GENETIC FINE MAPPING IN SLE PAIR FAMILIES

SLE 对家族的遗传精细定位

• 批准号: 6348943
• 负责人: TIMOTHY W. BEHRENS
• 金额: $ 19.12万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6348943
• 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.

全身性红斑狼疮（SLE）和高高的家族聚类 单卵双胞胎的一致性率表明遗传很强 对SLE敏感的组件。作为标识的一种方法 狼疮基因，我们的实验室目前正在执行全基因组 标记屏幕是为了将染色体区域定位 狼狼疮基因。超过180个家庭至少有两个受影响的SLE 亲戚（主要是SIB对家族）已入学。在 初步研究，人类染色体1的三个不同区域显示 在105 SLE SIB对的初始队列中可能连接的证据 家庭。随着基因组屏幕的进行，可能还有其他候选人 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家庭收藏。这将通过共享持续的 与我们在OMRF的同事（项目＃2）的基因分型数据进行比较 导致两个SLE家族收藏。初步映射结果 MN还将与我们在UAB（项目＃3）的同事共享协助 在筛选染色体1q候选基因中。 MN家族 然后，收集将通过OMRF研究的标记进行基因分型，因此 可以直接比较该链接结果。有趣的染色体 然后，对于高密度标记屏幕和罚款，将区域生病优先考虑 映射。三人家庭（一名与父母双方的SLE患者）一起收集 该SCOR应用的组成部分将用于不平衡映射 在目标区域。然后将采用各种策略 确定这些区域中的SLE基因。 SLE基因的最终隔离和克隆将提供第一个 在遗传水平上了解导致缺陷的机会 狼疮患者的临床免疫失调特征。 这些见解应建议对该患者的新疗法途径， 包括体细胞基因疗法的潜力。有趣的是，狼疮 - 容易发生的家庭也增加了其他自身免疫的发病率 包括类风湿关节炎，甲状腺疾病和糖尿病在内的疾病。 因此，鉴定引起人SLE的基因可能是 提高我们对器官的遗传学和病理生理学的理解 特定的自身免疫性。