Identification of the IBD genes on chromosomes 3p and 6p

描述(申请人提供)：克罗恩病(CD)和溃疡性结肠炎(UC)是两种常见的胃肠道炎症性疾病，统称为炎症性肠病(IBD)。据估计，多达100万美国人受到这些令人衰弱的疾病的影响。IBD可能发生在所有年龄段的人中，但它主要是一种出现在青少年和年轻人中的疾病。目前还没有已知的治疗IBD的方法。在过去的五年中，一些IBD基因(CARD15、IBD5、MYO9B、IL23R、ATG16L1)已经被发现，但这些基因并不能解释IBD的所有遗传风险。我们之前已经报告了与基因组的两个区域(位于3号和6号染色体的短臂上)相关联的证据--表明存在其他IBD基因。在过去的四年中，我们对这两个染色体区域进行了候选和位置关联作图研究，从而在目标区域识别出显著相关的等位基因或假定的遗传风险因素。在这一应用中，我们建议识别我们已识别的基因中的所有偶然等位基因，并识别我们已发现显著证据的次要危险因素。在过去的几年里，人们也清楚地看到，复杂遗传特征研究中的主要挑战之一是确定疾病基因及其相应的等位基因如何对健康和疾病的生物学产生影响。因此，我们的目标是采用一套有限的功能方法，这些方法将普遍应用于一组IBD风险基因。这种系统的途径分析将有助于指导未来的深入功能研究，并将提供一个共同框架的开端，通过该框架，我们可以建立一个模型，说明这些遗传变异如何影响最终导致IBD发展的生物途径。

DESCRIPTION (provided by applicant): Crohn's disease (CD) and ulcerative colitis (UC) are two common inflammatory diseases of the gastrointestinal tract, collectively known as the inflammatory bowel diseases (IBD). It is estimated that as many as one million Americans are affected with these debilitating diseases. IBD may occur in people of all ages, but it is primarily a disease that arises in adolescents and young adults. Currently there is no known cure for IBD. Over the last five years, a number of IBD genes (CARD15, IBD5, MYO9B, IL23R, ATG16L1) have been identified, but these do not explain all of the genetic risk to IBD. We have previously reported evidence of linkage to two regions of the genome (located on the short arms of chromosomes 3 and 6) - indicating the presence of additional IBD genes. In the last four years we performed candidate and positional association mapping studies of these two chromosomal regions that have led to the identification of significantly associated alleles or putative genetic risk factors in the targeted regions. In this application, we propose to identify all of the casual alleles in the genes that we have identified and also to identify secondary risk factors for which we have found significant evidence. In the last few years it has also become clear that one of the major challenges in the study of complex genetic traits is to determine how disease genes and their corresponding alleles exert their influence on the biology of health and disease. We therefore aim to employ a limited set of functional approaches that will be commonly applied to a set of IBD risk genes. This systematic pathway analysis will help guide future in-depth functional studies and will provide the beginnings of a common framework by which we can build a model of how these genetic variants influence biological pathways eventually leading to the development of IBD.