Polymorphisms of Tumor Necrosis Factor-α but Not MDR1 Influence Response to Medical Therapy in Pediatric-Onset Inflammatory Bowel Disease
ABSTRACT We investigated the contribution of variants of tumour necrosis factor (TNF)-alpha and MDR1 genes in the predisposition and response to medical therapy in a large pediatric cohort of patients with Crohn disease (CD) and ulcerative colitis (UC).
In this study, 200 patients with CD, 186 patients with UC, 434 parents (217 trios), and 347 healthy unrelated controls were investigated. Single-nucleotide polymorphisms -G308A and -C857T of the TNF-alpha gene and C3435T of the MDR1 gene were investigated and correlated with clinical subphenotypes and efficacy of medical therapy.
The frequency of the -308A allele of the TNF-alpha gene was significantly increased in both patients with CD (15%; odds ratio [OR] = 2.79; P < 0.01) and patients with UC (11%; OR = 1.96; P < 0.003) compared with controls (6%). Carriers of this allele were 27% in CD (OR = 2.94; P < 0.01) and 19% in UC (OR = 1.86; P = 0.015) compared with 11% in healthy controls. No significant difference was found for both the -C857T and C3435T single-nucleotide polymorphisms. With the genotype/phenotype analysis, no correlation in patients with UC with the MDR1 gene was found. CD carriers of the -308A allele had a higher frequency of surgical resection (35% vs 20%; OR = 2.1; P = 0.035) and more frequent resistance to steroids (22% vs 8%; OR = 0.29; P = 0.032) compared with noncarriers. These findings were confirmed by stepwise logistic regression.
In our pediatric cohort, the promoter -308A polymorphism of TNF-alpha but not the MDR1 gene is significantly involved in the predisposition to both CD and UC. This polymorphism carries a significant reduction in response to steroid therapy, probably leading to a more frequent need for surgical resection.
- SourceAvailable from: R. William Depaolo
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- "Other genetic variants that impact disease behavior include an SNP in IRGM (rs4958847), which was significantly associated with frequency of surgery in a study of 66 patients with ileocecal CD, and a negative association was found between ileal disease and TLR1 S602I.76 Genetic variants may also impact the response to certain immune therapies; polymorphisms in multidrug resistant 1, TNF, and migration inhibitory factor genes have all been associated with sensitivity to corticosteroid,77,78 while variants in apoptosis genes have been used to predict the response to infliximab therapy.79 The identification of genetic variants could be an important tool in predicting disease behavior and responsiveness of certain patients to specific treatments; however, this may be complicated by the major role that other factors, such as the environment, plays in CD pathogenesis. "
ABSTRACT: Crohn's disease is an immune-related disorder characterized by inflammation of the gastrointestinal mucosa, which can occur in any area throughout the digestive tract. This life-long disease commonly presents with abdominal pain, diarrhea, vomiting, and weight loss. While the exact etiology of this disease is largely unknown, it is thought to arise from an interaction between microbial, immunological, and environmental factors in a genetically susceptible host, whereby the immune system attacks the intestine as it cross reacts against gut microbial antigens. The study of genetic variants associated with Crohn's disease has shed light on our understanding of disease pathophysiology. A large number of genetic variants identified in Crohn's disease are related to genes targeting microbial recognition and bacterial wall sensing, the most common being NOD2/CARD15 gene. This review will discuss the recent advance in our knowledge of genetic variants of this disease and how they influence the disease course and prognosis.The Application of Clinical Genetics 07/2013; 6:25-32. DOI:10.2147/TACG.S33966
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- "Single nucleotide polymorphisms (SNPs) in the TNF-α, TNFRSF1A and TNFRSF1B genes have been identified, however functional data pertaining to these polymorphisms in scarce. Nonetheless, the putative role of these polymorphisms in disease susceptibility has been examined in genetic association studies of various inflammatory disorders, including Crohn's disease [10-13], ulcerative colitis [10,11,14], systemic lupus erythematosus [15-17] and rheumatoid arthritis [18,19]. More recently, given that cancer progression is preceded by a long period of subclinical inflammation [20-22], the genetic polymorphisms of TNF-α, TNFRSF1A and TNFRSF1B have been examined in terms of susceptibility to various cancers [23-28]. "
ABSTRACT: Currently definitive 5-fluorouracil (5-FU)/cisplatin (CDDP) -based chemotherapy is recognized as one of the most promising treatments for esophageal cancer. A series of studies performed found genetic polymorphisms and the plasma concentration of 5-FU to be predictive of acute severe toxicities and clinical response. Genetic polymorphisms of tumor necrosis factor (TNF) -alpha and its surface receptors, TNFRSF1A and TNFRSF1B have been examined in terms of susceptibility to various cancers. In this study, genetic polymorphisms of TNFRSF1B gene were evaluated Japanese esophageal squamous cell carcinoma (ESCC) patients treated with the definitive 5-FU/CDDP-based chemoradiotherapy and their predictive values of prognosis or severe acute toxicities were assessed. Forty-six patients with ESCC were treated with the definitive 5-FU/CDDP-based chemoradiotherapy, one course of which consisted of the continuous infusion of 5-FU for days 1-5 and 8-12, the infusion of CDDP on days 1 and 8, and the radiation at 2 Gy/day on days 1-5, 8-12, and 15-19, with a second course repeated after 2-week interval. Genetic polymorphisms of a TNF-alpha receptor TNFRSF1B gene were determined by a TaqMan(R) MGB probe-based polymerase chain reaction. The genotype of TNFSR1B A1466G, but not M196R/T587G or C1493T, was found to be predictive of clinical response, i.e., a complete response or not (p = 0.040). Clinical response was predicted by tumor size (p = 0,002), lymph node metastasis (p = 0.007), distant metastasis (p = 0.001) and disease stage (p < 0.001), but TNFRSF1B A1466G genotype was independent of these factors. Genetic polymorphism of TNFRSF1B A1466G was found to be predictive response in Japanese ESCC patients with a definitive 5-FU/CDDP-based chemoradiotherapy. Further clinical investigation with a large number of patients or experiments in vitro should be performed to assess the predictive value of TNFRSF1B A1466G genotype after chemoradiotherapy.Journal of Experimental & Clinical Cancer Research 07/2010; 29(1):100. DOI:10.1186/1756-9966-29-100 · 4.43 Impact Factor
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ABSTRACT: Approximately 20% of all inflammatory bowel disease (IBD) first presents in childhood or adolescence, and approximately 10% of the estimated 1.4 million Americans with IBD are under age 17. Diagnosis in pediatric patients may be complicated at presentation due to atypical symptoms and/or extraintestinal manifestations (eg, short stature, chronic anemia, unexplained fever, arthritis, mouth ulcers). Pediatric IBD is traditionally diagnosed using endoscopic evaluations of the upper and lower gastrointestinal tract with mucosal biopsies for histologic confirmation. Less invasive serologic testing for IBD may be particularly valuable in pediatric patients, particularly given the association between serum immune reactivity and severe disease phenotypes that is drawing increasing attention. These serologic markers may help stratify risk and identify appropriate pediatric candidates for early aggressive therapy. Serologic testing in pediatric patients includes traditional IBD serologic markers such as anti–Saccharomyces cerevisiae antibodies and perinuclear antineutrophil cytoplasmic antibody, as well as newer antimicrobial antibodies, including antibodies to outer membrane porin C; I2, a bacterial sequence derived from Pseudomonas fluorescens; and CBir1 flagellin, a colitogenic antigen of the enteric microbial flora in C3H/HeJBir mice strain. Given recent data associating seropositivity with aggressive clinical phenotypes and rapid disease progression, serologic testing may allow early initiation of therapy, maintenance of remission, reduction of corticosteroid exposure, facilitation of mucosal healing, and restoration of normal growth velocity.