Genetic Association in American Blacks with Lupus

美国黑人与狼疮的遗传关联

• 批准号: 7185172
• 负责人: John Barker Harley
• 金额: $ 50.17万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-30 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7185172
• 关键词: 11p13; 11q14; 1q23; 2q34; Affect; African American; American; Arthritis; Candidate Disease Gene; Chromosomes, Human, Pair 2; Collection; DNA Sequence; Data; Development; Disease; European; Exanthema; Family; Functional disorder; Genes; Genetic; Genetic Polymorphism; Immune System Diseases; Individual; Inheritance Patterns; Injury; Kidney; Link; Linkage Disequilibrium; Lupus; Lupus Nephritis; Maps; Methods; Molecular Target; Myocardial Infarction; Nephritis; Organ; Other Finding; Pericarditis; Phenotype; Pleurisy; Population; Raynaud Disease; Recommendation; Relative (related person); Resources; Rheumatology; Single Nucleotide Polymorphism; Stroke; Susceptibility Gene; Systemic Lupus Erythematosus; Therapeutic; Ulcer; Variant; Vasculitis; Woman; Work; base; case control; college; cytopenia; genetic association; genetic pedigree; human FCGR3A protein; improved; prognostic

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a serious disease among African-Americans affecting up to 1 in every 250 women, and often causing severe organ injury (nephritis, ulcers, arthritis, pericarditis, pleuritis, rashes, strokes, heart attacks, vasculitis, nervous dysfunction, cytopenias, Raynaud's disease, and immune dysfunction). Lupus is familial, but like other diseases with no obvious pattern of inheritance, the data suggest many different genes are contributing to the phenotype. Our results from AR42460 show the profound differences dominating lupus genetics of African- Americans relative to European-derived populations. Among other findings, this project has produced four established (LOD equal to or greater than approximately 3.2 or p equal to or less than 0.00002) and independently confirmed (LOD equal to or greater than approximately 1.2 or p equal to or p less than or equal too 0.01) linkages in African-American pedigrees multiplex for lupus at 1q23, 2q34, 11p13, and 11q14. Association has been found at Fc gamma RIIIA making this a strong candidate for explaining the linkage at 1q23. The most robust of these linkages is at 2q34 with strong aggregate evidence for linkage (p=0.0000006). The 2q34 linkage is found in the African-American pedigrees multiplex for lupus with renal involvement in at least one of the affecteds. We enthusiastically embrace the reviewers' recommendation to focus the available resources on a single linkage. We will concentrate on the 2q34 linkage for the competitive renewal. We will fine map to reduce the support interval for linkage and then will search for the responsible gene by linkage disequilibrium. There are 7991 dbSNPs available in the current 2q34 linkage interval from 205 mb to 227 mb on chromosome 2. We will exploit the HapMap project to choose the single nucleotide polymorphisms (SNPs) that appear to be the most informative for a search for linkage disequilibrium in cases from linked pedigrees and unrelated controls, beginning with the candidate genes in the 2q34 linkage interval. Tentative associations will be further explored by family based association methods to help eliminate false positives. Then, the surviving association(s) will be explored in a separate set of African-American isolated SLE nephritis cases and controls. Association(s) convincingly replicated will then be explored across individual genes, and their polymorphisms, using DNA sequencing and functional gene studies. We anticipate that the proposed translational work under AR42460 will culminate in the identification of a gene important in the cause of nephritis in African-Americans with lupus, as well as a more complete explanation of the pathophysiologic mechanisms, improved prognostic assessment in lupus nephritis, and the introduction of new molecular targets for therapeutic development.

描述（由申请人提供）： 系统性红斑狼疮（SLE）是非洲裔美国人中的一种严重疾病，每250名妇女中就有1名受到影响，并且经常引起严重的器官损伤（肾炎、溃疡、关节炎、心包炎、胸膜炎、皮疹、中风、心脏病发作、血管炎、神经功能障碍、血细胞减少症、雷诺氏病和免疫功能障碍）。狼疮是家族性的，但像其他疾病一样，没有明显的遗传模式，数据表明许多不同的基因都有助于表型。我们从AR42460的研究结果显示，非洲裔美国人相对于欧洲裔人群的狼疮遗传学存在显著差异。除其他调查结果外，该项目已产生四个既定的（LOD等于或大于约3.2或p等于或小于0.00002）并独立确认（LOD等于或大于约1.2或p等于或p小于或等于0.01）连锁在非洲裔美国人家系多发性狼疮在1q23，2q34，11p13，11Q14已在Fc γ RIIIA发现关联，使得其成为解释1q23处的连锁的强有力候选者。这些联系中最强的是在2q34，具有强有力的联系综合证据（p=0.0000006）。2q34连锁在非裔美国人多发性狼疮谱系中发现，至少有一名受影响者肾脏受累。我们热烈欢迎审查者关于将现有资源集中用于单一联系的建议。我们将专注于2q34链接的竞争性更新。我们将精细定位以减少连锁的支持区间，然后通过连锁不平衡来寻找责任基因。在2号染色体上从205 mb到227 mb的当前2q34连锁区间中有7991个dbSNP可用。我们将利用HapMap项目选择单核苷酸多态性（SNPs），似乎是最有用的连锁不平衡的情况下，从连锁家系和无关的控制搜索，开始在2q34连锁区间的候选基因。将通过基于家庭的关联方法进一步探索初步关联，以帮助消除假阳性。然后，将在一组单独的非裔美国人孤立的SLE肾炎病例和对照组中探索存活的相关性。然后，将使用DNA测序和功能基因研究，在单个基因及其多态性之间探索令人信服地复制的关联。我们预计，AR42460下的翻译工作将最终鉴定出一个在非裔美国人狼疮肾炎病因中起重要作用的基因，以及更完整地解释病理生理机制，改善狼疮肾炎的预后评估，并引入新的分子靶点用于治疗开发。