IDENTIFICATION OF SUSCEPTIBILITY LOCI FOR CROHNS DISEASE

克罗恩病(CD)是一种慢性、特发性炎症性疾病。 胃肠道，影响到大约250,000人 美国人。CD的临床表现多种多样， 并发症。并发症包括营养不良，狭窄形成， 脓肿、瘘管形成、胃肠道出血、眼睛、皮肤和 关节发炎，结直肠癌风险增加。那里 是Cd至少部分地是一种基因的确凿证据 疾病。在双胞胎研究中，同卵双胞胎的一致性有所不同 从44%增加到85%。总体而言，大约20%的CD患者有 克罗恩病或溃疡性结肠炎的家族病史。没有 有证据表明家庭聚集性是由环境因素造成的。这个 CD的发病率一直是德系犹太人中最普遍的， 他们的流行率比他们的非犹太邻居高2到9倍， 无论地理位置如何。 CD的遗传不符合任何简单的孟德尔模型。最近， 全基因组已经确定了CD的潜在易感基因 多厅影院系列中的屏幕。一个法国组织报告了CD的证据 16号染色体上的易感基因座，以及来自英国牛津的一群人 3、7和12号染色体上已报告的易感基因座。信息 在疾病亚型上，两项研究都没有报道。加州大学洛杉矶分校的一项研究 确认与染色体16q12.1和16q12.2之间的区域连锁 在非犹太人中，但在犹太人中没有发现关联的证据。 我们研究的目的是(1)确定是否有证据表明 约翰·霍普金斯大学受影响的亲属对中的支撑链 克罗恩病家系数据库与上述推测的易感性 以及(2)进行全基因组筛查以识别其他 易感基因座。我们研究组的所有患者都已经 根据种族血统分类，肠道定位 疾病、并发症和表型表现。诊断结果是 得到了研究人员的证实。 这项研究是在关键的情况下启动并继续进行的 OPD-GCRC的协助。在撰写本报告时，我们有 202项研究中采集的血液样本和临床信息 参与者来自84个家庭。我们已经开始分析微卫星 确认与上述基因座连锁的标记。我们的最终目标是 获取200个家庭的样本。通过GCRC，我们还进行了 确定诊断所需的有限数量的研究 CD先证者亲属中的克罗恩病。约三分之一的美国人 病人都是犹太人后裔。 在门诊服务中心协助下取得的临床资料有 使我们获得克罗恩结肠炎基金会颁发的一等奖 为期三年的5万美元，获奖时间为1997年1月1日，以确定 上述可能的CD基因座的易感基因。此外，我们正在 在合作中开始全基因组筛选的过程中 在芝加哥大学工作。我们一起拿到了DNA样本 200对受影响的亲属对。我们将申请美国国立卫生研究院联合拨款 以帮助支持这一全基因组的筛选。

Crohn's disease (CD) is a chronic, idiopathic inflammatory disease of the gastrointestinal tract, which affects approximately 250,000 Americans. CD has a wide variety in its clinical presentations and complications. Complications include malnutrition, stricture formation, abcesses, fistula formation, gastrointestinal bleeding, eye, skin and joint inflammation, and an increased risk of colorectal cancer. There is substantial evidence that CD is, at least in part, a genetic disease. In twin studies, concordance for monozygotic twins has ranged from 44 to 85%. Overall, approximately 20% of patients with CD have a family history of Crohn's disease or ulcerative colitis. There is no evidence that familial clustering is due to environmental factors. The incidence of CD is consistently most prevalent in Ashkenazi Jews, having a prevalence of 2 to 9 times greater than their non-Jewish neighbors, regardless of geographic location. Inheritance of CD does not fit any simple Mendelian models. Recently, potential susceptibility loci for CD have been identified by genome-wide screens in multiplex families. A French group reported evidence for CD susceptibility loci on chromosome 16, and a group from Oxford, England reported susceptibility loci on chromosomes 3, 7 and 12. Information on disease subtype was not reported for either study. A UCLA study confirmed linkage to the region between chromosome 16q12.1 and 16q12.2 in non-Jews, but found no evidence for linkage in Jews. The purpose of our study is to (1) determine if there is evidence to support linkage in affected relative pairs from the Johns Hopkins Crohn's Disease Family Database to the above putative susceptibility loci; and (2) perform a genome-wide screen to identify additional susceptibility loci. All patients in our study group have been classified on the basis of ethnic descent, intestinal localization of disease, complications and phenotypic presentation. Diagnosis has been confirmed by the study investigators. This study was initiated and continues to be performed with the critical assistance of the OPD-GCRC. At the time of writing this report we have collected blood samples and clinical information on 202 study participants from 84 families. We have begun analyzing microsatellite markers to confirm linkage to the above loci. Our final goal is to obtain samples on 200 families. Through the GCRC we have also performed a limited number of studies necessary to firmly establish a diagnosis of Crohn's disease in relatives of CD probands. About 1/3 of our patients are of Jewish descent. Clinical material obtained with the assistance of the OPD-GCRC has allowed us to obtain a First Award from the Crohn's Colitis Foundation of America for $50,000 for three years, awarded 1/1/97, to identify susceptibility genes in the above putative CD loci. Furthermore, we are in the process of embarking on a genome-wide screen in a collaboration with the University of Chicago. Together we have DNA samples on over 200 affected relative pairs. We will be applying for a joint NIH grant to help support this genome-wide screen.