Chromosome 1 Regions Linked to SLE in Multiplex Families

描述(申请人提供)：系统性红斑狼疮(SLE) 一种异质性自身免疫性疾病，其特征是 免疫病理表现，包括产生自身抗体 各种核部件。遗传易感性显然是一个重要的因素 然而，在系统性红斑狼疮的风险中，许多人仍然难以捉摸。基因组扫描 已经在小鼠和人的SLE中定位了许多SLE易感基因。一 小鼠1号染色体远端的基因组区域及其同线人 对应的1q23-44已显示出强烈的证据表明存在系统性红斑狼疮易感性 小鼠和人类多个独立基因组扫描中的基因。我们有 在我们的队列中观察到1q23和1q41-42与系统性红斑狼疮相关的证据 受影响的兄弟姐妹家庭。在本应用程序中，我们建议识别基因 1q21-44内与SLE或SLE亚集相关的多态 队列，并探索相同或功能相关的基因是否有助于 小鼠和人之间易感间期的共线守恒。我们的 目标如下：1)继续对另外150人进行家庭查明 SLE多户型家庭和另外500个单户型家庭并评估 熟悉系统性红斑狼疮表现。扩大后的多厅家庭将允许 每个分层子集中的更多样本(按种族、SLE表现或 发病年龄)，因此有更大的统计能力来定位相关的 时间间隔。扩大的单纯形家庭将允许更大的统计能力 用于每个民族的联想研究。家族性系统性红斑狼疮的表现 用来对我们的家族集合进行分层，以减少基因 随后的连锁和关联研究中的异质性。2)执行 对染色体1q21-44进行靶向基因组扫描并缩小连锁间隔 对SLE的易感性。3)进行连锁不平衡作图 缩小基因组间隔以最终定位遗传多态 与系统性红斑狼疮易感性有关。4)评估候选人的人类同源物 寻找小鼠SLE易感基因(Sle1d、Nba2和Lbw7)的证据 在我们的队列中有关联。SLE易感基因的鉴定可以 揭示自身免疫发病的潜在机制，并提供 疾病管理的潜在目标。

DESCRIPTION (provided by the applicant): Systemic lupus erythematosus (SLE) is a hetereogeneous autoimmune disease characterized by a plethora of immunopathologic manifestations including the production of autoantibodies to various nuclear components. Genetic predisposition clearly plays an important role in risk for developing SLE, however, many remain elusive. Genome scans have mapped many SLE susceptibility loci in both murine and human SLE. One genomic region on the distal end of mouse chromosome 1 and its syntenic human counterpart 1q23-44 has shown strong evidence to harbor SLE susceptibility genes in multiple independent genome scans of both mice and humans. We have observed evidence for linkage to SLE at 1q23 and 1q41-42 in our cohort of affected sibpair families. In this application, we propose to identify genetic polymorphisms within 1q21-44 that are associated with SLE or SLE subsets in our cohort, and to explore if the same or functionally related genes contribute to syntenic conservation in susceptibility intervals between mice and humans. Our aims are as follows: 1) To continue family ascertainment for an additional 150 SLE multiplex families and an additional 500 simplex families and to assess familiality of SLE manifestations. The enlarged multiplex families will allow more samples in each stratified subset (by ethnicity, SLE-manifestations, or age of disease-onset), hence greater statistical power to localize the linked interval. The enlarged simplex families will allow greater statistical power for association studies in each ethnic group. Familial SLE manifestations will be used in stratification of our family collection to reduce genetic heterogeneity in subsequent linkage and association studies. 2) To perform a targeted genome scan of chromosome 1q21-44 and to narrow the intervals linked to SLE susceptibility. 3) To perform linkage disequilibrium mapping of the narrowed genomic intervals to eventually localize genetic polymorphisms associated with SLE susceptibility. 4) To assess human homologues of candidate murine SLE susceptibility genes (Sle1d, Nba2, and Lbw7) for evidence of association in our cohort. The identification of SLE susceptibility genes can reveal underlying mechanisms in the pathogenesis of autoimmunity and provide potential targets for disease management.