Identification of Lupus Predisposing Variants by Comparing Multiple Populations

描述（由申请人提供）：系统性红斑狼疮（SLE或狼疮）是一种多器官、复杂的自身免疫性疾病，具有大量遗传成分。狼疮是一种严重的健康问题，流行病学报告表明，非洲或亚洲血统的人患狼疮的比例至少是白种人的3至5倍。不同种族的临床表现和疾病严重程度也有显著差异。截至2010年2月，全基因组关联研究（GWAS）和候选基因研究已经确定了大约35个与狼疮密切相关的基因（P<5 × 10-8），主要来自欧洲和一些亚洲（中国和日本）人群。此外，最近的一些报告表明，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相关，这表明存在共同的自身免疫基因。虽然目前已知约35个狼疮易感基因/区域，但很少有“功能性”变异被确定。我们假设，通过同时使用全面的精细图谱并比较多个种族人群之间的连锁不平衡（LD）模式，我们将能够检测SLE易感基因中强大的和/或种族功能相关的变异。在这项研究中，我们建议使用最近开发的“免疫芯片”进行密集的精细定位，使用来自4个不同种族人群（欧美人、非裔美国人、哥伦比亚人和印度人）的2000例病例和3000例对照。该免疫芯片将利用来自HapMap和1000Genomes Project的196,000个选择的单核苷酸多态性（snp），在与12种自身免疫性疾病表型相关的184个相关基因组区域，包括最近鉴定和建立的35个（P<5x10-8） SLE易感基因，提供具有成本效益的精细定位。我们预计许多狼疮相关基因将在多个人群中复制，并且这些基因中以前未知的功能变异将被发现。此外，从剩余的149个与其他自身免疫表型相关的精细定位基因中，我们期望确定几个也增加狼疮风险的基因。该提案的目标是：(A)评估遗传关联的稳健性，并检测SLE和其他炎症性疾病的已知易感基因/区域的功能变异，以及(B)评估与狼疮临床亚表型的遗传关联。对于每个相关基因，我们期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发展有关，也可能与一部分患者有关。最终，通过这些实验获得一套全面的狼疮相关功能变异，将为未来的生物学实验提供基础，以确定这些功能变异如何促进狼疮的病理机制。

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.