Identification of Lupus Predisposing Variants by Comparing Multiple Populations

通过比较多个人群来识别狼疮易感变异

基本信息

批准号：
8249819
负责人：
Swapan K. Nath
金额：
$ 20.25万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8249819
关键词：
African African American American Asian Americans Asians Autoantibodies Autoimmune Diseases Autoimmune Process Autoimmunity Biological Biological Assay Candidate Disease Gene Caucasians Caucasoid Race Chinese People Chromosome Mapping Clinical Complex Controlled Study Development Disease Environmental Risk Factor Epidemiology Ethnic Origin European Foundations Future Genes Genetic Genetic Variation Genomics Genotype Goals Health Heterogeneity Hispanics Individual Inflammatory Japanese Population Learning Letters Linkage Disequilibrium Lupus Maps Medical Research Oklahoma Organ Pathogenesis Patients Pattern Phenotype Population Population Heterogeneity Predisposition Prevalence Process Relative (related person)Reporting Research Design Risk Sampling Severity of illness Single Nucleotide Polymorphism Susceptibility Gene Systemic Lupus Erythematosus Testing Time United States Variant base case control cost effective density design disease phenotype genetic association genome wide association study global health improved public health relevance research study risk sharing

项目摘要

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.

描述（由申请人提供）：全身性红斑狼疮（SLE或狼疮）是一种多器官，复杂的自身免疫性疾病，具有大量的遗传成分。狼疮是一个重大的健康问题，流行病学报告表明，在非洲或亚洲血统的人群中，它至少比白人血统高3至5倍。不同种族之间的临床表现和疾病严重程度也有很大差异。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与狼疮的35个健壮的遗传关联（P <5x10-8），其中大多数来自欧洲和一些亚洲（中国和日本）人群。此外，最近的几份报告表明，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有关，这表明存在共同的共享自身免疫基因。尽管目前已知〜35个狼疮敏感性基因/区域，但很少发现“功能性”变体。我们假设，通过同时使用全面的精细映射并比较多个民族人群之间的连锁不平衡（LD）模式，我们将能够检测到SLE敏感基因中的鲁棒和/或种族与功能相关的变体。在这项研究中，我们建议在最近开发的“免疫光化”中使用2000例案例和3000个对照组（欧美，非裔美国人，哥伦比亚人和印度人口）进行密集的精细图。免疫芯片将使用HAPMAP和1000基因组项目的196,000个选定选定的单核苷酸多态性（SNP）提供具有成本效益的精细映射，该项目在184个相关的基因组区域，与12个自身免疫性疾病表型相关，包括最近鉴定和已建立的35个（P <5x10-8）（P <5X10-8）。我们希望其中许多相关的基因将在多个种群中复制，并且将发现这些基因中未知的功能变体。此外，从与其他自身免疫表型相关的其余149个精细图基因中，我们希望鉴定出几种基因，也会增加狼疮的风险。该提案的目标是：（a）评估遗传关联的鲁棒性，并检测SLE和其他炎症性疾病的已建立易感基因/区域中的功能变异，以及（b）评估lupus临床亚表征的遗传关联。对于每个相关的基因，我们希望确定一组功能变异及其相对贡献，这些变体可能与一般或一部分患者中狼疮的发展有关。最终，通过这些实验提供的一组全面的相关功能变体将为将来的生物学实验提供基础，以定义这些功能变体如何促进狼疮的病理机制。公共卫生相关性：全身性红斑狼疮（SLE或狼疮）是一个重大的全球健康问题。在美国，超过200万人患有这种毁灭性疾病。该疾病的患病率因人群而异，非洲或亚洲血统的人群至少比白人血统高3至5倍。狼疮的遗传基础已经很好地确定，迄今为止，大约有35个敏感性基因。拟议的研究将尝试确定一组狼疮相关的功能变体，这些变体可能为未来的生物学实验提供定义狼疮病理机制的基础。