【作者】 曹倩；

【导师】 姒健敏；

【作者基本信息】 浙江大学 ， 内科学， 2005， 博士

【摘要】 炎症性肠病(Inflammatory Bowel Disease,IBD:MIM 601458)包括克罗恩氏病(Crohn’s Disease,CD;MIM 266600)和溃疡性结肠炎(Ulcerative Colitis,UC:MIM 191390),是一类慢性非特异性肠道炎症。 当前对IBD发病机制并不完全明确,近年来的观点均认为携带遗传易感基因的宿主在环境因素的参与下,由于慢性肠道感染,粘膜抗原屏障的缺陷,抗原主动免疫失控等,最终导致疾病的发生。由于对致病因素的作用机制的理解非常有限,所以当前的治疗主要局限于对病人症状的缓解,激素和免疫抑制剂仍是内科治疗活动期病变的基础药物,但疗效不佳。因此,明确IBD的病因,以期对因治疗是消化病临床迫切期待解决的问题。 IBD的发生与遗传相关这一观点正在逐渐明朗,已有学者们认为基因不仅可以影响易感性还会影响疾病的表型,根据这一观点,如果我们能发现IBD的易感基因,那么我们可以对IBD进行更准确的分子学分型诊断。如果我们能发现IBD的易感基因,就可以对高危人群进行筛查,甚至有可能提供预后分析,比如可以预测哪些患者可能发生肠外表现,而哪些可能获得长期缓解,哪些需要手术治疗,哪些可能有发生癌变的危险。如果我们能发现IBD易感基因,就更有可能提供患者个性化的特异的药物和手术治疗。 目前国际上对IBD遗传易感基因的寻找方兴未艾,而对中国人群的研究很少。研究不同种族地域人群的疾病遗传易感基因,有助于全面揭示疾病的发病机理,有助于将来更好的个体化治疗。为了了解中国人群炎症性肠病与遗传易感基因的相关性,我们设计了以下两步骤的研究。 第一步,因为NOD2/CARD15基因(以下简称NOD2基因)是被明确与高加索白种人相关的第一个CD的易感基因,但在日本人中未能发现其相关性。因此本研究选取来自中国浙江地区的32例汉族CD患者,110例UC患者和292例健康对照者,通过特异引物—聚合酶链反应(PCR-SSP)及DNA测序方法,来研究NOD2基因与中国汉族CD患者的相关性。结果发现高加索白种人中常见的NOD2基因单核苷酸多态性在中国人中并不存在。更多还原

【Abstract】 Inflammatory bowel disease (IBD) is currently classified as ulcerative colitis (UC) or Crohn’s disease (CD) on he basis of clinical, radiological and histological criteria. While the aetio-pathogenesis of IBD is unknown, the effpeople all agree that IBD is chronic inflammatory disorders of the intestines characterized by a dysregulated mucosal immune response, increasing evidence suggests that it is likely to be caused by combination of environmental factors at work in a genetically susceptible host. A a number of lines of epidemiological evidence support a role for genetics in determining IBD susceptibility. Recent research has focused on the role that genes may play in determining the clinical phenotype of disease in addition to susceptibility. If the hypothesis is right, then we can determine clinical phenotype lies in defining accurately different clinical subtypes according to the genotype. If it proves possible to define genes which determine clinical phenotype then we may be able give patients an accurate assessment of their prognosis at the time of diagnosis. UC and CD are chronic diseases that affect young adults just at the time when they may be going through education or making important life choices, and this may be very helpful in their overall management. We may be able to predict which patients might develop extra-intestinal manifestations, which patients will relapse most often and so benefit most from maintenance treatment, and which patients will be likely to require surgery. If we are able to predict which patients may be at greatest risk of developing UC associated cancer, then we might target screening procedures more efficiently.To study the relationship of genes and IBD patients in Chinese Han population, this thesis performed a two-stage study.Previous studies have shown NOD2/CARD15 gene is the first susceptibility gene toCrohn’s disease, three single nucleotide polymorphisms(SNPs) of the gene have been identified to be associated with Crohn’s disease in the Caucasians, but not in the Japanese. So we have evaluated the N0D2/CARD gene polymorphisms in Chinese patients to determine whether the gene is associated with susceptibility to CD in Chinese Han population. Blood samples were obtained from 32 paients with CD, 110 patients with ulcerative colitis, and 292 healthy controls in Zhejiang location. None of the patients with CD had heterozygous or homozygous common SNP variants, but we first found other two rare SNP variants in Exon 4. It suggested that NOD2 gene may be still play an important role in the pathogenesis of CD in Chinese Han population.Recent association studies have evaluated the role of TNF promoter polymorphisms in Caucasian populations but data have been inconsistent. Interpretation of these data is limited by the complex patterns of LD across this region and the lack of reliable techniques to study the functional effects of specific promoter polymorphisms. Trans-racial mapping in an ethnically distinct but homogenous population may help clarify these associations. To investigate the association between TNF promoter polymorphisms and susceptibility to UC in the Chinese Han population. We studied 110 unrelated UC patients and 292 healthy controls from Zhejiang location. Genotyping for 6 common TNF promoter polymorphisms was carried out using polymerase chain sequence-specific primer (PCR-SSP). We found TNF-308A was associated with disease. We report the first association study of TNF promoter polymorphisms in Chinese patients with ulcerative colitis. We also studied the relation ship between Chinese UC patients and another good candidate gene—NKG2D, but got negative result.This thesis also support a role for genetics in determining Chinese IBD susceptibility, further mapping of this gene-dense region in a larger cohort of Chinese Han population is now required.更多还原