Identification Of Susceptibility Genes For SLE Of Amerindian Origin In Hispanics

使用一组强大的、独特的、特征良好的西班牙裔个人，他们被选为 我们将进行全基因组关联扫描，以确定新的系统性 美洲土著人中的红斑狼疮基因。拉美裔在美国是一个不断扩大的少数群体，他们 尤其容易发展成严重的早发性狼疮。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有关。通过选择 发病年龄较早的个人、多胎家庭的先证者和来自高年龄组的个人 美洲印第安人混血国家，我们将最大限度地确定美洲印第安人基因的可能性 导致疾病易感性的因素。 项目3的目标是1：用1200个标记中的1,800,000个进行全基因组关联扫描 拉美裔病例和600名对照人员，以及近700名研究外对照人员，作为迈向 狼疮起源于美洲印第安人的基因鉴定；2：复制推测的遗传关联 第二阶段分析中的独立西班牙裔病例和对照；3：使用跨种族映射来确定 疾病风险等位基因和单倍型的起源和进化史以及常见的或 不同人群的易感基因差异；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，以识别所有潜在的功能变异。在……里面 结合项目1，将对MHC区域进行更详细的分析，以便其 定义了人类白细胞抗原-DRB1基因或其他基因的贡献。 我们希望确定狼疮的主要和新的易感基因，并通过有针对性的重新测序， 确定对疾病易感性有主要影响的基因的风险突变。 相关性(请参阅说明)： 通过识别拉美裔的风险基因。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性。我们希望能够找到 这些基因与结果指标之间的关联。这项研究的结果应该有助于搜索 对于新的药物靶点，这将导致改进治疗的可能性。

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.