Genome-Wide Association Study in African-Americans with Rheumatoid Arthritis

描述(由申请人提供)： 类风湿关节炎(RA)是最常见的炎症性关节炎。其原因尚不清楚，但遗传和环境因素都有影响。新出现的数据显示，与类风湿性关节炎相关的基因变异因种族/民族而异。RA在非洲黑人中并不常见，但在非裔美国人中很常见，这表明祖先非洲人可能存在保护因素。骨质疏松症是一种常见的类风湿性关节炎并存疾病，在非裔美国人中比在欧洲血统的人中要少得多。与类风湿性关节炎相关的遗传因素及其放射学严重性已经在欧洲和亚洲血统的人中进行了广泛的研究，但由于缺乏大型数据集，因此无法在非裔美国人中进行类似的分析。通过从NIH资助的Clear(早期类风湿性关节炎非裔美国人纵向评估联合会)注册、其资助的辅助研究和其他数据收集中收集的大量数据，我们在分析非裔美国人的RA遗传学方面处于独特的地位。我们试图通过分析总共3200名非裔美国人来确定基因对非裔美国人患类风湿性关节炎的易感性或保护作用的影响。在目标1中，我们将使用Illumina Human 1M Duo珠芯片在1,600名非裔美国人(800名抗CCP+RA患者和800名对照)中进行全基因组关联研究(Gwas)。AIM 2将通过分析1600名非洲裔美国人(800名CCP+RA患者和800名对照)的约12000个单核苷酸多态(SNPs)来复制和扩展这些发现。在目标3中，我们将对与类风湿性关节炎相关的基因区域进行额外的定位。此外，我们将利用现有的RA相关表型数据对遗传数据进行探索性分析，包括3年病程的放射学严重程度，以及早期RA和对照的骨密度。我们还将使用CLEAR患者外周血单个核细胞现有的基因表达微阵列数据来确定表达数量性状基因座(EQTL)(影响基因表达的近或远遗传变异)，特别是与RA放射学严重程度相关的基因表达变异。这项建议将把临床风湿学、生物技术和统计遗传学的进展转化为新的信息，以改善诊断或预后评估，或为非裔美国人的类风湿性关节炎开发有针对性的治疗方法。公共卫生相关性：项目叙述类风湿性关节炎(RA)是一种常见的自身免疫性关节炎，涉及遗传和环境因素。我们具有得天独厚的优势，可以通过NIH赞助的Clear Region(早期类风湿关节炎非裔美国人纵向评估联盟)和其他数据收集，对非裔美国RA患者和健康对照进行首次大规模基因分析。我们还将利用这些基因数据，对非裔美国人的类风湿相关疾病，如关节放射损伤、骨质疏松症，以及开启或关闭血细胞基因表达的因素，获得新的见解。

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is the most common form of inflammatory arthritis. Its cause is unknown, but both genetic and environmental factors are involved. Emerging data show that genetic variants associated with RA differ by race/ethnicity. RA is uncommon in black Africans, but it is common among African-Americans, suggesting that there may be protective factors in ancestral Africans. Osteoporosis, a common co-morbid condition with RA, is much less common among African-Americans than among persons of European ancestry. Genetic factors associated with RA and its radiographic severity have been extensively studied in persons of European and of Asian ancestry, but the lack of large datasets has precluded similar analyses in African-Americans. We are uniquely positioned to analyze the genetics of RA in African- Americans through the extensive data collected from the NIH-funded CLEAR (Consortium for the Longitudinal Evaluation of African-Americans with Early Rheumatoid Arthritis) Registry, its funded ancillary studies, and other data collections. We seek to identify genetic influences on susceptibility to, or protection from, RA in African-Americans by analyzing a total of 3,200 African-Americans. In Aim 1, we will perform a genome-wide association study (GWAS) using the Illumina Human 1M Duo BeadChip in 1,600 African-Americans (800 with anti-CCP+ RA and 800 controls). Aim 2 will replicate and extend these findings by analyzing ~12,000 single nucleotide polymorphisms (SNPs) in an independent set of 1,600 African-Americans (800 CCP+ RA patients and 800 controls). In Aim 3, we will perform additional mapping of the genetic regions associated with RA. In addition, we will perform exploratory analyses of genetic data with existing data on RA-related phenotypes, including radiographic severity at 3 years disease duration, and bone mineral density in early RA and controls. We will also use existing gene expression microarray data from peripheral blood mononuclear cells in CLEAR patients to identify expression quantitative trait loci (eQTL) (nearby or distant genetic variants that influence gene expression), particularly those associated with radiographic severity of RA. This proposal will translate advances in clinical rheumatology, biotechnology, and statistical genetics into new information to improve diagnosis, or assessment of prognosis, or develop targeted therapies for RA in African-Americans. PUBLIC HEALTH RELEVANCE: Project Narrative Rheumatoid arthritis (RA), a common autoimmune arthritis, involves both genetic and environmental factors. We are uniquely positioned to perform the first large-scale genetic analyses of African-American RA patients and healthy controls through the NIH-sponsored CLEAR Registry (Consortium for the Longitudinal Evaluation of African-Americans with Early Rheumatoid Arthritis) and other data collections. We will also use these genetic data to gain new insights into RA-related conditions in African-Americans, such as radiographic damage of joints, osteoporosis, and factors that turn on or off expression of genes in blood cells.