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

描述(由申请人提供)：国际狼疮遗传学联合会(SLEGEN)发表了一项全基因组关联研究(GWAS)，多次重复与系统性红斑狼疮(SLE)有关的主要关联(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，迄今为止被研究的拉美裔美国人没有很强的人类白细胞抗原相关性，而在欧洲血统的女性中，这是最强的关联(OR=2.36，p&lt；10E-50)。我们建议使用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名美洲印第安人混杂拉美裔、一半病例和一半对照中测试38,000种珠子类型(约33,000个标记)，复制GWAS和其他美洲印第安人混杂拉美裔研究中的候选关联。我们将最大限度地发挥美洲印第安人的作用，选择美洲印第安人含量高、非洲血统低的人群。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，随机预测)。这些美洲印第安人混杂的西班牙裔人将可能完成一项正在进行的实验，该实验在14,000名欧洲人、非裔美国人和东亚血统(由其他来源资助)的14,000名受试者(狼疮病例和对照)中使用了38,000种珠子类型。这将使遗传效应的跨祖先图谱成为可能。TRIO和其他美洲印第安人混合的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，这些将在后续组织，超出这里要求的资金。我们希望确定对美洲印第安人混杂拉美裔很重要的基因，确定风险等位基因来自欧洲人还是美洲原住民基因组，并使用来自其他祖先来源的受试者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催生这种致命疾病的新诊断和治疗方法。

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.