| Background Inflammatory bowel disease (IBD) is a chronic and non-specificity inflammatory disease witch comprise Crohn's disease(CD) and ulcerative colitis(UC). The pathogenesis of IBD is not clear. It is commonly presumed to be a multifactorial disease caused by the effect of enterobacteria and environmental factors on the hereditary susceptibility cohorts, and presented with excessive immunoreaction in intestinal mucosa. Epidemiological evidence shows a strong hereditary susceptibility contribution to IBD including high incidence of IBD in certain ethnic groups, family-clnster phenomenon and the concordance in identical twins. This was validated by the results of holo-genome scanning and predisposing genes.Recently, some important progresses have got on the predisposing genes of IBD and definited some predisposing genes in IBD. For instance, NOD2/CARD15 gene was identified as the first susceptibility locus for CD adjacent to the centromere on chromosome 16 in 1996. The NOD2/CARD15 gene product is expressed in monocytes, and can activate nuclear transcription factor kappa-B (NF-κB) in inflammatory response together with bacteria lipopolysaccharides and peptidoglycans. Stoll and colleagues confirmed two haplotypes of DLG5 gene on chromosome 10q23 which were associated with IBD. Simultaneously, a Canadian group reported that functional mutations in the OCTN genes on chromosome 5q31 were associated with CD. It is suggested that IBD is a complicated and multigenic hereditary susceptibility disease. The predisposing genes and the virulence genes could be discovered and identified with the cognition for genetic mechanism of IBD, which plays important roles in the genetic treatment, genetic counseling and reasonable preservation of susceptible population.Previous investigations showed that the polymorphisms of NOD2/CARD15 gene, DLG5 gene and OCTN gene were associated with IBD of European. Japanese and Hong Kong's investigators reported that the polymorphism of NOD2/CARD15 gene is inexistence in Oriental. In our country, small sample investigations confirmed the polymorphism of NOD2/CARD15 gene is inexistence in Chinese. Genetics study showed that DLG5 gene and OCTN gene were not associated with CD in Japanese. But there was no report about the relationship between DLG5 gene, OCTN gene and IBD in Oriental. It can be concluded that there exists the mutation of one gene or some genes which are associated with IBD in Chinese inevitably. Therefore, many studies focused on finding the predisposing genes of IBD. Key genes involved in the regulation of the inflammatory processes, such as COXs, are obvious candidates to look for variants predisposing to IBD. One of the two COXs isoforms, COX-2, is expressed in epithelial cells and mononuclear cells in IBD, and it is induced in response to pro-inflammatory cytokines, including interleukin-1. COX-2 is the rate limiting enzyme in the production of prostaglandins. Prostaglandins are thought to be essential in the process of wound healing in the gastrointestinal tract. The use ofnon-steroidal anti-inflammatory drugs (NSAIDs), whichinhibit both the transcription and activity of COX-2, exacerbates the symptoms in UC and may even activate quiescent IBD. Thus, the expression of COX-2 in the inflamed intestine might be a protective response within the wound healing process. Consequently, polymorphisms that change the amount of prostaglandins produced in inflamed cells could cause susceptibility to IBD.Objective To detect the genetic polymorphism of COX-2 gene and the relationship with IBD(CD and UC) in a large population of independent Chinese Han.Methods The study population comprised 66 CD patients, 291ulcerative colitis (UC) patients and 286 healthy controls from Chinese Han people., The patients were recruited from 4 medical centers including the Department of Gastroenterology of Xijing Hospital, Xi'an, Department of Gastroenterology of Xi'an Municipal Central Hospital, Xi'an , Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang and Department of Gastroenterology of Zhongshan Medical University, Guangzhou from March 2000 to May 2007. Genotyping for COX-2(-1195G→A, -1290A→G and -8473T→C) were carried out using polymerase chain reaction fragment length polymorphism (PCR-PFLP) and DNA sequencing for single nucleotide polymorphisms (SNP).Data were analyzed byχ2 test and haplotype by SAS statistic software.Results Both the -1195G→A -1290A→G and -8473T→C polymorphisms were not associated with increased risk of IBD.For the 1195 G→A polymorphism, the frequencies of the AA,AG and GG genotypes were 27.2﹪,53.9﹪,18.9﹪, respectively, among the cases of UC and 13.6﹪,65.2﹪,21.2﹪respectively among the cases of CD and 26.2﹪,51.4﹪,22.4﹪respectively among the controls. However, these differences were not statistically significant ( P=0.586 in UC and P=0.065 in CD). Similarly, the frequencies of the AA, AG and GG genotypes of the -1290A→G were 82.8﹪,17.2﹪,0﹪respectively, among the cases of UC and 86.4﹪,13.6﹪,0﹪respectively, among the cases of CD and 86.4﹪,13.6﹪,0﹪respectively, among the controls. These differences were not statistically significant in UC(P=0.238) and CD(P=1). For the -8473T→C polymorphism, the frequencies of TT, TC and CC genotypes were 58.8﹪,36.7﹪,4.5﹪,respectively, among the cases of UC and 64.3﹪,30.3﹪,1.5﹪,respectively, among the cases of CD and 64.3﹪,33.9﹪,1.8﹪,respectively, among the controls. These differences were not statistically significant (P=0.107 in UC and P=0.840 in CD).The COX-2 haplotypes with 1-4 variant alleles(-1195G/A和-8473C/T) were not associated with IBD.Conclusion:In the present study, we investigated the associations of the three SNPs of COX-2 gene with risk of UC and CD in a Chinese Han population. No significant association with disease risk was identified for these 3 polymorphisms. In 2001, using positional cloning and candidate gene approaches, two groups identified NOD2 (also designated CARD15)as a susceptibility gene to CD. Since then, several additional susceptibility loci have been implicated in inflammatory bowel disease and confirmed by replication: DLG5; SLC22A4 and SLC22A5; IL-23R and ATG16L. Three major polymorphisms in NOD2 gene, R702W, G908R and 1007fs, were confirmed to be associated with susceptibility to Caucasian CD patients by independent groups, but the variants were absence in Japanese, Korean and Chinese populations. The results suggested that these candidate genes were not common variants to IBD among Asia and Caucasian populations. In consideration of the increased prevalence of IBDs in Asian, systematic screening should be carried out as GWA studies among various populations with different ethnical backgrounds and it will lead to elucidate the contribution of susceptibility genes to IBD.
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