Chromosome 1 Regions Linked to SLE in Multiplex Families

描述（由申请人提供）：系统性红斑狼疮（SLE）是 一种异质性自身免疫性疾病，特征是过多的 免疫病理学表现，包括自身抗体的产生， 各种核部件。遗传易感性显然在 然而，在发展SLE的风险中的作用，许多仍然难以捉摸。基因组扫描 已经在小鼠和人类SLE中定位了许多SLE易感基因座。一 小鼠1号染色体远端的基因组区域及其同线人类 而1 q23 -44则显示了SLE易感性的强有力证据 在小鼠和人类的多个独立的基因组扫描中的基因。我们有 在我们的队列中观察到1 q23和1 q41 -42与SLE相关的证据， 影响sibpair家庭。在本申请中，我们提出鉴定遗传的 在我们的研究中，1 q21 -44内的多态性与SLE或SLE亚群相关， 队列，并探索是否相同或功能相关的基因有助于 在小鼠和人类之间的易感性间隔中的同线保守性。我们 目标如下：1）继续家庭确认，增加150人 SLE多重家族和另外500个单纯家族，并评估 SLE的常见表现。扩大的多功能家庭将允许 每个分层子集中的更多样本（按种族、SLE表现或 发病年龄），因此更大的统计能力，以本地化的相关 interval.扩大的单纯形族将允许更大的统计功效 对每个民族群体进行关联研究。家族性SLE表现将 用于对我们的家族标本进行分层， 随后的连锁和关联研究中的异质性。2)执行 对染色体1 q21 -44进行靶向基因组扫描， SLE的易感性。3)进行连锁不平衡作图， 缩小基因组间隔，最终定位遗传多态性 与SLE易感性相关。4)评估候选人的人类同源物 小鼠SLE易感基因（Sle 1d、Nba 2和Lbw 7）作为证据， 在我们的队列中。SLE易感基因的鉴定可以 揭示自身免疫发病机制的潜在机制，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.