COX-2基因多态性与炎症性肠病的相关性研究
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摘要
背景:炎症性肠病(IBD)包括溃疡性结肠炎(UC)和克罗恩病(CD),是一类病因不明的慢性肠道非特异性炎症性疾病。其发病机制至今尚不十分清楚,大多数学者认为是由肠道细菌和环境因素作用于遗传易感的人群,导致肠道粘膜免疫反应过高所致。遗传因素作为IBD发病过程中的一个重要因素,最早而且最有说服力的证据来自对双生子的研究,发现同卵双生子的同病率明显高于异卵双生子,另外流行病学调查发现IBD患者具有家族聚集现象,并且IBD患者的一级亲属发病率明显高于正常人群。以后发展的全基因组扫描研究及IBD易感基因的研究,均证实IBD发病具有遗传易感性。近年来,在IBD遗传因素这一研究领域取得了一些重要进展,确定了一些易感基因。例如,1996年发现位于16号染色体着丝粒附近的NOD2/CARD15基因,并于2001年证实该基因是CD的第一个易感基因。Stoll等证实位于10号染色体上的DLG5基因上两个位点的SNP与CD有关。加拿大的一个研究组报道了位于5号染色体上的OCTN基因与CD相关。2006年,美国的IBD多中心协作研究显示一种编码促炎症细胞因子白介素-23(IL-23)亚单位的基因,似乎可影响炎症性肠病的易感性,再次发现了IBD的易感基因。由此可见,IBD是一种复杂的多基因遗传易感性疾病。通过对该病遗传机制的研究,可确定或发现IBD易感基因或致病基因,对该病的基因治疗、遗传咨询以及易感人群的合理预防起到重要作用。
既往研究显示NOD2/CARD15基因、DLG5基因及OCTN基因多态性与欧洲人群IBD发病相关。日本和香港的研究显示NOD2/CARD15基因常见的SNP位点在亚洲IBD人群中没有多态性,我国人群的小样本研究也证实NOD2/CARD15在中国人群无多态性。日本人群遗传学研究显示DLG5、OCTN与日本人群CD无显著相关,我们实验室的研究发现DLG5、OCTN与IBD无相关性,由此可见,遗传存在有很大的异质性,那么也就必然存在一个或者一些基因的突变与我国IBD人群相关。因此,寻找和鉴定与我国IBD人群相关的基因成为目前IBD研究的一个热点。调节炎症过程的关键性分子如环氧合酶(COXs)是针对IBD易感变异的一个重要候选基因。COX-2基因的变异能够改变酶的功能从而影响个体对炎症的反应。环氧合酶-2(COX-2)作为COX的一种重要形式表达于IBD患者的肠道上皮细胞和单核细胞,当受到炎症细胞因子如IL-1诱导后产生。COX-2是产生前列腺素的关键限制酶之一。前列腺素在胃肠道创伤愈合的过程中起着关键作用。非甾体消炎药抑制COX-2的转录和活性,不但加重UC的症状,甚至可以出现疾病活动的增加。因此,多态性可能通过改变炎症细胞前列腺素的释放从而引起IBD的易感性。为了验证这一假说,我们设计了本试验。
目的:检测我国汉族人群COX-2基因启动子区-1195G/A,-1290A/G和3′非编码区的8473C/T位点的遗传多态性及其与IBD可能的相关性。
方法:采用PCR-RFLP及DNA序列测定技术,对291例溃疡性结肠炎、66例克罗恩病以及286名健康对照的COX-2基因(-1195G/A,-1290A/G与-8473C/T)的遗传多态性进行分析。数据统计使用SAS软件进行χ2检验和单倍体分析。
结果:COX-2基因(-1195G/A,-1290A/G与-8473C/T)在我国人群中存在遗传多态性,①-1195G/A位点在UC患者中的AA、AG和GG这三个基因型频率分别为27.2﹪,53.9﹪,18.9﹪,CD患者中这三个基因型频率分别为13.6﹪,65.2﹪,21.2﹪,健康对照者中分别为26.2﹪,51.4﹪,22.4﹪。②-1290A/G位点的AA、AG和GG在UC中分别为82.8﹪,17.2﹪,0﹪,CD中分别为86.4﹪,13.6﹪,0﹪,健康对照组分别为86.4﹪,13.6﹪,0﹪。③-8473T/C位点的TT、TC和CC在UC中分别为58.8﹪,36.7﹪,4.5﹪,CD中分别为64.3﹪,30.3﹪,1.5﹪,健康对照组分别为64.3﹪,33.9﹪,1.8﹪,但这三个位点各自的遗传多态性与IBD的发病无相关性。对-1195G/A和-8473C/T进行单倍体分析,发现这两个位点同时突变与IBD亦没有相关性。
结论:本研究发现COX-2(-1195G/A,-1290A/G与-8473C/T)这三个位点存在有基因多态性,但是其多态性与IBD之间没有关系,并且-1195G/A和-8473C/T这两个位点同时突变与汉族IBD亦不存在相关性。自从2001年Hugot等发现并证实CD的第一个易感基因CARD15(NOD2)以来,寻找炎症性肠病的遗传易感基因成为了IBD研究领域的一个热点,随后人们又陆续发现了很多其他的易感基因,如DLG15、OCTN、IL-23R、ATG16L1等,并且这些基因在不同的国家、不同的人群中被得到证实,但是这些基因并没有在日本、韩国、和中国等我们亚洲国家得到证实,这些结果提示给我们同一疾病在不同的种群之间存在有很大的异质性。
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.
既往研究显示NOD2/CARD15基因、DLG5基因及OCTN基因多态性与欧洲人群IBD发病相关。日本和香港的研究显示NOD2/CARD15基因常见的SNP位点在亚洲IBD人群中没有多态性,我国人群的小样本研究也证实NOD2/CARD15在中国人群无多态性。日本人群遗传学研究显示DLG5、OCTN与日本人群CD无显著相关,我们实验室的研究发现DLG5、OCTN与IBD无相关性,由此可见,遗传存在有很大的异质性,那么也就必然存在一个或者一些基因的突变与我国IBD人群相关。因此,寻找和鉴定与我国IBD人群相关的基因成为目前IBD研究的一个热点。调节炎症过程的关键性分子如环氧合酶(COXs)是针对IBD易感变异的一个重要候选基因。COX-2基因的变异能够改变酶的功能从而影响个体对炎症的反应。环氧合酶-2(COX-2)作为COX的一种重要形式表达于IBD患者的肠道上皮细胞和单核细胞,当受到炎症细胞因子如IL-1诱导后产生。COX-2是产生前列腺素的关键限制酶之一。前列腺素在胃肠道创伤愈合的过程中起着关键作用。非甾体消炎药抑制COX-2的转录和活性,不但加重UC的症状,甚至可以出现疾病活动的增加。因此,多态性可能通过改变炎症细胞前列腺素的释放从而引起IBD的易感性。为了验证这一假说,我们设计了本试验。
目的:检测我国汉族人群COX-2基因启动子区-1195G/A,-1290A/G和3′非编码区的8473C/T位点的遗传多态性及其与IBD可能的相关性。
方法:采用PCR-RFLP及DNA序列测定技术,对291例溃疡性结肠炎、66例克罗恩病以及286名健康对照的COX-2基因(-1195G/A,-1290A/G与-8473C/T)的遗传多态性进行分析。数据统计使用SAS软件进行χ2检验和单倍体分析。
结果:COX-2基因(-1195G/A,-1290A/G与-8473C/T)在我国人群中存在遗传多态性,①-1195G/A位点在UC患者中的AA、AG和GG这三个基因型频率分别为27.2﹪,53.9﹪,18.9﹪,CD患者中这三个基因型频率分别为13.6﹪,65.2﹪,21.2﹪,健康对照者中分别为26.2﹪,51.4﹪,22.4﹪。②-1290A/G位点的AA、AG和GG在UC中分别为82.8﹪,17.2﹪,0﹪,CD中分别为86.4﹪,13.6﹪,0﹪,健康对照组分别为86.4﹪,13.6﹪,0﹪。③-8473T/C位点的TT、TC和CC在UC中分别为58.8﹪,36.7﹪,4.5﹪,CD中分别为64.3﹪,30.3﹪,1.5﹪,健康对照组分别为64.3﹪,33.9﹪,1.8﹪,但这三个位点各自的遗传多态性与IBD的发病无相关性。对-1195G/A和-8473C/T进行单倍体分析,发现这两个位点同时突变与IBD亦没有相关性。
结论:本研究发现COX-2(-1195G/A,-1290A/G与-8473C/T)这三个位点存在有基因多态性,但是其多态性与IBD之间没有关系,并且-1195G/A和-8473C/T这两个位点同时突变与汉族IBD亦不存在相关性。自从2001年Hugot等发现并证实CD的第一个易感基因CARD15(NOD2)以来,寻找炎症性肠病的遗传易感基因成为了IBD研究领域的一个热点,随后人们又陆续发现了很多其他的易感基因,如DLG15、OCTN、IL-23R、ATG16L1等,并且这些基因在不同的国家、不同的人群中被得到证实,但是这些基因并没有在日本、韩国、和中国等我们亚洲国家得到证实,这些结果提示给我们同一疾病在不同的种群之间存在有很大的异质性。
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.
引文
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