GENETIC STUDIES OF CROHN'S DISEASE AND ULCERATIVE COLITIS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定是研究者机构。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。在美国，CD和UC的估计合并患病率为0.2%-0.3%，在中欧或东欧血统的犹太裔美国人（德系犹太人）中的患病率是非犹太裔美国人的2 - 8倍。CD可累及胃肠道的任何部分，但最常见的是结肠和末端回肠。肠道炎症是不连续的，透壁的，可能含有肉芽肿。CD也与肠狭窄和肠及肛周瘘有关。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。不能明确确定为CD或UC的结肠疾病称为“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强有力证据表明，CD和UC在很大程度上是遗传的，并且遵循复杂的非孟德尔遗传模式。国际上努力鉴定导致IBD遗传易感性的基因，已经鉴定并确认了12号和16号染色体上的易感基因座。我们以前曾报道过在我们的患者队列中复制，16号染色体基因座IBD 1，首先由Hugot等人鉴定，1996年在法国人群中进行的试验（参见Brant等，Gastroenterology，1998）。在2000年12月，我们报道了更年轻的诊断年龄和更严重的疾病显著降低了IBD 1基因座的遗传异质性（Brant等人，胃肠病学，2000年）。在与来自芝加哥大学、密歇根大学和匹兹堡大学的研究人员的合作中，对定位于IBD 1位点的候选基因NOD 2在克罗恩病家族中的突变进行了检测。鉴定出三种突变是高度相关的突变（参见Ogura等人，Nature，2001）。最突出的突变是移码突变，Leu 1007 fsInsC/3020，在DNA编码区的位置3020处插入单个胞嘧啶核苷酸。该区域编码被称为富含亮氨酸区（LRR）的基序，并且被认为对Nod 2蛋白与核转录因子NF-κ B的相互作用具有特异性。这些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，这些机制在受到阻碍时会导致肠道慢性炎症。我们也在确定NOD 2突变的临床特征。有趣的是，NOD 2突变在少数克罗恩病患者中发现，并且不是溃疡性结肠炎的危险因素。我们先前对来自174个IBD多重家族的297个CD、UC或混合亲属对进行的10 cM全基因组筛选的结果（Cho等人，PNAS，1998）提供了在三个新基因座上连锁的强有力证据：1 p、3q和4 q。此外，还有其他证据支持其他染色体3 p和7 q上的潜在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IBD个体、其受累和未受累亲属以及对照个体的数据库信息和血液样本，以继续鉴定其他基因并定义其他IBD基因座。

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.