Identification Of Susceptibility Genes For SLE Of Amerindian Origin In Hispanics

西班牙裔美洲印第安人 SLE 易感基因的鉴定

• 批准号: 7774742
• 负责人: MARTA E ALARCON-RIQUELME
• 金额: $ 28.94万
• 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: 2009-08-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7774742
• 关键词: Admixture; Affect; African American; Age of Onset; Alleles; American; Amerindian; Clinical; Complex; Controlled Study; Country; Development; Disease; Disease susceptibility; Drug Delivery Systems; Ethnic group; European; Family; Gene Expression; Gene Mutation; Genes; Genome; Genomics; HLA-DRB1; Haplotypes; Hispanics; Individual; Instruction; Lead; Lupus; Maps; Minority; Mutation; Native Americans; Outcome Measure; Pathogenesis; Patients; Population; Probability; Publishing; Recording of previous events; Risk; Severities; Staging; Susceptibility Gene; Systemic Lupus Erythematosus; Therapeutic; Variant; case control; disorder risk; early onset; genetic association; genome wide association study; improved; novel; proband

Using a powerful and uniquely well characterized set of Hispanic individuals selected for having only Amerindian-European admixture, we will perform a genome-wide association scan to identify novel systemic lupus erythematosus genes in Native Americans. Hispanics are an expanding minority in the US and are particulariy susceptible to develop severe and early onset lupus. Indeed, recent evidence suggests that ncreased risk for lupus correlates with the proportion of Amerindian genome in patients. By selecting individuals with early age of onset, probands from multiplex families and individuals originating from high Amerindian admixture countries, we will maximize the probabilities of identifying Amerindian genes contributing to disease susceptibility. The aims of Project 3 are to 1: Perform a genome-wide association scan with 1,800,000 markers in 1,200 Hispanic cases and 600 controls in addition to neariy 700 out-of-study controls as a first stage towards the identification of genes of Amerindian origin for lupus; 2: Replicate the putative genetic associations in independent Hispanic cases and controls in a second stage analysis; 3: Use trans-racial mapping to define the origin and evolutionary history of the disease risk alleles and haplotypes as well as the common or divergent susceptibility genes across populations; and 4: Perform re-sequencing and gene expression analysis of novel and convincingly associated genes to identify all potential functional variation. In conjunction with Project 1, a much more detailed analysis of the MHC region will be performed so that its contribution, whether due to HLA-DRB1 genes or other genes, is defined. We expect to identify major and novel susceptibility genes for lupus and through focused re-sequencing, to identify the risk mutations for the genes with the major effects on disease susceptibility. RELEVANCE (See instructions): Through the identification of the risk genes for Hispanics. we will be able to study their relevance in the eariy development of the disease as well as with severity of the clinical presentation. We expect to be able to find associations between these genes and outcome measures. Results of this study should facilitate the search for novel drug targets that will lead to the possibility of improved therapeutics.

使用一组强大且独特且特征鲜明的西班牙裔个体，这些个体被选为仅拥有 美洲印第安人和欧洲人的混合，我们将进行全基因组关联扫描，以确定新的系统性 美洲原住民的红斑狼疮基因拉美裔是美国不断扩大的少数民族， 特别容易发展成严重的和早发性狼疮。事实上，最近的证据表明， 狼疮风险的增加与患者中美洲印第安人基因组的比例相关。通过选择 发病年龄早的个体，来自多重家族的先证者和来自高血压的个体， 在美洲印第安人混合国家，我们将最大限度地提高识别美洲印第安人基因的可能性 导致疾病易感性。 项目3的目标是1：在1200个基因组中使用180万个标记进行全基因组关联扫描。 西班牙裔病例和600名对照，以及近700名研究外对照，作为第一阶段， 狼疮美洲印第安人起源基因的鉴定; 2：复制 第二阶段分析中的独立西班牙裔病例和对照; 3：使用跨种族映射来定义 疾病风险等位基因和单倍型的起源和进化历史，以及常见或 不同人群中不同的易感基因;以及4：进行重新测序和基因表达 分析新的和令人信服的相关基因，以确定所有潜在的功能变异。在 结合项目1，将对MHC区域进行更详细的分析， 定义了HLA-DRB 1基因或其他基因的贡献。 我们希望通过集中重新测序， 以确定对疾病易感性有主要影响的基因的风险突变。 相关性（参见说明）： 通过对拉美裔人的风险基因的识别。我们将能够在早期研究它们的相关性 疾病的发展以及临床表现的严重程度。我们希望能够找到 这些基因和结果测量之间的关联。这项研究的结果应有助于搜索 寻找新的药物靶点，这将带来改进治疗方法的可能性。