Comprehensive Candidate Pathway Analysis in SLE

SLE 的综合候选通路分析

• 批准号: 6858347
• 负责人: TIMOTHY W. BEHRENS
• 金额: $ 59.1万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-15 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6858347
• 关键词: CD40 molecule; alleles; clinical research; gene expression; gene mutation; genetic markers; genetic polymorphism; genetic screening; genetic susceptibility; human genetic material tag; human subject; interferons; pathologic process; sex hormones; single nucleotide polymorphism; systemic lupus erythematosus; tumor necrosis factor alpha

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.

描述（由申请人提供）：全身性红斑狼疮（SLE）是一种慢性自身免疫性疾病，其特征是对许多自我抗原的自身抗体产生，导致全身性血管和靶心器官炎症。 来自可用基因组的微卫星筛选的数据表明，多个基因有助于SLE的发病机理。尽管经典的连锁分析在识别具有强大遗传作用的稀有变体方面非常有效，但这种方法具有有限的能力来检测具有适度渗透率的更常见变体。 因此，我们假设许多对SLE表型重要的等位基因将无法通过基因组筛选来识别。当前建议中，我们的总体目标是采用一种新颖的“候选途径”关联方法来鉴定有助于SLE的基因和基因变体。 SLE显示出惊人的女性占主导地位，大约为10：1女性：男性病例比率。与其他数据表明性类固醇在SLE发病机理中起重要作用，我们建议检查编码区域单核苷酸多态性（SNP）和44个性类固醇途径基因的单倍型结构，以证明有关联的证据。为此，我们将键入我们的MN家庭收藏集，该系列目前由250个同胞家族，300个三重奏家族（单身患者与父母双方的单身患者）以及300例案例对照组和匹配的对照组成。 Behrens实验室的最新数据表明，大约70％的SLE患者在其外周血细胞中携带了特征性干扰素诱导的基因表达特征。有趣的是，几乎所有具有最严重类型狼疮类型的患者都可以观察到这种特征。我们假设干扰素途径的激活反映了易于疾病的途径内的等位基因变异。我们将在此途径与SLE关联的途径中识别并键入基因中的编码SNP和单倍型。最后，我们的小组最近确定了与SLE密切相关的CD40基因中的突变。 CD40是B细胞和树突状细胞上的关键受体，对T依赖性免疫和炎症反应很重要。确定的突变是一种“功能的增益”多态性，它“预载”了CD40的胞质尾部，并具有信号蛋白TRAF2。携带该突变的细胞显示出改变的信号传导。我们建议在CD40途径中筛选其他分子，以及TNF受体基因家族的其他关键成员，以进行与SLE相关的其他多态性。所有推定的关联将在2,000个SLE案件和2,000个对照组的大量队列中复制。 该项目是明尼苏达大学的SLE遗传组与Broad Institute/Massachusetts综合医院之间的合作。 Broad Institute是基因组宽单倍型映射（HAP-MAP）项目的主要中心之一。因此，当前的研究将可以使用最新的方法来识别相关的单倍型以及基因分型和数据分析。我们预计拟议的研究将导致对有助于人类SLE的新等位基因的鉴定，并且这种新知识将迅速转化为更好地诊断和治疗这种重要疾病。