Comprehensive Candidate Pathway Analysis in SLE

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种慢性自身免疫性疾病，其特征是产生针对许多自身抗原的自身抗体，导致系统性血管和靶器官炎症。 现有的全基因组微卫星筛查数据表明，多种基因参与SLE的发病机制。尽管经典的连锁分析在鉴定具有强遗传效应的罕见变异方面是相当有效的，但是这种方法对于检测具有适度遗传效应的更常见的变异具有有限的能力。 因此，我们假设许多对SLE表型很重要的等位基因将不能通过基因组筛选鉴定。我们在目前的建议的总体目标是采取一种新的“候选途径”的关联方法来识别基因和基因变异，有助于SLE。 SLE显示出显著的女性优势，女性：男性病例比例约为10：1。与其他数据表明性类固醇在SLE发病机制中的重要作用，我们建议检查编码区单核苷酸多态性（SNP）和44个性类固醇途径基因的单倍型结构的关联证据。为此，我们将输入我们的MN家族集合，其目前包括250个同胞对家族、300个三人家族（双亲均为SLE的单个患者）和300个病例和匹配对照的病例对照队列。Behrens实验室的最新数据显示，约70%的SLE患者外周血细胞中携带特征性干扰素诱导的基因表达特征。有趣的是，几乎所有最严重类型的狼疮患者都观察到了这种特征。我们假设干扰素通路的激活反映了该通路内易患疾病的等位基因变异。我们将确定并分型编码单核苷酸多态性和单倍型的基因，从这个途径与系统性红斑狼疮。最后，我们小组最近发现了一个与SLE密切相关的CD 40基因突变。CD 40是B细胞和树突状细胞上的关键受体，其对于T依赖性免疫和炎症反应是重要的。鉴定的突变是一种“功能获得”多态性，其用信号蛋白TRAF 2“预加载”CD 40的胞质尾区。携带这种突变的细胞显示出改变的信号。我们建议筛选CD 40通路中的其他分子，以及TNF受体基因家族的其他关键成员，以寻找与SLE相关的其他多态性。所有假定的关联将在2,000例SLE病例和2,000例对照的大型队列中重复。 该项目是明尼苏达大学SLE遗传学小组和布罗德研究所/马萨诸塞州总医院之间的合作。布罗德研究所是全基因组单倍型作图（hap-map）项目的主要中心之一。因此，目前的研究将获得最先进的方法来鉴定相关的单倍型，基因分型和数据分析。我们预计，拟议的研究将导致识别新的等位基因，有助于人类SLE，这一新的知识将迅速转化为更好的诊断和治疗这一重要疾病。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies against many self-antigens resulting in systemic blood vessel and target organ inflammation. Data from the available genome-wide microsatellite screens suggest that multiple genes contribute to the pathogenesis of SLE. Although classic linkage analysis is quite effective in identifying rare variants with a strong genetic effect, this approach has limited power to detect more common variants with modest penetrance. Thus, we hypothesize that many alleles important for the SLE phenotype will not be identified through genome screens. Our overall objective in the current proposal is to take a novel "candidate pathway" association approach to the identification of genes and gene variants that contribute to SLE. SLE shows a striking female predominance with approximately a 10:1 female:male case ratio. Together with other data indicating an important role for sex steroids in the pathogenesis of SLE, we propose to examine coding region single nucleotide polymorphisms (SNPs) and the haplotype structure of 44 sex steroid pathway genes for evidence of association. For this, we will type our MN family collection, which currently is comprised of 250 sib-pair families, 300 trio families (single SLE patient with both parents), and a case control cohort of 300 cases and matched controls. Recent data from the Behrens laboratory have shown that about 70% of individuals with SLE carry a characteristic interferon-induced gene expression signature in their peripheral blood cells. Interestingly, this signature is observed in nearly all patients with the most severe type of lupus. We hypothesize that activation of the interferon pathway reflects allelic variation within the pathway that predisposes to disease. We will identify and then type coding SNPs and haplotypes within genes from this pathway for association with SLE. Finally, our group has recently identified a mutation in the CD40 gene that is strongly associated with SLE. CD40 is a key receptor on B cells and dendritic cells which is important for T-dependent immune and inflammatory responses. The identified mutation is a "gain of-function" polymorphism that "pre-loads" the cytoplasmic tail of CD40 with the signaling protein TRAF2. Cells carrying this mutation show altered signaling. We propose to screen additional molecules within the CD40 pathway, and other key members of the TNF receptor gene family, for additional polymorphisms associated with SLE. All putative associations will be replicated in a large cohort of 2,000 SLE cases and 2,000 controls. This project is a collaboration between the SLE genetics group at the University of Minnesota and the Broad Institute/Massachusetts General Hospital. The Broad Institute is one of the primary centers for the genome wide haplotype mapping (hap-map) project. Thus, the current study will have access to state-of-the-art methods for identification of relevant haplotypes, and for genotyping and data analysis. We anticipate that the proposed studies will lead to the identification of novel alleles that contribute to human SLE, and that this new knowledge will translate rapidly to better diagnosis and treatment of this important disease.