Genetic Linkage in Lupus

描述（由申请人提供）：系统性红斑狼疮（SLE）通常很严重，可引起肾炎、口腔溃疡、关节炎、心包炎、胸膜炎、皮疹、中风、心脏病发作、血管炎、神经功能障碍、细胞减少、雷诺病和免疫功能障碍。SLE具有复杂的遗传学，许多基因对表型有影响。该项目名为AI242717，已经建立或确认了17种不同的健壮遗传效应，包括两个易感基因。竞争更新的核心是在自身免疫性甲状腺疾病的SLE谱系中，确定负责5q14常染色体显性连锁的基因。这一关联已经建立（LOD=4.96）并被独立证实（LOD=3.15），从而为这种关联提供了令人信服的证据。最优联合两点LOD=9.95。5q14位点的连锁先前在自身免疫性甲状腺疾病中有报道。我们已经探索了599个snp在连锁区间的关联，并确定了一个强候选基因。虽然还有很多工作要做，但现有的证据（通过重复和独立复制）特别令人信服，即一组标记，跨越22 kb，假定与候选基因的致病变异处于连锁不平衡状态，与SLE密切相关。如果后续结果不能继续支持候选基因的参与，在5q14从91 mb到100 mb的连锁区间内，有数千个未测试的SNPs，包括2051个dbSNPs，可用于帮助发现遗传关联。我们计划确定与SLE相关的候选基因变异。此外，四(4)个不同的验证性患者组可用于测试这种关联，希望加强明确的基因鉴定。如果这个项目成功了，那么5q14的相关基因将被令人信服地确定。我们将探索负责基因的特性，以描述通过该基因产生SLE的功能变异。一旦在5q14的相关基因上完成这项工作，我们将重新部署AI24717的实验能力，以探索下一个最有希望的连锁。此时，在吸烟的SLE家系和抗ro和抗la自身抗体的SLE家系中发现了两次3p21位点的连锁，这是下一个最有说服力的。根据审稿人的建议，其他先前提出的具体目标已从重新提交的AI24717-17A1提案中删除。鉴定的基因和由此产生的更完整的狼疮遗传模型将为狼疮的病理生理学提供更好的理解，改善狼疮疾病评估的预后工具，以及其他自身免疫性疾病，以及治疗的新分子靶点。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is often severe, causing nephritis, oral ulcers, arthritis, pericarditis, pleuritis, rashes, strokes, heart attacks, vasculitis, nervous dysfunction, cytopenias, Raynaud's disease, and immune dysfunction. SLE has complex genetics with many genes contributing to the phenotype. This project, AI242717, has established or confirmed 17 different robust genetic effects, including two susceptibility genes. The centerpiece of the competitive renewal is to identify the gene responsible for the autosomal dominant linkage at 5q14 with SLE in pedigrees containing an SLE affected with autoimmune thyroid disease. This linkage has been established (LOD=4.96) and independently confirmed (LOD=3.15), thereby providing convincing evidence for linkage. The optimal combined two- point LOD=9.95. Linkage at 5q14 has been previously reported in autoimmune thyroid disease. We have explored 599 SNPs for association in the linkage interval and have identified a strong candidate gene. Though there is much work left to do, the available evidence is particularly convincing (by repetition and independent replication) that a group of markers, spanning 22 kb and presumed to be in linkage disequilibrium with the causative variant(s) of the candidate gene, is strongly associated with SLE. There are many thousands of untested SNPs in the 5q14 linkage interval from 91 mb to 100 mb available to help find genetic association if subsequent results do not continue to support candidate gene involvement, including 2051 dbSNPs. We plan to identify the candidate gene variants associated with SLE. In addition, four (4) different confirmatory patient groups are available to test the association, hopefully reinforcing unambiguous gene identification. If this project is successful, then the responsible gene at 5q14 will have been convincingly identified. We will explore the properties of the responsible gene to describe functional variations that work through this gene to generate SLE. Once this work with the responsible gene at 5q14 is complete we will redeploy the experimental capacity of AI24717 to explore the next most promising linkage. At this time, a linkage at 3p21 found twice, in pedigrees with SLE cigarette smokers and in SLE pedigrees with anti-Ro and anti-La autoantibodies, is the next most convincing. As suggested by the reviewers, other previously presented specific aims have been removed from the resubmitted AI24717-17A1 proposal. The identified genes and resulting more complete genetic model of lupus will provide better understanding of the pathophysiology of lupus, improved prognostic tools for disease assessment in lupus as well as, perhaps, in other autoimmune diseases, and new molecular targets for therapeutics.