Fine Mapping and Functional Analysis of RANKL Variants in Early RA Onset

RA 早期发病时 RANKL 变异的精细定位和功能分析

基本信息

批准号：
7295106
负责人：
BETTY P TSAO
金额：
$ 19.87万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7295106
关键词：
Adult Affect African American Age Alleles Alternative Splicing Autoimmune Diseases Biological Markers Bone and Cartilage Funding Caucasians Caucasoid Race Chronic Chronic Childhood Arthritis Cohort Studies Complement Factor B DNA Data Development Ethnic group Family Future Gene Expression Genes Genetic Genetic Polymorphism Genotype Glass Haplotypes Immune response Individual Inflammation Inflammatory Joints Lead Letters Ligands Localized Maps Molecular Nuclear Onset of illness Parents Pathogenesis Patients Personal Satisfaction Pharmaceutical Preparations Phenotype Play Proteins Registries Resources Rheumatoid Arthritis Rheumatoid Factor Risk Role Sample Size Sampling TNFSF11 gene Testing Therapeutic Intervention Variant age related arthritis therapy arthropathies base bone cohort early onset genetic risk factor insight mRNA Stability novel prevent receptor trend

项目摘要

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of the joints, which may lead to structural damage of the cartilage and bone. The receptor activator of nuclear factor B ligand (RANKL) has been shown to play a pivotal role in inflammatory joint diseases. Its functions in bone destruction and immune responses make RANKL an important target for future RA therapies. Our preliminary data showed that RANKL genetic polymorphisms were associated with younger age of the disease onset in rheumatoid factor positive (RF+) Caucasian RA patients. This association was confirmed in RF+ African-American RA patients. The proportion of RF+ African-American patients carrying 2 copies of the RANKL risk haplotype was highest (33%) in those who developed RA during the third decade, with a declining trend among those who developed RA during their fourth (20%), fifth (6%), sixth (9%), and later (0%) decades (p = 0.004 for the age-related declining trend). This declining trend of proportion in age of RA onset was also evident in anti-CCP+ African- American patients (p = 0.0006) and RF+ Caucasian patients (p = 0.03). A significantly increasing trend of the RANKL risk haplotype was observed in normal Caucasian controls (10%), RF+ Caucasian RA patients (17%), and RF+ polyarticular juvenile idiopathic arthritis (JIA) Caucasian patients (26%) (p = 0.002). Our results showed significant association of novel RANKL polymorphisms with an earlier age at RA onset in two distinct ethnic groups. These results also suggested genetic differences between patients with early-onset and those with late-onset RA. We propose to 1) fine-map the RANKL gene to identify boundaries of haplotype block(s) associated with younger age of RA onset in both Caucasian and African-American RF+ RA patients, 2) assess potential functional polymorphisms within RA-associated haplotype block(s) to localize RANKL causal variant(s). Results from this study may identify biomarkers for who is at greatest risk for early RA and may shed new insights of molecular mechanisms leading to early development of RA, which may have implications for therapeutic interventions in the future. This study aims to identify genetic polymorphisms and to understand potential molecular mechanisms that predispose to early development of rheumatoid arthritis (RA). Results from this study are likely to provide information on the identification of individuals at high risk for RA at young ages, which may allow early therapeutic interventions to prevent bone erosions. The understanding of molecular mechanisms for the pathogenesis of RA may lead to the development of novel targeted medications.

描述（由申请人提供）：类风湿关节炎（RA）是一种全身性自身免疫性疾病，其特征是关节的慢性炎症，这可能导致软骨和骨骼的结构损害。核因子B配体（RANKL）的受体活化剂已显示在炎症关节疾病中起关键作用。它在骨骼破坏和免疫反应中的功能使RANKL成为未来RA疗法的重要目标。我们的初步数据表明，RANKL遗传多态性与类风湿因子阳性（RF+）高加索RA患者的疾病发作年龄相关。 RF+非裔美国人RA患者证实了这种关联。在第三个十年中发生RA的RF+非裔美国人的RF+非裔美国人患者的比例最高（33％），在第三个十年中发生RA的患者，在第四次（20％），第五（6％），第五（6％），第六（9％）和十年（0％）和十年后（p = 0.004的年龄段）中，RA的趋势下降了。在反CCP+非裔美国人患者（P = 0.0006）和RF+高加索患者（P = 0.03）中，RA发作年龄比例的下降也很明显。在正常的高加索对照组（10％），RF+高加索RA患者（17％）和RF+多关节少年特发性关节炎（JIA）高加索患者（JIA）高加索患者（26％）（26％）（P = 0.002）中，观察到RANKL风险单倍型的趋势显着增加。我们的结果表明，新型RANKL多态性的显着关联与两个不同种族的RA发作年龄较早。这些结果还表明，早发患者与患有晚期发作的患者之间的遗传差异。我们建议1）对RANKL基因进行细微地图，以鉴定高加索和非裔美国人RF+ RA患者在与RA的年龄较小相关的单倍型块的边界，2）评估RA相关的单倍型块中潜在的功能性多态性的潜在功能性多态性，以将RANKL Causal Causal Causal Causal Variant（s）进行定位。这项研究的结果可能会确定生物标志物的生物标志物，谁对早期RA有最大的风险，并可能对导致RA的早期发展的分子机制进行新的见解，这可能对未来的治疗干预产生影响。这项研究旨在鉴定遗传多态性，并了解易于早期发展类风湿关节炎（RA）的潜在分子机制。这项研究的结果可能会提供有关年轻年龄段RA高风险的个体鉴定的信息，这可能会允许早期的治疗干预措施预防骨骼侵蚀。对RA发病机理的分子机制的理解可能导致新的靶向药物的发展。