IBD-Associated TL1A Gene (TNFSF15) Haplotypes Determine Increased Expression of TL1A Protein

Michelsen, Kathrin S.; Thomas, Lisa S.; Taylor, Kent D.; Yu, Qi; Mei, Ling; Landers, Carol J.; Derkowski, Carrie; McGovern, Dermot P.; Rotter, Jerome I.; Targan, Stephan R.

doi:10.1371/journal.pone.0004719

Cited by 88 publications

(65 citation statements)

References 41 publications

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“…Whether the rs4263839 polymorphism has direct functional effects had not been addressed previously and, although our in-vitro experiments did not support this hypothesis, we demonstrated a correlation between genotype at this SNP and TNFSF15 mRNA levels in peripheral blood leucocytes and rectal mucosal tissue. This is consistent with findings from previous studies, in which extended TNFSF15 haplotypes (spanning the entire coding region) have been shown to influence TNFSF15 protein (TL1A) or mRNA expression in, respectively, monocytes and stimulated T lymphocytes 17 34. Very strong LD exists throughout the entire TNFSF15 coding region (figure 4), and it is therefore conceivable that the CD/IBS risk allele rs4263839 G studied here only represents a marker for other, true causative variants of functional relevance.…”

Section: Discussionsupporting

confidence: 93%

Association of TNFSF15 polymorphism with irritable bowel syndrome

Zucchelli

Camilleri

Andréasson

et al. 2011

Gut

112

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Background Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder, affecting more than 10% of the general population worldwide. Although a genetic component is suspected, unambiguous susceptibility genes have so far not been identified. This study tested the hypothesis that genes contributing to epithelial barrier integrity, control of mucosal immune responses and interactions with bacteria in the gut are associated with IBS. Methods Single nucleotide polymorphisms (SNPs) corresponding to top signals of association with Crohn's disease at 30 known susceptibility loci were tested for their effect on IBS risk in 1992 individuals from two independent case–control cohorts from Sweden and the USA. Association tests included a conservative Bonferroni correction for multiple comparisons, and were also performed on specific subgroups of patients characterised by constipation (IBS-C), diarrhoea (IBS-D) or alternating constipation and diarrhoea (IBS-A). Results The Crohn's disease risk allele rs4263839 G in the TNFSF15 gene was significantly associated with an increased risk of both IBS (p=2.2×10–5; OR 1.37) and more pronouncedly, IBS-C (p=8.7×10–7; OR 1.79) in the entire sample. Similar associations and risk effects of the same magnitude were observed in the two cohorts analysed separately. A correlation between rs4263839 genotype and TNFSF15 mRNA expression was detected both in peripheral blood and in rectal mucosal biopsies from healthy individuals (combined p=0.0033). Conclusions TNFSF15 is a susceptibility gene for IBS and IBS constipation. As TL1A, the protein encoded by TNFSF15, contributes to the modulation of inflammatory responses, the results support a role of immune activation in IBS.

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Section: Discussionsupporting

confidence: 93%

Association of TNFSF15 polymorphism with irritable bowel syndrome

Zucchelli

Camilleri

Andréasson

et al. 2011

Gut

112

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“…One variant that is highly associated with CD is rs1004819, whereas rs11209026 confers protection against CD. IL23R plays an essential role in Strongly associated with CD for Japanese and Jewish cohorts, but not for Europeans [4,15,16] IL23R rs11209026 Strongly associated with conferring protection against CD [4,33] rs1004819…”

Section: Resultsmentioning

confidence: 99%

“…Although the risk haplotype was identified in both cohorts, there was a weaker effect size (P = 0.02 in both family-based and case-control association panels). In addition, another study involving a Jewish cohort also showed an association of TNFSF15 with CD, and also suggested that in response to FC-gamma receptor stimulation, TNFSF15 gene variation aggravates induction of TNFSF15 [16] . However, in a separate study using a Belgian CD cohort, no significant association was observed between CD and TNFSF15 [4] .…”

Section: Family 15mentioning

confidence: 94%

Role ofATG16L,NOD2andIL23Rin Crohn’s disease pathogenesis

Naser

Arce²,

Khaja³

et al. 2012

WJG

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Inflammatory bowel disease is a group of diseases that includes Crohn's disease (CD) and ulcerative colitis. CD is characterized as a chronic inflammatory disease of the gastrointestinal tract, ranging from the mouth to the anus. Although there are gross pathological and histological similarities between CD and Johne's disease of cattle, the cause of CD remains controversial. It is vital to understand fully the cause of this disease because it affects approximately 500,000 people in North America and Europe. It ranges from 27 to 48 cases per 100,000 people. There are many theories on the cause of CD ranging from possible association with environmental factors including microorganisms to imbalance in the intestinal normal flora of the patients. Regardless of the environmental trigger, there is strong evidence that a genetic disposition is a major key in acquiring CD. Many studies have proven the link between mutations in the ATG16L, NOD2/CARD15, IBD5, CTLA4, TNFSF15 and IL23R genes, and CD. The purpose of this review is to examine all genetic aspects and theories of CD, including up to date multiple population studies performed worldwide.

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“…The polymorphism of TL1A genes is associated with an increased risk for CD [26]. INTERLEUKIN 1 Interleukin 1 (IL-1) along with TNF-α is important in the pathogenesis of IBD due to its upregulatory and pro-inflammatory activity.…”

Section: Pro-inflammatory Cytokinesmentioning

confidence: 99%

Cytokines in inflammatory bowel disease

Moldoveanu

Diculescu

Braticevici

2015

Romanian Journal of Internal Medicine

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Inflammatory bowel diseases are chronic afflictions, characterized by active and remission periods. Inflammation is the most common type of response that the human body uses as a defense mechanism against aggressors from the environment. The frequency and degree of inflammation depends on the size of the affected tissues. The gastrointestinal tract is, by far, the most susceptible tissue to inflammatory responses, because of its constant exposure to various antigenic, mutagenic and toxic factors. In inflammatory bowel diseases there is a loss of immune tolerance to intestinal flora that is mediated by various substances, including cytokines. Cytokines represent a key signal in the intestinal immune response. Activated dendritic cells and macrophages secrete cytokines that actively intervene in inflammation regulation, in both Crohn’s disease and ulcerative colitis. After their secretion by antigen presented cells, cytokines activate and differentiate T cells, stirring up the adaptive immune response. Cytokines have an important role in the pathogenesis of inflammatory bowel diseases. The identification of new cytokines, as well as the changing of the pathogenesis paradigms in inflammatory bowel diseases has been done on animal tests and clinical studies. Thus, there is promising evidence basis for future therapy research based on cytokines, and anti-cytokine antibodies.

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IBD-Associated TL1A Gene (TNFSF15) Haplotypes Determine Increased Expression of TL1A Protein

Cited by 88 publications

References 41 publications

Association of TNFSF15 polymorphism with irritable bowel syndrome

Association of TNFSF15 polymorphism with irritable bowel syndrome

Role ofATG16L,NOD2andIL23Rin Crohn’s disease pathogenesis

Cytokines in inflammatory bowel disease

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