GENETIC FINE MAPPING IN SLE PAIR FAMILIES

系统性红斑狼疮（SLE）的家族聚集性和高 单卵双胞胎的一致率表明， SLE易感性的一个组成部分。作为一种识别方法， 狼疮基因，我们的实验室目前正在进行全基因组 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 初步研究表明，人类1号染色体的三个不同区域显示， 在105个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， 间隔会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家族收藏这将通过不断分享 基因分型数据与我们的同事在OMRF（项目#2）进行比较 导致两个SLE家族的集合。初步测绘结果 MN也将与我们在UAB的同事分享（项目#3），以帮助 在染色体1 q候选基因的筛选中。MN家族 然后将用来自OMRF研究的标记物对收集的样本进行基因分型， 这种联系的结果可以直接比较。有趣的染色体 然后，区域将优先用于高密度标记筛选， 映射.收集三个家庭（一名SLE患者与双亲）， 该SCOR应用程序的一个组件将用于不平衡映射 在目标地区。然后将采用各种策略， 确定这些区域中的SLE基因。 SLE基因的最终分离和克隆将提供第一个 有机会在基因水平上了解导致 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- 易感家族也有其他自身免疫性疾病的发病率增加， 包括类风湿性关节炎、甲状腺疾病和糖尿病在内的疾病。 因此，导致人类SLE的基因的鉴定很可能 提高我们对器官的遗传学和病理生理学的理解， 特异性自身免疫

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.