Gene Mapping in Women with Systemic Lupus Erythematosus

描述(由申请人提供)：本竞争性续签申请 概述了我们绘制并最终识别易感基因的计划 治疗人类系统性红斑狼疮。在第一个资助期内，我们 已成功招募了250多个SLE同胞和多胎家庭，如 以及130个三人(受影响的SLE患者的双亲)家庭。全基因组 在这些明尼苏达州的家系中已经进行了标记筛选，并有几个 看起来可能含有SLE易感基因的染色体区域 已被确认身份。密集的微卫星标记作图已经在 显示出最有说服力的连锁证据的几个染色体区域 在我们的家族收藏中(1q41、6p21(人类白细胞抗原)、16q21、20q和20p)。更多 最近，我们已经开始分析这些区域的几个候选基因。 我们的SLE家族是世界上最大的家族之一，我们是 做好准备在下一个资金期推进这个项目。在 未来五年，我们建议继续收集额外的SLE同胞对和 三人家庭，目标是招募125个兄弟姐妹家庭和300个三人家庭。 此外，我们还将收集200名年龄、性别和种族匹配的人 病例/对照关联研究的对照个体与累积的 标记数据。我们将进一步细化易感基因座的位置 在人类白细胞抗原区域内使用重组祖先单倍型方法，以及 然后尝试识别在人类白细胞抗原中的序列变异 系统性红斑狼疮的风险。最后，我们将继续对非人类白细胞抗原染色体进行精细定位 与狼疮表型相关的区域。在时间范围内 在接下来的五年里，我们希望开始识别与疾病相关的序列 增加人类系统性红斑狼疮风险的基因多态。狼疮的辨证 基因对于加深我们对此的理解将是至关重要的 疾病，以及合理地瞄准新的疗法。

DESCRIPTION (provided by applicant): This competitive renewal application outlines our plans to to map and eventually identify the susceptibility genes for human systemic lupus erythematosus. During the first funding period, we have successfully recruited over 250 SLE sib-pair and multiplex families, as well as 130 trio (affected SLE patient with both parents) families. Genome-wide marker screens have been performed in these Minnesota pedigrees, and several chromosomal regions that appear likely to harbor SLE susceptibility genes have been identified. Dense microsatellite marker mapping has been initiated in several chromosomal regions that show the most convincing evidence for linkage in our family collection (1q41, 6p21 (HLA), 16q21, 20q, and 20p). More recently, we have begun to analyze several candidate genes in these regions. Our collection of SLE families is one of the largest in the world, and we are well poised to move this project forward in the next funding period. In the next five years we propose to continue collection additional SLE sib-pair and trio families, with a goal of recruiting 125 sib-pair families and 300 trios. In addition we will collect a group of 200 age-, sex- and ethnicity-matched control individuals for case/control association studies with the accumulated marker data. We will further refine the location of the susceptibility loci within the HLA region using the recombinant ancestral haplotype approach, and then attempt to identify the sequence variations within the HLA that confer risk for SLE. Finally, we will continue fine mapping in the non-HLA chromosomal regions that show linkage to the lupus phenotype. Within the time frame of the next five years we hope to begin identifying the disease-associated sequence polymorphisms that confer risk for human SLE. The identification of the lupus genes will be critically important for furthering our understanding of this disease, and for rationally targeting new therapies.