Protective Association of Tumor Necrosis Factor Superfamily 15 (TNFSF15) Polymorphic Haplotype with Ulcerative Colitis and Crohn's Disease in an Indian Population (original) (raw)
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Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn's disease
Human Molecular Genetics, 2005
The inflammatory bowel diseases (IBDs), Crohn's disease (CD) and ulcerative colitis, are chronic inflammatory disorders of the digestive tract. The pathogenesis of IBD is complicated, and it is widely accepted that immunologic, environmental and genetic components contribute to its etiology. To identify genetic susceptibility factors in CD, we performed a genome-wide association study in Japanese patients and controls using nearly 80 000 gene-based single nucleotide polymorphism (SNP) markers and investigated the haplotype structure of the candidate locus in Japanese and European patients. We identified highly significant associations (P 5 1.71 3 10 214 with odds ratio of 2.17) of SNPs and haplotypes within the TNFSF15 (the gene encoding tumor necrosis factor superfamily, member 15) genes in Japanese CD patients. The association was confirmed in the study of two European IBD cohorts. Interestingly, a core TNFSF15 haplotype showing association with increased risk to the disease was common in the two ethnic groups. Our results suggest that the genetic variations in the TNFSF15 gene contribute to the susceptibility to IBD in the Japanese and European populations.
The American journal of gastroenterology, 2009
Inflammatory bowel disease (IBD), e.g., Crohn's disease (CD) and ulcerative colitis (UC), is a complex genetic disorder. Tumor necrosis factor (ligand) superfamily, member 15 (TNFSF15) has been previously identified as a susceptibility gene for CD in Japanese and UK cohorts. This replication study was designed in order to confirm and further validate the role of TNFSF15 in IBD. A total of 666 IBD families (corresponding to 2,982 relatives) with European ancestry were genotyped for the rs6478108 and rs7869487 polymorphisms, which define the main TNFSF15 haplotypes previously associated with CD. An association between the main haplotypes and CD, UC and IBD was tested using the Genehunter TDT and Unphased statistics. Caspase recruitment domain 15 (CARD15)/TNFSF15 interaction and genotype/phenotype correlations were also studied. The previously reported "high-risk" haplotype (A) was associated with IBD (P=0.001) (OR=1.25 (1.05-1.50)) and CD (P=0.02) (OR=1.31 (1.03-1.67)) w...
Clinical and Experimental Immunology, 2007
In 153 patients with IBD, 64 with Crohn's disease (CD), and 89 with ulcerative colitis (UC), as well as in 54 healthy controls (HC), the frequencies of four known di-allelic polymorph isms in the genes for TNF-a and Iymphotoxin alpha (LTa) were investigated. In the Dutch population, the alleles of these four polymorphisms are present in only five combinations, called TNF haplotypes: TNF-C, -E, -H, -I, -Po Furthermore, the relation with the presence of perinuclear anti-neutrophil cytoplasmic autoantibodies (P-ANCA) was studied. A small, but statistically significant, associa tion between the polymorphism at position -308 in the promoter region of the TNF-a gene and UC was found. The frequency of the uncommon TNF-a -308 allele 2 was found to be decreased in patients with UC compared with HC (allele frequency of allele 2 in UC patients O· 15 versus 0·25 in HC, P = 0,044). No significant differences in distribution of the TNF haplotypes were found between IBD patients and HC, although there was a tendency towards a higher frequency of the TNF-C haplotype in UC patients compared with controls (haplotype frequency 22% versus 13%; P = 0'19). No statistically significant differences in distribution of the TNF haplotypes were observed between P-ANCA-positive and P-ANCA-negative UC patients. The strength of the associations indicates that TNF genes are not markers for the predisposition to suffer from IBD. They may, however, be markers of subsets of patients with UC and CD.
Journal of Gastrointestinal Cancer, 2011
Objective Inflammatory bowel diseases (IBDs), namely ulcerative colitis (UC) and Crohn's disease (CD), are characterized by chronic and idiopathic inflammatory conditions of gastrointestinal tract that are immunologically mediated. Single nucleotide polymorphisms in cytokine genes have been reported to modulate inflammation. Therefore, we analyzed the association of pro/ anti-inflammatory cytokine genes polymorphism with IBD susceptibility. Methods Genotyping of interleukin (IL)-4 repeat polymorphism in intron-3, IL-10 (G-1082A and C-819T), and tumor necrosis factor-alpha (TNF-A) (−1031 T>C, −863 C>A, and −857 C>T) was performed in 153 patients with IBD and in 207 controls. Results TNF-A −863 AA genotype was associated with enhanced IBD susceptibility (odds ratio (OR), 4.82; 95% confidence interval (CI), 2.60-8.96), more so for UC (OR, 5.79; 95% CI, 2.99-11.21), Crohn's disease [CD] (OR, 3.13; 95% CI, 1.16-8.47). TNF-A T/C/T (OR, 4.40; 95% CI, 1.64-11.81) and C/A/C (OR, 4.15; 95% CI, 2.48-6.96) haplotypes were associated with increased IBD risk. The frequency of IL-4, B2 carrier (B1/B2+B2/B2) was significantly lower in left-sided UC (17.1%) than proctosigmoiditis (47.6%); p, 0.016. In contrast, TNF-A −863 AA genotype frequency was much higher in pancolitis (45.5) than in proctosigmoiditis (14.2); p, 0.037. Variant genotypes of IL-4 (B1/B2+B2/B2) were absent in colonic type CD. IL-10 polymorphisms did not demonstrate any association with IBD. None of the polymorphisms were associated with steroid treatment and surgery. Conclusion The present study depicts that high-producing genotype of TNF-A (−863 AA) was associated with increased risk of IBD more so with UC. Similarly, combined effect of TNF-A polymorphisms in haplotype analysis demonstrated additively increased risk of IBD.
Journal of Inflammation Research, 2016
Inflammatory bowel disease (IBD) is a complex, multifactorial, chronic inflammatory disorder of the gastrointestinal tract in which immune dysregulation caused by genetic and/or environmental factors plays an important role. The aim of this casecontrol study was to evaluate the association of tumor necrosis factor-alpha (TNF-α) (308) and-β (+252) polymorphisms with susceptibility of IBD. A total of 379 Saudi subjects including 179 IBD patients (ulcerative colitis (UC) =84 and Crohn's disease (CD) =95) and 200 age-and sex-matched healthy controls were recruited. TNF-a and TNF-b genes were amplified using an amplification refractory mutation systems polymerase chain reaction methodology to detect TNF-α (-308) and-β (+252) polymorphisms. The frequency of the GA genotype of TNF-α (-308G/A) was higher, and the frequencies of the GG and AA genotypes were significantly lower in IBD patients compared with those in controls, indicating that genotype GA-positive individuals are susceptible to IBD and that the GG and AA genotypes exert a protective effect. The frequency of allele A of TNF-α (-308G/A) was significantly higher and that of allele G was lower in IBD patients compared with those in controls, indicating an association of allele A with IBD risk in Saudi patients. On stratification of IBD patients into UC and CD, an almost similar pattern was noticed in both the groups. The results of TNF-β (+252A/G) polymorphisms showed a significant increase in the frequency of the GG genotype in IBD patients, suggesting a positive association of GG genotype with IBD risk. On stratification of IBD patients into UC and CD, the genotype GG of TNF-β was associated with susceptibility risk to UC but not CD. The frequencies of alleles and genotypes of both TNF-α and-β polymorphisms are not affected by sex or type of IBD (familial or sporadic). TNF-α (-308G/A) and TNF-β (+252A/G) polymorphisms are associated with risk of developing IBD in Saudi population.
Contribution of TNFSF15 gene variants to Crohnʼs disease susceptibility confirmed in UK population
Inflammatory Bowel Diseases, 2008
Background: Identification of Crohn's disease (CD)-associated genetic variants is key to understanding pathogenic pathways underlying disease susceptibility. Recent reports of an association between TNFSF15 variants and CD have been modestly replicated in European populations, suggesting heterogeneity at this locus with stronger CD association in Japanese than European populations. Methods: We investigated the association between variants in TNFSF15 and CD in 756 CD patients and 636 controls. Disease subphenotype associations were also investigated. Results: TNFSF15 single nucleotide polymorphism (SNP) variants were associated with CD in our panel with peak odds ratio (OR) 1.2 (95% confidence interval [CI] 1.01-1.41) P ϭ 0.033. The presence of a risk haplotype was replicated for the first time in a European population (frequency 67% in cases and 61% in controls) OR ϭ 1.44 (95% CI 1.23-1.68) P ϭ 0.00012. This result mirrors the UK panel in the index study (Yamazaki et al [2005] Hum Mol Genet 14:3499-3506) but is less significant than that reported in Japanese populations. There was no evidence of association with any individual CD subphenotype. Conclusions: Variants in TNFSF15 contribute to overall CD susceptibility in European populations, although to a lesser extent than that seen in the Japanese. Further studies to define the precise disease-causing variants as well as targeted functional studies are now required in human CD as TNFSF15 is a potential target for biological therapies.
Middle East journal of digestive diseases, 2014
BACKGROUND Inflammatory bowel disease (IBD) is a chronic, relapsing, inflammatory disorder of the gastrointestinal tract that includes two entities, Crohn's disease (CD) and ulcerative colitis (UC). As with other complex diseases, both genetic susceptibility and environmental factors play role in the pathogenesis of these diseases. The tumor necrosis factor α (TNF-α) gene is located in the IBD3 region on chromosome 6p21 which is a good functional candidate for involvement in susceptibility to IBD. In addition, the promoter region of TNF-α contains various polymorphisms that have shown a significant association with IBD. METHODS In this case control study we investigated the TNF-α -857 polymorphism in 109 patients (89 UC and 16 CD) who suffered from IBD and 100 healthy age, sex and ethnicity matched adults selected from the same population, as the control group. The polymorphism was checked by amplification refractory system (ARMS) and polymerase chain reaction (PCR). RESULTS Inv...
World Journal of Gastroenterology Wjg, 2008
AIM: To investigate the role that single nucleotide polymorphisms (SNPs) in the promoter of the tumour necrosis factor-alpha (TNF-α) gene play in the risk of inflammatory bowel diseases (IBDs) in a New Zealand population, in the context of international studies.METHODS: DNA samples from 388 patients with Crohn’s disease (CD), 405 ulcerative colitis (UC), 27 indeterminate colitis (IC) and 201 randomly selected controls, from Canterbury, New Zealand were screened for 3 common polymorphisms in the TNF-α receptor: -238 G→A, -308 G→A and -857C→T, using a TaqmanR assay. A meta-analysis was performed on the data obtained on these polymorphisms combined with that from other published studies.RESULTS: Individuals carrying the -308 G/A allele had a significantly (OR = 1.91, χ2 = 17.36, P < 0.0001) increased risk of pancolitis, and a 1.57-fold increased risk (OR = 1.57, χ2 = 4.34, P = 0.037) of requiring a bowel resection in UC. Carrying the -857 C/T variant decreased the risk of ileocolonic CD (OR = 0.56, χ2 = 4.32, P = 0.037), and the need for a bowel resection (OR = 0.59, χ2 = 4.85, P = 0.028). The risk of UC was reduced in individuals who were smokers at diagnosis, (OR = 0.48, χ2 = 4.86, P = 0.028).CONCLUSION: TNF-α is a key cytokine known to play a role in inflammatory response, and the locus for the gene is found in the IBD3 region on chromosome 6p21, known to be associated with an increased risk for IBD. The -308 G/A SNP in the TNF-α promoter is functional, and may account in part for the increased UC risk associated with the IBD3 genomic region. The -857 C/T SNP may decrease IBD risk in certain groups. Pharmaco- or nutrigenomic approaches may be desirable for individuals with such affected genotypes.
TNF-857 polymorphism in Israeli Jewish patients with inflammatory bowel disease
International Journal of Immunogenetics, 2006
Tumour necrosis factor (TNF)-α is an important proinflammatory cytokine that has been implicated in the pathogenesis of inflammatory bowel disease (IBD). The promoter TNF-857 C→T single nucleotide polymorphism (SNP) is functional through the binding to the transcription factor octamer transcription factor-1 (OCT-1). In order to investigate the frequency of this SNP in Israeli Jewish IBD patients, we analysed a cohort of wellcharacterized patients, 153 with Crohn's disease (CD) and 78 with ulcerative colitis (UC) and 188 healthy controls individually matched for age, sex and ethnicity. Forty-one per cent of the patients were of Ashkenazi and 48% were of non-Ashkenazi background. The remaining 11% were of mixed Ashkenazi-non-Ashkenazi background. Patients and controls were genotyped for the TNF-857 SNP by Taqman technology. Stratification for the CARD15 Arg702Trp, Gly908Arg and Leu1007fsinsC mutations took place in 136 CD patients. Carrier frequency of TNF-857T between CD and controls (36% vs. 40%; P = 0.556; OR: 1.18, 95% CI 0.74-1.88), or between UC and controls (41% vs. 37%; P = 0.743; OR: 0.85, 95% CI 0.45-1.62) did not differ significantly. Neither did stratifying for the presence of at least one of the common CARD15 mutations result in a significant difference between CD and controls. No associations were found between TNF-857T and CD phenotype as defined by the Vienna classification, perianal disease or extra-intestinal disease irrespective of CARD15 carrier status. In conclusion, it appears that TNF-857 SNP does not contribute to susceptibility of IBD, neither does it define the phenotype of CD in Israeli Jewish IBD patients.
Association of TNFSF15 With Crohn's Disease in Koreans
The American Journal of Gastroenterology, 2008
A recent genomewide association study from a Japanese population identified tumor necrosis factor superfamily member 15 (TNFSF15) as an inflammatory bowel disease gene. Previous studies have shown that expression of TNFSF15 was upregulated in macrophages and lymphocytes of the intestinal lamina propria of Crohn's disease (CD) patients. Here, we have tested four single nucleotide polymorphisms (SNPs) of TNFSF15 in Korean patients to determine whether the gene is associated with susceptibility to CD in a closely related population. METHODS: Four SNPs across TNFSF15 were genotyped in 380 patients with CD and 380 healthy controls. RESULTS: Carriers of three polymorphisms, including rs3810936, rs6478108, and rs7848647, showed statistically significant association with CD (adjusted OR [aOR] 2.81, 95% confidence interval [CI] 1.94-4.07, P = 4.4 × 10 −8 ; aOR 3.49, 95% CI 2.42-5.04, P = 2.7 × 10 −11 ; and aOR 3.49, 95% CI 2.42-5.03, P = 2.2 × 10 −11 , respectively). Following haplotype analysis, homozygotes carrying two copies of the haplotype consisting of the risk alleles of those three SNPs showed statistically significant association with CD (aOR 5.39, 95% CI 3.19-9.10, P = 3.07 × 10 −10). CONCLUSIONS: Our data support the hypothesis that the TNFSF15 genotypes play an important role in the pathogenesis of CD in Koreans.