GENETIC STUDIES OF CROHN'S DISEASE AND ULCERATIVE COLITIS

克罗恩病和溃疡性结肠炎的遗传学研究

• 批准号: 7378775
• 负责人: Steven R Brant
• 金额: $ 0.05万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7378775
• 关键词: GENETIC; STUDIES; CROHN; DISEASE; ULCERATIVE

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The idiopathic inflammatory bowel diseases, Crohn's disease (CD) and ulcerative colitis (UC), are chronic, frequently disabling diseases of the gastrointestinal tract. CD and UC have an estimated combined prevalence of 0.2% to 0.3% in the United States, and are two to eight times more prevalent in Jewish Americans of Central or Eastern European descent (Ashkenazi Jews) as compared to non-Jewish Americans. CD may involve any part of the gastrointestinal tract, but most often the colon and terminal ileum. Bowel inflammation is discontinuous, transmural, and may contain granulomas. CD is also associated with bowel stenoses and intestinal and perianal fistulas. UC, by contrast, involves continuous, non-granulomatous inflammation of the colon and rectum, limited to the mucosal layers. Fistulas are not observed. Colonic disease that cannot be clearly identified as CD or UC is designated "indeterminate colitis." The etiology of CD and UC is unknown. There is strong evidence from twin studies and familial aggregation that CD and UC are in large part genetic, and follow a complex, non-Mendelian mode of inheritance. International efforts to identify the genes that result in the observed genetic susceptibility to IBD have identified and confirmed susceptibility loci on chromosomes 12 and 16cen. We have previously reported replicating in our patient cohort, the chromosome 16 locus, IBD1, that was first identified by Hugot et al., in a French population in 1996 (see Brant et al, Gastroenterology, 1998). In December 2000, we reported that younger age- at-diagnosis and more severe disease markedly decreased genetic heterogeneity for the IBD1 locus (Brant et al., Gastroenterology, 2000). In a collaboration with investigators from University of Chicago, University of Michigan and University or Pittsburgh, a candidate gene, NOD2, which mapped to the IBD1 locus was tested for mutations in Crohn's disease families. Three mutations were identified that were highly associated mutations (see Ogura et al., Nature, 2001). The most prominent mutation is a frame shift mutation, Leu1007fsInsC/3020, an insertion of a single cytosine nucleotide at position 3020 of the DNA coding region. This region codes for a motif known as a leucine-rich-region (LRR) and is believed to be of specific import to the Nod2 protein's interaction with the nuclear transcription factor NF-Kb. Results such as these further our understanding of the disease process as well as provide clues about the underlying molecular mechanisms that when hampered, contributes to the chronic inflammation of the intestinal tract. We are also in the process of defining the clinical characteristics of NOD2 mutations. Intriguingly, NOD2 mutations are found in a minority of patients with Crohn's disease and are not risk factors for ulcerative colitis. Our previous results from our 10 cM genome-wide screen on 297 CD, UC or mixed relative pairs from 174 families multiplex for IBD (Cho et al, PNAS, 1998) provided strong evidence of linkage on three novel loci: 1p, 3q and 4q. Furthermore, there is additional evidence supporting potential IBD susceptibility genes on other chromosomes, 3p and 7q. These data are an impetus for the continual pursuit of other disease-causing genes. To this end, the overall objective of this protocol is to continue to ascertain database information and blood samples from individuals with IBD, their affected and unaffected relatives and control individuals to continue to identify additional genes and defining additional IBD loci.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中出现。列出的机构是中心的机构，不一定是研究者的机构。特发性炎症性肠病、克罗恩病 (CD) 和溃疡性结肠炎 (UC) 是慢性且经常致残的胃肠道疾病。在美国，CD 和 UC 的综合患病率估计为 0.2% 至 0.3%，中欧或东欧血统的犹太裔美国人（德系犹太人）的患病率是非犹太裔美国人的 2 至 8 倍。 CD 可能累及胃肠道的任何部分，但最常见的是结肠和回肠末端。肠道炎症是不连续的、透壁的，并且可能含有肉芽肿。 CD 还与肠狭窄以及肠瘘和肛周瘘有关。相比之下，UC 涉及结肠和直肠的持续性非肉芽肿性炎症，仅限于粘膜层。未观察到瘘管。不能明确鉴定为 CD 或 UC 的结肠疾病被称为“不确定性结肠炎”。 CD 和 UC 的病因尚不清楚。 来自双胞胎研究和家族聚集的有力证据表明，CD 和 UC 在很大程度上是遗传性的，并且遵循复杂的非孟德尔遗传模式。国际上为鉴定导致观察到的 IBD 遗传易感性的基因所做的努力已经鉴定并确认了 12 号和 16cen 染色体上的易感性位点。我们之前报道过在我们的患者队列中复制了 16 号染色体位点 IBD1，该基因座是由 Hugot 等人于 1996 年在法国人群中首次发现的（参见 Brant 等人，胃肠病学，1998）。 2000 年 12 月，我们报道，诊断时年龄越小，疾病越严重，IBD1 基因座的遗传异质性显着降低（Brant 等人，Gastroenterology，2000）。与芝加哥大学、密歇根大学和匹兹堡大学的研究人员合作，对映射到 IBD1 基因座的候选基因 NOD2 进行了克罗恩病家族突变检测。鉴定出三个高度相关的突变（参见 Ogura 等人，Nature，2001）。最显着的突变是移码突变 Leu1007fsInsC/3020，即在 DNA 编码区的 3020 位插入单个胞嘧啶核苷酸。该区域编码一个称为富含亮氨酸区域 (LRR) 的基序，并且被认为对于 Nod2 蛋白与核转录因子 NF-Kb 的相互作用具有特定的重要性。诸如此类的结果进一步加深了我们对疾病过程的理解，并提供了有关潜在分子机制的线索，这些分子机制在受到阻碍时会导致肠道慢性炎症。我们还正在确定 NOD2 突变的临床特征。有趣的是，NOD2 突变存在于少数克罗恩病患者中，但并不是溃疡性结肠炎的危险因素。我们之前对来自 174 个 IBD 家族的 297 个 CD、UC 或混合相关对进行 10 cM 全基因组筛选的结果（Cho 等人，PNAS，1998）提供了三个新基因座连锁的有力证据：1p、3q 和 4q 。此外，还有其他证据支持其他染色体 3p 和 7q 上存在潜在的 IBD 易感基因。这些数据是不断寻找其他致病基因的动力。为此，本协议的总体目标是继续确定 IBD 患者、其受影响和未受影响的亲属以及对照个体的数据库信息和血液样本，以继续识别其他基因并定义其他 IBD 位点。