBD and pooled analysis of 4805 cases of IBD validates the published association of a TLR4 allele with risk of IBD (odds ratio (OR): 1.30, 95% confidence interval (CI): 1.15-1.48; P ¼ 0.00017) and Crohn's disease (OR: 1.33, 95% CI: 1.16-1.54; P ¼ 0.000035) but not ulcerative colitis. We also describe novel suggestive evidence that TIRAP (OR: 1.16, 95% CI: 1.04-1.30; P ¼ 0.007) has a modest effect on risk of IBD. Our analysis, therefore, offers additional evidence that the TLR4 pathway -in this case, TLR4 and its signaling molecule TIRAP -plays a role in susceptibility to IBD.

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A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease

Cited by 4,528 publications

References 21 publications

A TaqI polymorphism in the 3′UTR of the IL-12 p40 gene correlates with increased IL-12 secretion

A TaqI polymorphism in the 3′UTR of the IL-12 p40 gene correlates with increased IL-12 secretion

No association between TNFSF15 and IL23R with ulcerative colitis in Koreans

The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases

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