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

描述（由申请人提供）：国际狼疮遗传学协会（SLEGEN）发表了一项全基因组关联研究（GWAS），对系统性红斑狼疮（SLE）的主要关联进行了多次重复（Nat Gen 40:204,2008），确定了18种遗传效应，其中13种以前没有描述过。这项研究仅限于欧洲血统的女性，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女性的HLA相关性并不强，而欧洲血统女性的HLA相关性最强（OR=2.36, p<10E-50）。我们建议利用RFA-CA-09-003“基因环境与健康倡议（GEI）的复制和精细定位研究”的资源，通过在3440名美洲印第安混合西班牙裔人中测试38,000种头型（约33,000个标记），一半是病例，一半是对照，来复制GWAS和其他研究中美洲印第安混合西班牙裔人的候选关联。我们将最大化美洲印第安人的组成部分，选择具有高美洲印第安人含量和低非洲血统的人口。数据清理和分层校正将遵循我们以前的经验，并利用最近的进展（例如，随机投影）。这些美洲印第安人与西班牙人的混合将使一项正在进行的实验成为可能，该实验有38,000种头型，14000名欧洲、非洲裔美国人和东亚血统的受试者（狼疮病例和对照）（由其他来源资助）。这将使遗传效应的跨祖先图谱成为可能。三人组和其他美洲印第安混合西班牙病例和对照材料可用于进一步的复制、精细制图和测序，这些工作将在本文件要求的资金之外随后组织。我们希望鉴定出对美洲印第安混血儿西班牙人重要的基因，确定风险等位基因是否来自欧洲或美洲原住民基因组，并使用来自其他祖先起源的受试者进一步限制其基因组位置。这些基因在狼疮的发病机制中很重要，它们的发现和特征将产生新的诊断和治疗方法来治疗这种致命的疾病。

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.