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）：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，导致全身血管和靶器官炎症。来自现有全基因组微卫星筛选的数据表明，多个基因参与SLE的发病机制。尽管经典连锁分析在识别具有强烈遗传效应的罕见变异方面非常有效，但这种方法在检测具有适度外显率的更常见变异方面的能力有限。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确定。我们当前提案的总体目标是采用一种新的“候选途径”关联方法来鉴定导致SLE的基因和基因变异。