MAPPING THE GENES FOR INFLAMMATORY BOWEL DISEASE

炎症性肠病(IBD)由克罗恩病(CD)和 溃疡性结肠炎--两种慢性特发性炎症性疾病 胃肠道的。遗传流行病学和遗传流行病学研究 动物模型表明，这些疾病在很大程度上是由 用遗传因素来衡量。这些数据还表明，UC和CD 共享一些共同的遗传因素，但有其他不同的基因 决定因素。然而，遗传因素的特殊性 对这两种疾病或其中一种疾病的易感性仍然没有明确的定义。 为了确定这些疾病的易感基因，我们有 已经在CD家族中启动了系统扫描，标记为10 Cm间隔，确定了19个易感IBD基因的区域 可能被定位(包括CHR上的座位)。12和Chr.16和MHC 区域)。该项目的目标是进一步确认和细化 初步的连锁发现，并最终确定基因 易患IBD或IBD亚型的个体。我们将首先 随着CD家族数量的增加，执行精细的连锁图谱 密度在2-3厘米的区域，初步证据表明 观察到与Cd的联系(目标1)。任何有证据表明 然后，将在UC和混合(UC和CD)中测试与CD的链接 家庭(目标2)。对于那些有强有力的证据表明 将进行连锁、连锁不平衡作图，利用 多阶段设计中的家庭和病例控制面板，以缩小 包含易感基因的区域(目标4)。那么，候选人 这些区域的基因将通过筛选突变和 表达水平的变化(目标5)。所有链接和链接 将在样本中进行不平衡作图分析 整体，以及按种族定义的子组，亚临床 标记，或已知的连锁基因座(目标3)。两点和多点 所有的链接分析都将采用链接分析方法。这个 传递/不平衡检验将用于链接不平衡 映射。这项研究最终将导致识别基因 容易患上这些最令人衰弱的胃肠道疾病， 对IBD个体风险评估的影响， 患者的诊断和临床管理，以及基本的 对疾病发病机制的了解为 开发新的和个性化的治疗方法。

Inflammatory bowel disease (IBD) consists of Crohn's disease (CD) and ulcerative colitis (UC)-- two chronic idiopathic inflammatory diseases of the gastrointestinal tract. Studies of the genetic epidemiology and of animal models demonstrate that these diseases are determined in large measure by genetic factors. These data also indicate that UC and CD share some common genetic factors, but have additional distinct genetic determinants. However, the specific nature of the genetic factors predisposing to both or either of these diseases remains poorly defined. In order to identify susceptibility genes for these diseases, we have already initiated a systematic scan in CD families with markers at 10 cM interval and identified 19 regions where genes predisposing to IBD may be located (including loci on chr. 12 and chr. 16 and the MHC region). The goal of this project is to further confirm and refine the initial linkage findings and ultimately to identify the genes predisposing an individual to IBD or subforms of IBD. We will first perform, with an increased number of CD families, fine linkage mapping to a density of 2-3 cM in those regions where initial evidence for linkage to CD was observed (aim 1). Any regions showing evidence of linkage to CD will then be tested in UC and mixed (both UC and CD) families (aim 2). For those regions where there is strong evidence of linkage, linkage disequilibrium mapping will be carried out, utilizing both family and case-control panels in a multi-phase design to narrow the region containing the susceptibility genes (aim 4). Then, candidate genes at these regions will be evaluated by screening for mutations and changes in the level of expression (aim 5). All linkage and linkage disequilibrium mapping analysis will be conducted in the sample as a whole, as well as in subgroups defined by ethnicity, subclinical markers, or known linked loci (aim 3). Both two point and multipoint linkage analysis methods will be employed for all linkage analyses. The transmission/disequilibrium test will be used for linkage disequilibrium mapping. This study will eventually lead to identifying genes predisposing to these most debilitating of gastrointestinal diseases, with implications for the assessment of individual risk for IBD, for diagnosis and clinical management of patients, and for basic understanding of the mechanisms of disease pathogenesis fundamental for the development of novel and individualized therapies.