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

描述（由申请人提供）：风湿性关节炎（RA）是一种全身性自身免疫性疾病，其特征为关节慢性炎症，可导致软骨和骨的结构损伤。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发挥关键作用。其在骨破坏和免疫反应中的功能使RANKL成为未来RA治疗的重要靶点。我们的初步数据显示，RANKL基因多态性与类风湿因子阳性（RF+）白人RA患者的发病年龄相关。这种关联在RF+非洲裔美国人RA患者中得到证实。携带2个RANKL风险单倍型拷贝的RF+非洲裔美国患者的比例在30年内发生RA的患者中最高（33%），在40年（20%）、50年（6%）、60年（9%）和以后（0%）发生RA的患者中呈下降趋势（年龄相关下降趋势p = 0.004）。在抗CCP+非洲裔美国人患者（p = 0.0006）和RF+高加索人患者（p = 0.03）中，RA发病年龄比例的下降趋势也很明显。在正常白人对照（10%）、RF+白人RA患者（17%）和RF+多关节幼年特发性关节炎（JIA）白人患者（26%）中观察到RANKL风险单倍型显著增加的趋势（p = 0.002）。我们的研究结果表明，在两个不同的种族群体中，新的RANKL多态性与RA发病的早期年龄显著相关。这些结果还表明早发性和晚发性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，以确定白人和非裔美国人RF+ RA患者中与较年轻RA发病年龄相关的单倍型块的边界，2）评估RA相关单倍型块内的潜在功能多态性，以定位RANKL因果变异体。这项研究的结果可能会确定早期RA风险最大的生物标志物，并可能揭示导致RA早期发展的分子机制的新见解，这可能对未来的治疗干预措施产生影响。本研究的目的是确定遗传多态性，并了解潜在的分子机制，易患类风湿关节炎（RA）的早期发展。这项研究的结果可能会提供信息，在年轻的时候，这可能会允许早期治疗干预，以防止骨侵蚀的RA的高风险的个人识别。对RA发病机制的分子机制的理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.