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

描述（由申请人提供）： 风湿性关节炎（RA）是最常见的炎性关节炎。其原因尚不清楚，但涉及遗传和环境因素。新出现的数据显示，与RA相关的遗传变异因种族/民族而异。类风湿性关节炎在非洲黑人中并不常见，但在非洲裔美国人中很常见，这表明祖先非洲人可能存在保护因素。骨质疏松症是类风湿关节炎的常见并发症，在非洲裔美国人中比欧洲血统的人中要少见得多。与类风湿性关节炎及其放射学严重程度相关的遗传因素已在欧洲和亚洲血统的人中进行了广泛研究，但缺乏大型数据集，无法在非洲裔美国人中进行类似的分析。我们具有独特的优势，可以通过从NIH资助的CLEAR（非洲裔美国人早期风湿性关节炎纵向评估联盟）登记处收集的广泛数据，及其资助的辅助研究和其他数据收集来分析非洲裔美国人的RA遗传学。我们试图通过分析总共3,200名非洲裔美国人来确定遗传因素对非洲裔美国人对RA的易感性或保护作用。在目标1中，我们将使用Illumina Human 1 M Duo BeadChip在1，600名非洲裔美国人（800名抗CCP + RA和800名对照）中进行全基因组关联研究（GWAS）。目标2将通过分析1,600名非洲裔美国人（800名CCP+ RA患者和800名对照）的约12，000个单核苷酸多态性（SNP）来复制和扩展这些发现。在目标3中，我们将对与RA相关的遗传区域进行额外的定位。此外，我们将对遗传数据和RA相关表型的现有数据进行探索性分析，包括3年病程时的影像学严重程度，以及早期RA和对照组的骨密度。我们还将使用CLEAR患者外周血单核细胞的现有基因表达微阵列数据来鉴定表达数量性状位点（eQTL）（影响基因表达的近源或远源遗传变异），特别是与RA放射学严重程度相关的基因。该提案将把临床流变学、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，或开发针对非裔美国人RA的靶向治疗。

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.