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

患有类风湿性关节炎的非洲裔美国人的全基因组关联研究

基本信息

批准号：
7649598
负责人：
S Louis Bridges
金额：
$ 85.58万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-25 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7649598
关键词：
Admixture Affect African African American Alleles American Ancillary Study Asians Biological Biotechnology Blood Cells Bone Density Chromosome Mapping Chromosomes Clinical Complex Copy Number Polymorphism Custom DNA Data Data Collection Data Set Development Diagnosis Distant Environmental Risk Factor Epitopes Ethnic Origin European Evaluation Functional disorder Funding Gene Expression Genes Genetic Genotype Goals HLA-DRB1 Haplotypes Human Linkage Disequilibrium Minority Groups Osteoporosis PTPN22 gene Patients Pattern Peptide antibodies Peripheral Blood Mononuclear Cell Persons Phenotype Population Positioning Attribute Predisposition Prevention strategy Quantitative Trait Loci Race Registries Rheumatoid Arthritis Rheumatology STAT4 gene Sampling Severities Single Nucleotide Polymorphism Structure Testing Translating Treatment Cost arthritis registry autoimmune arthritis base cyclic citrullinated peptide disability genetic analysis genetic association genetic variant genome wide association study human disease illness length improved insight joint injury novel novel therapeutics outcome forecast public health relevance

项目摘要

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.

描述（由申请人提供）：类风湿关节炎（RA）是炎症性关节炎的最常见形式。它的原因尚不清楚，但涉及遗传因素和环境因素。新兴数据表明，与RA相关的遗传变异因种族/种族而不同。 RA在黑人非洲人中并不常见，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。骨质疏松症是与RA的常见合并症，在非裔美国人中的普遍性要比欧洲血统的人少得多。与RA相关的遗传因素及其放射学严重程度已在欧洲和亚洲血统的人中进行了广泛的研究，但是缺乏大型数据集已排除了非裔美国人的类似分析。通过从NIH资助的Clear（对非裔美国人的纵向评估具有早期类风湿关节炎的纵向评估联盟）收集的广泛数据，我们的资助术语研究和其他数据收集。我们试图通过分析总共3200名非裔美国人来确定对非裔美国人对RA的易感性或保护RA的易感性的影响。在AIM 1中，我们将使用1,600名非裔美国人（800种抗CCP+ RA和800个对照组）中使用Illumina Human Duo Beadchip进行全基因组关联研究（GWAS）。 AIM 2将通过分析约12,000个独立的1,600名非裔美国人（800 CCP+ RA患者和800个对照组）的独立组中的约12,000个单核苷酸多态性（SNP）来复制和扩展这些发现。在AIM 3中，我们将对与RA相关的遗传区域进行其他映射。此外，我们还将对遗传数据进行探索性分析，并使用有关RA相关表型的现有数据，包括3年疾病持续时间的射线照相严重程度，以及早期RA和对照组中的骨矿物质密度。我们还将使用清晰患者的外周血单核细胞中现有的基因表达微阵列数据来鉴定表达定量性状基因座（EQTL）（EQTL）（附近或远距离遗传变异，会影响基因表达），尤其是与RA的射线照相严重程度相关的表达性状。该建议将把临床风湿病，生物技术和统计遗传学的进步转化为新信息，以改善诊断或评估预后，或开发针对非裔美国人RA的目标疗法。公共卫生相关性：一种常见的自身免疫性关节炎的项目叙事类风湿关节炎（RA）涉及遗传和环境因素。我们在非洲裔美国人RA患者和健康对照中进行首次大规模的遗传分析，并通过NIH赞助的清晰注册中心（用于对非洲裔美国人患有早期类风湿关节炎的纵向评估）和其他数据收集。我们还将使用这些遗传数据来获得对非裔美国人与RA相关条件的新见解，例如关节的射线照相损害，骨质疏松症以及打开或关闭血细胞基因表达的因素。