Mapping of Systemic Lupus Erythematosus (SLE) Susceptibility in African Americans

非裔美国人系统性红斑狼疮 (SLE) 易感性绘图

• 批准号: 8249124
• 负责人: Swapan K. Nath
• 金额: $ 26.4万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8249124
• 关键词: Admixture; Affect; African; African American; Alleles; Autoimmune Diseases; Biochemical; Biological; Candidate Disease Gene; Chromosomes; Complex; Development; Disease; Disease susceptibility; Ethnic group; European; Family; Genes; Genetic; Genome Scan; Genomics; Genotype; Goals; Haplotypes; Individual; Inherited; Lead; Linkage Disequilibrium; Maps; Methods; Minority; Pathogenesis; Population; Predisposition; Probability; Recording of previous events; Resources; Risk; Sampling; Scanning; Signal Transduction; Susceptibility Gene; Systemic Lupus Erythematosus; Testing; Time; base; case control; density; design; follow-up; gene discovery; genome-wide; meetings; novel; novel therapeutic intervention; patient population; programs; tool; trait

Systemic lupus erythematosus (SLE) is a complex, autoimmune disorder in which susceptibility is determined by a combination of genetic, environmental and stochastic factors. SLE disproportionately affects African-Americans (AA) compared to the people of European descent. For disorders with a poorly understood biochemical basis, like SLE, identification of genes contributing to disease susceptibility is a prerequisite to understanding its biological basis. Admixture mapping is a promising 'new' tool for discovering genes that contribute to complex traits. The idea is simple¿near a disease gene, patient populations descended from the recent mixing of two or more ethnic groups should have an increased probability of inheriting the DMA derived from the ethnic group with more risk. Admixture between genetically different populations may produce long-range linkage disequilibrium (LD) or gametic association between loci as a function of genetic difference between parental populations and the admixture rate. These admixed populations facilitate mapping complex disease genes of small effect size (risk ~ 1.5 fold), which is beyond the current power of family-based linkage approach. Though haplotype-based or direct association methods are able to detect these genes, however, they require at least 100 times more markers (300,000 to 500,000) than markers required in admixture mapping approach (1500 to 3000). The present day AA population is a unique resource for mapping SLE susceptibility genes with similar effect size. The overall goal of this proposal is to identify SLE susceptibility genes in AA using the admixture mapping approach. To meet this goal, two Specific Aims will be accomplished¿(1) Perform an admixture genome scan for finding the candidate SLE susceptibility regions, and (2) Follow up the most convincing susceptibility region with high-density SNPs using the haplotype-based approach for fine genomic mapping and identify the causal susceptibility gene(s). We will perform admixture mapping on a sample of at least 2000 SLE cases and 2000 AA controls, using a recently validated panel of ~2000 highly informative ancestry informative markers (AIM). Using an ideal admixed population in which LD has been sustained at longer chromosome segments, genotyping sufficient AIMs, controlling for spurious association, and employing an admixture mapping followed by targeted high-density haplotype-mapping strategies, this proposal maximizes the opportunity to identify the novel genomic regions that contain SLE susceptibility genes. Therefore, identification of these genes will help us understanding the development and pathogenesis of this disease in a minority population, and may lead to novel therapeutic interventions.

系统性红斑狼疮（SLE）是一种复杂的自身免疫性疾病， 由遗传、环境和随机因素的组合决定。SLE不成比例 影响非洲裔美国人（AA）相比，欧洲血统的人。对于那些 了解生化基础，如SLE，鉴定基因有助于疾病易感性是一个重要的研究领域。 这是了解其生物学基础的前提。 混合物作图是一种很有前途的“新”工具，用于发现有助于复杂性状的基因。 这个想法很简单，在疾病基因附近，病人群体是最近两种或两种以上基因混合的后代。 更多的种族群体应该有更大的可能性遗传来自种族的DMA。 风险更大的群体。遗传上不同的群体之间的混合可能产生长距离连锁 基因座之间的不平衡（LD）或配子关联作为亲本之间遗传差异的函数， 人口和混合率。这些混合的人群有助于绘制复杂的疾病基因 小的影响大小（风险~ 1.5倍），这超出了目前的权力，以家庭为基础的联系方法。 尽管基于单倍型或直接关联的方法能够检测这些基因，但是， 需要比混合物作图中所需的标记多至少100倍的标记（300，000至500，000 （1500 - 3000）。目前的AA人群是一个独特的资源映射SLE 易感基因具有相似的效应量。 本提案的总体目标是使用混合物鉴定AA中的SLE易感基因。 映射方法为了实现这一目标，将实现两个具体目标：（1）进行混合 基因组扫描以寻找候选SLE易感区域，和（2）随访最有说服力的 使用基于单体型的方法进行精细基因组定位的具有高密度SNP的易感区域 并鉴定致病易感基因。我们将对至少以下样本执行混合映射 2000例SLE病例和2000例AA对照，使用最近验证的约2000例高度信息化的样本组 祖先信息标记（AIM）。使用理想的混合群体，其中LD已持续在 较长的染色体片段，对足够的AIM进行基因分型，控制假关联， 采用混合作图，然后是有针对性的高密度单体型作图策略， 该提案最大限度地提高了识别包含SLE易感性的新基因组区域的机会 基因.因此，这些基因的鉴定将有助于我们了解发展， 这一疾病的发病机制在少数人群中，并可能导致新的治疗干预。