GENETIC FINE MAPPING IN SLE PAIR FAMILIES

SLE 对家族的遗传精细定位

• 批准号: 6493281
• 负责人: TIMOTHY W. BEHRENS
• 金额: $ 15.73万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6493281
• 关键词: chromosomes; clinical research; family genetics; genetic mapping; genetic markers; genetic susceptibility; genotype; human subject; linkage disequilibriums; linkage mapping; molecular cloning; patient /disease registry; siblings; systemic lupus erythematosus

The familial clustering of systemic lupus erythematosus (SLE) and the high rate of concordance in monozygotic twins suggests a strong genetic component for susceptibility to SLE. As one approach to the identification of lupus genes, our laboratory is currently performing a genome-wide marker screen in an effort to localized the chromosomal regions that harbor lupus genes. Over 180 families with at least two affected SLE relatives (mostly sib pair families) are enrolled in this study. In preliminary studies, three distinct regions of human Chromosome 1 show evidence of possible linkage in an initial cohort of 105 SLE sib pair families. As the genome screen proceeds it is likely that other candidate intervals will emerge on other chromosomes. The primary goal of the SCOR project is to accelerate the gene search in the MN SLE family collection. This will be accomplished by sharing ongoing genotyping data with our colleagues at OMRF (project #2) to compare results in the two SLE family collections. Preliminary mapping results at MN will also be shared with our colleagues at UAB (project #3) to assist in their screening of Chromosome 1q candidate genes. The MN family collection will then be genotyped with markers from the OMRF study, so that linkage results can be directly compared. Interesting chromosomal regions ill then be prioritized for high density marker screens and fine mapping. Trio families (one SLE patient with both parents) collected as a component of this SCOR application will be used in disequilibrium mapping in the targeted areas. A variety of strategies will then be employed to identify the SLE gene(s) in these regions. The ultimate isolation and cloning of SLE genes will provide the first opportunity to understand at the genetic level the defects that lead to the clinical immune dysregulation characteristic of patients with lupus. These insights should suggest new avenues of treatments for this patients, including the potential for somatic gene therapy. Interestingly, lupus- prone families also have an increased incidence of other autoimmune diseases including rheumatoid arthritis, thyroid disease, and diabetes. Thus, the identification of genes that cause human SLE is likely to improve our understanding of the genetics and pathophysiology of organ- specific autoimmunity.

系统性红斑狼疮（SLE）的家族聚集性和高发病率 同卵双胞胎的一致性率表明强大的遗传因素 系统性红斑狼疮 (SLE) 易感性的组成部分。作为一种识别方法 对于狼疮基因，我们的实验室目前正在进行全基因组研究 标记筛选，以定位染色体区域 携带狼疮基因。超过 180 个家庭至少患有两种 SLE 亲属（主要是同胞对家庭）参加了这项研究。在 初步研究，人类 1 号染色体的三个不同区域显示 105 例 SLE 同胞对的初始队列中可能存在关联的证据 家庭。随着基因组筛选的进行，其他候选者很可能 间隔将出现在其他染色体上。 SCOR项目的主要目标是加速基因搜索 MN SLE 家族系列。这将通过持续共享来实现 与 OMRF 的同事（项目 #2）进行基因分型数据进行比较 结果是两个 SLE 家族集合。初步测绘结果位于 MN 还将与 UAB 的同事共享（项目#3）以协助 他们筛选 1q 染色体候选基因。明尼家族 然后将使用 OMRF 研究中的标记对收集的样本进行基因分型，因此 可以直接比较联动结果。有趣的染色体 然后，区域将优先进行高密度标记筛选和精细 映射。三人家庭（一名 SLE 患者及其父母）作为 该 SCOR 应用程序的组件将用于不平衡映射 在目标区域。随后将采用多种策略 识别这些区域中的 SLE 基因。 SLE基因的最终分离和克隆将提供第一个 有机会在基因水平上了解导致的缺陷 狼疮患者的临床免疫失调特征。 这些见解应该为这些患者提供新的治疗途径， 包括体细胞基因治疗的潜力。有趣的是，狼疮—— 易感家庭其他自身免疫性疾病的发病率也有所增加 疾病包括类风湿性关节炎、甲状腺疾病和糖尿病。 因此，鉴定导致人类 SLE 的基因可能会 提高我们对器官遗传学和病理生理学的理解 特异性自身免疫。