Identification of Lupus Predisposing Variants by Comparing Multiple Populations

描述(申请人提供)：系统性红斑狼疮(SLE或狼疮)是一种具有实质性遗传成分的多器官、复杂的自身免疫性疾病。狼疮是一个严重的健康问题，流行病学报告表明，在非洲或亚洲血统的人中，它的患病率至少是高加索血统的3至5倍。临床表现和疾病严重程度在不同种族之间也有很大差异。截至2010年2月，全基因组关联研究和候选基因研究已经确定了大约35个与狼疮有关的强大遗传关联(P&lt；5x10-8)，大多数报告来自欧洲和一些亚洲(中国和日本)人群。此外，最近的一些报道表明，与其他自身免疫性疾病表型相关的一些主要基因也与狼疮易感性有关，这表明存在共同的自身免疫基因。尽管目前已知约35个狼疮易感基因/区域，但几乎没有“功能性”变异被发现。我们假设，通过同时使用全面的精细定位和比较多个种族群体之间的连锁不平衡(LD)模式，我们将能够检测到SLE易感基因中的稳健和/或种族功能相关变异。在这项研究中，我们建议使用来自4个不同种族的人群(欧洲裔美国人、非裔美国人、哥伦比亚人和印度人)的2000例病例和3000例对照，在最近开发的“免疫芯片”中进行密集精细定位。免疫芯片将使用HapMap和1000Genome Project中的19.6万个精选单核苷酸多态(SNPs)提供具有成本效益的精细图谱，涉及与12种自身免疫性疾病表型相关的184个基因组区域，其中包括35个最近发现和建立的(P&lt；5x10-8)SLE易感基因。我们预计，许多与狼疮相关的基因将在多个群体中复制，这些基因中以前未知的功能变异将被发现。此外，从其余149个与其他自身免疫表型相关的精细定位基因中，我们预计可以识别出几个也会增加狼疮风险的基因。这项建议的目标是：(A)评估遗传关联的稳健性，并在SLE和其他炎症性疾病的已建立的易感基因/区域中检测功能变异，以及(B)评估与狼疮临床亚型的遗传关联。对于每个相关基因，我们希望确定一组功能变异及其相对贡献，这些变异可能与狼疮的总体或部分患者的发展有关。最终，通过这些实验获得的一套与狼疮相关的全面的功能变体将为未来的生物学实验提供基础，以确定这些功能变体如何在狼疮的病理机制中发挥作用。 公共卫生相关性：系统性红斑狼疮(SLE或狼疮)是一个重大的全球健康问题。仅在美国，就有200多万人患有这种毁灭性的疾病。这种疾病的患病率在不同人口之间差异很大，非洲或亚洲血统的人至少比高加索血统的人高3到5倍。狼疮的遗传学基础已经确立，到目前为止已发现约35个易感基因。这项研究将试图确定一套完整的狼疮相关功能变异，这可能为未来的生物学实验确定狼疮的病理机制提供基础。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE or lupus) is a multi-organ, complex autoimmune disease with a substantial genetic component. Lupus is a significant health problem, and epidemiological reports indicate that it is at least 3 to 5 times more prevalent in people of African or Asian ancestry than Caucasian ancestry. Clinical manifestations and disease severity also vary significantly among different ethnicities. As of February 2010, genome-wide association studies (GWAS) and candidate gene studies have identified about 35 robust genetic associations (P<5x10-8) with lupus, mostly reported from European and some Asian (Chinese and Japanese) populations. Additionally, several recent reports demonstrated that some major genes associated with other autoimmune disease phenotypes are also associated with lupus susceptibility, suggests the existence of common shared autoimmunity genes. Although ~35 lupus susceptibility genes/regions are currently known, very few "functional" variants have been identified. We hypothesize that by simultaneously using a comprehensive fine-mapping and comparing the linkage disequilibrium (LD) pattern among multiple ethnic populations, we will be able to detect both robust and/or ethnic functionally relevant variants within SLE susceptibility genes. In this study, we propose to perform dense fine-mapping in a recently developed "ImmunoChip" using 2000 cases and 3000 controls from 4 ethnically diverse populations (European-American, African-American, Colombian, and Indian populations). The ImmunoChip will provide cost-effective fine- mapping using >196,000 selected single nucleotide polymorphisms (SNPs) from HapMap and 1000Genomes Project at 184 associated genomic regions associated with 12 autoimmune disease phenotypes, including 35 of recently identified and established (P<5x10-8) SLE susceptibility genes. We expect that many of these lupus associated genes will be replicated in multiple populations, and previously unknown functional variants within these genes will be discovered. Moreover, from the remaining 149 fine-mapped gene associated with other autoimmune phenotypes, we expect to identify several genes which also increase the risk of lupus. The goals of this proposal are to: (A) assess the robustness of genetic associations and detect functional variants in established susceptibility genes/regions for SLE and other inflammatory diseases, and (B) assess genetic associations with clinical sub-phenotypes of lupus. For each associated gene, we expect to identify a set of functional variants and their relative contributions that may be involved in the development of lupus in general or in a subset of patients. Ultimately, a comprehensive set of lupus associated functional variants made available through these experiments will provide a basis for future biological experiments to define how these functional variants contribute to the pathological mechanism in lupus. PUBLIC HEALTH RELEVANCE: Systemic lupus erythematosus (SLE or lupus) is a significant global health problem. In the United States only, more than 2,000,000 individuals suffer from this devastating disease. The disease prevalence varies significantly from population to population, at least 3 to 5 times higher in people of African or Asian ancestry than Caucasian ancestry. The genetic basis of lupus is well established, and about 35 susceptibility genes are identified to date. The proposed study will attempt to identify a comprehensive set of lupus associated functional variants which may provide a basis for future biological experiments to define pathological mechanisms of lupus.