Fine Mapping and Replication of a Genome-Wide Association Scan for SLE in Hispani

西班牙裔 SLE 的全基因组关联扫描的精细绘图和复制

• 批准号: 7743712
• 负责人: MARTA E ALARCON-RIQUELME
• 金额: $ 39.75万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-17 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7743712
• 关键词: Admixture; Affect; African; African American; Age of Onset; Alleles; Amerindian; Asians; Chromosome Mapping; Clinical; Complex; Data; Development; Disease; Environment; Ethnic group; European; Frequencies; Funding; Genes; Genetic; Genome; Genomics; Haplotypes; Health; Hispanics; Individual; International; Location; Lupus; Maps; Mutation; Native Americans; Pathogenesis; Population; Predisposition; Publishing; Resources; Risk; Signal Transduction; Source; Stratification; Systemic Lupus Erythematosus; Testing; Therapeutic; Variant; Woman; base; case control; experience; genome wide association study; novel diagnostics; research study

DESCRIPTION (provided by applicant): The International Consortium on the Genetics of Lupus (SLEGEN) published a genome wide association study (GWAS) with multiple replications of the major associations with Systemic Lupus Erythematosus (SLE) (Nat Gen 40:204, 2008), identifying 18 genetic effects, 13 of which were not previously described. This study was confined to European-ancestry women and we know that there are major differences between ancestral groups with regard to lupus susceptibility. For example, the Hispanics studied to date do not have a strong HLA association, which in European-ancestry women is the strongest association (OR=2.36, p<10E-50). We propose to use the resources of this RFA-CA-09-003 "Replication and Fine-Mapping Studies for the Genes Environment and Health Initiative (GEI)" to replicate candidate associations from the GWAS and other studies in Amerindian admixed Hispanics by testing 38,000 bead types (about 33,000 markers) in 3440 Amerindian admixed Hispanics, half cases and half controls. We will maximize the Amerindian component selecting populations that have high Amerindian content and low African ancestry. Data cleaning and stratification correction will follow our previous experience and exploit recent advances (e.g., random projection). These Amerindian admixed Hispanics will make possible completing an experiment underway with 38,000 bead types in 14,000 subjects (lupus cases and controls) of European, African-American, and East Asian ancestry (funded from other sources). This will make trans-ancestry mapping of genetic effects possible. Trios and additional Amerindian admixed Hispanic case and control materials are available for additional replication, fine mapping, and sequencing, which will be organized subsequently, beyond the funding requested herein. We expect to identify genes important for Amerindian admixed Hispanics, to identify whether the risk alleles are from European or Native American genomes, and to use subjects from other ancestral origins to further restrict their genomic location. These genes are important in lupus pathogenesis and their discovery and character will spawn new diagnostic and therapeutic approaches to this deadly disorder.

描述（由申请人提供）：国际狼疮遗传学联盟（SLEGEN）发表了一项全基因组关联研究（GWAS），其中多次重复了与系统性红斑狼疮（SLE）的主要关联（Nat Gen 40：204，2008），确定了18种遗传效应，其中13种先前未描述。这项研究仅限于欧洲血统的妇女，我们知道，在狼疮易感性方面，祖先群体之间存在重大差异。例如，迄今为止研究的西班牙裔人没有很强的HLA关联，而在欧洲血统的女性中，这种关联是最强的（OR=2.36，p<10 E-50）。我们建议使用本RFA-CA-09-003“基因环境和健康倡议（GEI）的复制和精细图谱研究”的资源，通过在3440名美洲印第安人混合西班牙裔（一半病例和一半对照）中检测38，000种微珠类型（约33，000种标记物），在美洲印第安人混合西班牙裔中复制GWAS和其他研究的候选关联。我们将最大限度地增加美洲印第安人的组成部分，选择美洲印第安人含量高、非洲血统低的人口。数据清理和分层校正将遵循我们以前的经验，并利用最新的进展（例如，随机投影）。这些美洲印第安人混合的西班牙裔将有可能完成一项正在进行的实验，该实验在欧洲，非洲裔美国人和东亚血统的14，000名受试者（狼疮病例和对照）中使用38，000种珠子类型（由其他来源资助）。这将使遗传效应的跨祖先映射成为可能。三人组和其他美洲印第安人混合西班牙裔病例和对照材料可用于额外的复制，精细绘图和测序，随后将组织，超出本文所要求的资金。我们希望确定美洲印第安人混合西班牙裔的重要基因，以确定风险等位基因是否来自欧洲或美洲原住民的基因组，并使用其他祖先来源的主题，以进一步限制他们的基因组位置。这些基因在狼疮发病机制中很重要，它们的发现和特征将为这种致命疾病产生新的诊断和治疗方法。