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

描述（由申请人提供）：类风湿关节炎（RA）是一种以关节慢性炎症为特征的系统性自身免疫性疾病，可导致软骨和骨的结构性损伤。核因子B配体受体激活因子（RANKL）已被证明在炎症性关节疾病中起关键作用。RANKL在骨破坏和免疫应答中的功能使其成为未来RA治疗的重要靶点。我们的初步数据显示，在类风湿因子阳性（RF+）的高加索RA患者中，RANKL基因多态性与发病年龄较年轻相关。这种关联在RF+非洲裔RA患者中得到证实。RF+非洲裔美国患者携带2拷贝RANKL风险单倍型的比例在第3个10年发生RA的患者中最高（33%），在第4个10年（20%）、第5个10年（6%）、第6个10年（9%）和后来10年（0%）发生RA的患者中呈下降趋势（与年龄相关的下降趋势p = 0.004）。在抗ccp +非裔美国患者（p = 0.0006）和RF+高加索患者（p = 0.03）中，RA发病年龄比例的下降趋势也很明显。RANKL风险单倍型在正常高加索对照（10%）、RF+高加索RA患者（17%）和RF+多关节幼年特发性关节炎（JIA）高加索患者（26%）中呈显著增加趋势（p = 0.002）。我们的研究结果显示，在两个不同的种族群体中，新型RANKL多态性与RA发病年龄较早有显著关联。这些结果也提示早发性RA患者和晚发性RA患者之间存在遗传差异。我们建议：1)对RANKL基因进行精细定位，以确定与白种人和非裔美国RF+ RA患者发病年龄较年轻相关的单倍型块边界；2)评估RA相关单倍型块内潜在的功能多态性，以定位RANKL致病变异。这项研究的结果可能确定早期RA风险最高的生物标志物，并可能为导致RA早期发展的分子机制提供新的见解，这可能对未来的治疗干预具有指导意义。本研究旨在确定遗传多态性并了解类风湿关节炎（RA）早期易感性的潜在分子机制。这项研究的结果可能为识别年轻时RA高风险个体提供信息，这可能允许早期治疗干预以预防骨侵蚀。对RA发病机制的分子机制的了解可能会导致新的靶向药物的开发。

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.