GENETIC STUDIES OF CROHN'S DISEASE AND ULCERATIVE COLITIS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，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），是慢性的，经常致残的胃肠道疾病。据估计，CD和UC在美国的总患病率为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。乳糜泻可累及胃肠道的任何部位，但最常累及结肠和回肠末端。肠道炎症是不连续的、跨壁的，可能包含肉芽肿。乳糜泻还与肠狭窄、肠和肛周瘘管有关。相比之下，UC涉及结肠和直肠持续的非肉芽肿性炎症，仅限于粘膜层。未观察到瘘管。不能明确确定为乳糜泻或UC的结肠疾病称为“不确定结肠炎”。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，乳糜泻和UC在很大程度上是遗传的，并遵循复杂的非孟德尔遗传模式。国际上为确定导致所观察到的IBD遗传易感性的基因所做的努力已经确定并确认了12号和16号染色体上的易感性位点。我们之前曾报道在我们的患者队列中复制Hugot等人于1996年在法国人群中首次发现的16号染色体位点IBD1（见Brant等人，胃肠病学，1998）。2000年12月，我们报道了较年轻的诊断年龄和更严重的疾病显著降低了IBD1位点的遗传异质性（Brant等人，胃肠病学，2000）。在与芝加哥大学、密歇根大学和匹兹堡大学的研究人员的合作中，研究人员对克罗恩病家族中IBD1位点的候选基因NOD2进行了突变检测。确定了三个高度相关的突变（见Ogura et al., Nature, 2001）。最突出的突变是帧移位突变，Leu1007fsInsC/3020，在DNA编码区3020位置插入单个胞嘧啶核苷酸。该区域编码一个被称为亮氨酸富区（LRR）的基序，并且被认为是Nod2蛋白与核转录因子NF-Kb相互作用的特定输入。诸如此类的结果进一步加深了我们对疾病过程的理解，并为潜在的分子机制提供了线索，这些机制在受到阻碍时，会导致肠道的慢性炎症。我们也在定义NOD2突变的临床特征。有趣的是，NOD2突变在少数克罗恩病患者中发现，并不是溃疡性结肠炎的危险因素。我们之前对174个IBD家族的297个CD、UC或混合亲属对进行了10 cM全基因组筛选（Cho et al .， PNAS, 1998），结果强有力地证明了三个新位点：1p、3q和4q的连锁。此外，还有其他证据支持其他染色体3p和7q上潜在的IBD易感基因。这些数据推动了对其他致病基因的持续研究。为此，本方案的总体目标是继续确定数据库信息和来自IBD患者、其受影响和未受影响的亲属以及对照个体的血液样本，以继续确定额外的基因并确定额外的IBD位点。

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.