TNF Promoter Polymorphisms and Modulation of Growth Retardation and Disease Severity in Pediatric Crohn's Disease

Levine, Arie; Shamir, Raanan; Wine, Eytan; Weiss, B; Karban, Amir; Shaoul, Ron; Reif, Shimon; Yakir, Benjamin; Friedlander, Marcello; Kaniel, Yael; Leshinsky‐Silver, Esther

doi:10.1111/j.1572-0241.2005.41737.x

Cited by 48 publications

(33 citation statements)

References 45 publications

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“…30 Moreover, growth retardation in IBD patients can be correlated with an increase in systemic TNF-a and IL-6 levels. 31,32 The bodyweight alterations observed both in Muc2 À/À and Muc2/ IL-10 DKO mice support this paradigm, as the weights of these mice correlated with the severity of inflammation. In addition, Muc2/IL-10 DKO animals also show occult blood loss to gross bleeding and diarrhea at 4 weeks, unlike the WT and IL-10 À/À mice.…”

Section: Mucin 2-interleukin 10-deficient Mice: Double Trouble M Van mentioning

confidence: 75%

Combined defects in epithelial and immunoregulatory factors exacerbate the pathogenesis of inflammation: mucin 2-interleukin 10-deficient mice

Sluis

Bouma

Vincent

et al. 2008

Laboratory Investigation

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Expression of the mucin MUC2, the structural component of the colonic mucus layer, is lowered in ulcerative colitis. Furthermore, interleukin (IL)-10 knockout (IL-10 À/À ) mice develop colitis and have reduced Muc2 levels. Our aim was to obtain insight into the role of Muc2 and IL-10 in epithelial protection. Muc2-IL-10 double-knockout (Muc2/IL-10 DKO ) mice were characterized and compared to Muc2 knockout (Muc2 À/À ), IL-10 À/À and wild-type (WT) mice. Clinical symptoms, intestinal morphology and differences in epithelial-specific protein levels were analyzed. In addition, levels of the proinflammatory cytokines in colonic tissue and serum were determined. IL-10 À/À mice were indistinguishable from WT mice throughout this experiment and showed no clinical or histological signs of colitis. Muc2/IL-10 DKO and Muc2 À/À mice showed significant growth retardation and clinical signs of colitis at 4 and 5 weeks, respectively. Muc2/IL-10 DKO mice had a high mortality rate (50% survival/5 weeks) compared to the other types of mice (100% survival). Microscopic analysis of the colon of Muc2/IL-10 DKO mice showed mucosal thickening, increased proliferation, superficial erosions and a diminished Muc4 expression. Furthermore, pro-inflammatory cytokines were significantly upregulated, both in tissue (mRNA) and systemically in Muc2/IL-10 DKO mice. In conclusion, Muc2/IL-10 DKO mice develop colitis, which is more severe in every aspect compared to Muc2 À/À and IL-10 À/À mice. These data indicate that (i) in case of Muc2 deficiency, the antiinflammatory cytokine IL-10 can control epithelial damage, though to a limited extent and (ii) the mucus layer is most likely a key factor determining colitis.

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Section: Mucin 2-interleukin 10-deficient Mice: Double Trouble M Van mentioning

confidence: 75%

Combined defects in epithelial and immunoregulatory factors exacerbate the pathogenesis of inflammation: mucin 2-interleukin 10-deficient mice

Sluis

Bouma

Vincent

et al. 2008

Laboratory Investigation

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“…4 Recently, TNF-α promoter polymorphisms have been indicated to be involved in the disease severity of chronic inflammatory disorders including pediatric Crohn's disease. 16 Studies have adapted TNF-α polymorphisms -1031 T/C, -863C/A, -857C/T, -308G/A and -238G/A for various diseases like hepatitis B virus (HBV) infection, hepatocellular carcinoma development and HBV persistence. [17][18][19] However, the correlation between TNF-α polymorphisms and MG is still limited, and therefore the present study explored the association of TNF-α-1031 T/C, -857C/T and -863C/A polymorphisms with the Abbreviations: anti-AchR, acetylcholine receptor antibody; NT-MG, nonthymoma-associated myasthenia gravis; T-MG, thymoma-associated myasthenia gravis; TNF-α, tumor necrosis factor-alpha.…”

Section: Discussionmentioning

confidence: 99%

Correlations of TNF-α gene promoter polymorphisms with the risk of thymoma-associated myasthenia gravis in a northern Chinese Han population

Lei

Xie

et al. 2017

Cancer Gene Ther

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This study was performed with the aim to investigate the correlations of tumor necrosis factor-alpha (TNF-α) gene promoter polymorphisms with the risk of thymoma-associated myasthenia gravis (T-MG) in a northern Chinese Han population. Between June 2005 and June 2015, 305 MG patients (150 males and 155 females, MG group) and 293 healthy volunteers (negative control (NC) group) were enrolled in this study. Among the MG patients, there were 121 patients with thymoma-associated MG (T-MG group) and 184 without T-MG (NT-MG group). Enzyme-linked immunosorbent assay (ELISA) was used for the serum TNF-α level. Polymerase chain reaction-restriction fragment length polymorphism was conducted to determine genotype and allele frequencies of TNF-α gene promoter -1031T/C, -857C/T and -863C/A. The haplotype was analyzed with the SHEsis software. Logistic regression analysis was performed for correlations between TNF-α gene promoter polymorphisms and the risk of T-MG. The T-MG group had higher frequencies of the CT/TT genotype and T allele of -857C/T than the NT-MG and NC groups. The frequencies of the CC genotype and C allele of -1031T/C were higher in the T-MG group than in the NT-MG and NC groups, and higher in male patients in the T-MG group than in male patients in the NC group. TTA and TTC haplotypes exhibited lower frequencies in the T-MG group than in the NT-MG group. The ocular MG patients exhibited lower frequencies of the TT genotype and T allele of -857C/T than the generalized MG patients did. The TNF-α level was elevated in the T-MG group compared with that in the NC and NT-MG groups, indicating that the TC+CC and CT+TT genotypes were increased compared with the TT and CC genotypes in the -1031T/C and -857C/T, respectively. Logistic regression analysis suggested that expressions of anti-acetylcholine receptor antibodies, Osserman's classification, -1031T/C and -857C/T polymorphisms and the TTA haplotype were the independent risk factors for T-MG. These findings reveal that TNF-α -1031T/C and -857C/T polymorphisms and the TTA haplotype may be correlated with the occurrence of T-MG in a Northern Chinese Han population.

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“…It remains feasible, however, that common genetic polymorphisms which alter cytokine expression may contribute to growth impairment, although not influence overall susceptibility to CD. A recent study of Israeli patients suggests that relatively common variations in the promoter region for TNF-␣ may have an independent effect on linear growth outcomes [22] . Similarly, data from Sawczenko et al [23] demonstrate a potential causal relationship between variation in the promoter region for Il-6, subsequent IL-6 expression, and a differential in linear growth impairment during active inflammation.…”

Section: Influence Of Genetic Factorsmentioning

confidence: 99%

Growth Retardation in Early-Onset Inflammatory Bowel Disease: Should We Monitor and Treat These Patients Differently?

Griffiths

2009

Dig Dis

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Growth impairment and associated pubertal delay are common complications of pediatric inflammatory bowel disease (IBD), particularly Crohn’s disease (CD). Chronic undernutrition (related primarily to inadequate intake) and pro-inflammatory cytokines are the two major and interrelated contributory factors. Pathogenic mechanisms include interference with growth hormone/insulin-like growth factor-1 axis, with gonadotropin-releasing hormone secretion patterns, and direct cytokine effects on growing bone. Chronic corticosteroid therapy compounds disease-related causes of growth impairment. The influence on growth of polymorphisms in IBD susceptibility or modifier genes is under study. Accurate recognition of impaired growth requires appreciation of normal growth. Pre-illness standard deviation scores (SDS) for height should be obtained and compared with height SDS at diagnosis, so that the impact of disease on growth can be fully appreciated. The greater the deficit prior to recognition of IBD, the greater is the demand for catch-up growth. Height velocity should be regularly monitored and its adequacy for age and pubertal stage assessed. Restoration and maintenance of pre-illness growth pattern indicate success of therapy. Current treatment regimens limit use of corticosteroids, via optimization of immunomodulatory drugs, use of enteral nutrition in CD, and, if necessary, surgery for ulcerative colitis and for intestinal complications of localized CD. Biologic agents with the potential for mucosal healing hold promise of growth enhancement even among children, whose growth with previously available therapies remained compromised. For all therapies, there is a window of opportunity to achieve normal growth before puberty is too advanced.

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TNF Promoter Polymorphisms and Modulation of Growth Retardation and Disease Severity in Pediatric Crohn's Disease

Abstract: Polymorphisms in the TNF-alpha promoter may independently modulate growth and disease severity in pediatric onset CD. The effect of these polymorphisms does not appear to be mediated via weight loss, and is relatively modest.

Cited by 48 publications

References 45 publications

Combined defects in epithelial and immunoregulatory factors exacerbate the pathogenesis of inflammation: mucin 2-interleukin 10-deficient mice

Combined defects in epithelial and immunoregulatory factors exacerbate the pathogenesis of inflammation: mucin 2-interleukin 10-deficient mice

Correlations of TNF-α gene promoter polymorphisms with the risk of thymoma-associated myasthenia gravis in a northern Chinese Han population

Growth Retardation in Early-Onset Inflammatory Bowel Disease: Should We Monitor and Treat These Patients Differently?

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