强直性脊柱炎和类风湿关节炎诊疗的临床特征与其易感基因多态性的关联性研究

Ankylosing Spondylitis (AS) and Rheumatoid Arthritis (RA) are two most common inflammatory arthritis affecting nearly 10 million Chinese. Characteristic clinical features of AS are inflammatory back pain, asymmetric peripheral arthritis, enthesitis, and anterior uveitis. The condition primarily affects the spine and sacroiliac joints of the pelvis, causing pain and stiffness and eventual fusion. RA is a chronic symmetrical polyarthrtis of unexplained cause. It is a systemic disorder characterized by chronic inflammatory synovitis of mainly peripheral joints. Its course is extremely variable and it is also associated with nonarticular features. In addition to causing substantial morbidity and increased mortality, both conditions cause substantial cost to the community. However, the pathogenesis of both diseases is very poorly understood although anti-TNF drugs (e.g. adalimumab, etanercept and infliximab) produce improvements in acute inflammation in diseases, there are no treatments which have to date induced remission of AS/RA or retarded progressive joint fusion that inevitably occurs in the diseases. Thus there is an urgent need for understanding the pathogenesis in order to develop more effective therapies...Genetics research has provided important information as to the aetiopathogenesis of AS and RA. There is a strong genetic component in the risk of developing AS, with heritability assessed in twins at >97%. Approximately 5% of carriers of the main susceptibility gene (HLA-B27) develop AS, and over 95% of AS cases are B27-positive, compared with around 8% of healthy Chinese. Similarly, the heritability of RA estimated from twin studies, is 53-65%, and the contribution from the MHC is estimated at 30% of the total genetic effect. However, the past studies did not carefully compare the disease characters with genetic polymorphism although we have already known the severity of disease is also largely genetically determined, with heritability of disease activity, functional impairment and radiographic disease extent of 51%, 76%, and 62% respectively in AS. The current proposal is aiming to address such important issue. The significance of this approach is not only to identify genes (genotypes) which are determining the development of diseases, but also find out their relevant to the clinical characters (phenotypes). Successful identification of such a relationship between genotypes and phenotypes would have a major impact, informing drug development, increasing our understanding of the diseases, potentially leading to improved diagnostic tests or tests capable of predicting future disease severity.

强直性脊柱炎（ AS）和类风湿性关节炎（RA）是两种最常见的炎症性关节炎。AS主要侵犯中轴骨，以骶髂关节炎和附着点炎为特征；而RA主要侵犯外周关节，以关节的滑膜炎为特征。这两种疾病在我国发病率高、致残率高、治疗费用高。因此，其发病机制的剖析以期提高诊断率和寻求有效治疗是亟待解决的重大课题。目前的研究表明，这两种疾病的致病机制与遗传因素有关，现已发现了AS和RA发病的多个易感基因。但国内外相关研究的不足之处是未将所发现的易感基因多态性与AS和RA的疾病特征相结合，即未进行基因型和表型的关联研究。而通过对易感基因与临床资料的关联分析，可以发现基因型和临床表现型间的相互关系，此将为AS和RA的诊治开拓新的前景，为新药物的研制提供有有效的临床信息。所产生的结果亦将对AS和RA的预警、诊断、治疗、个体化用药及新药研发具有十分重大的实践意义。

一、RA相关工作：1）项目组完成了汉族RA的全基因组关联研究，共发现4个新的RA致病位点，相关结果发表在Arthritis & Rheumatology.2014;66:1121-32；2）项目组参与完成迄今为止样本量最大的国际跨人种RA的遗传学研究，并用生物信息学方法鉴定出已有药物的27个基因靶点以及80个免疫相关的潜在治疗靶点，为RA今后的治疗提供了大量潜在药物。相关结果合作发表在Nature 2014;506:376-81.(38.597)；3）项目组对200例抗CCP抗体阳性的RA患者及208例健康对照进行靶向测序，挑选出PTPN22及其所在信号通路与相关基因共83个基因的外显子区域，我们坚定出5个SNP位点及CDHR5等四个基因上的10个罕见变异位点，为RA遗传易感性的种族间差异以及致病机制研究做出重要补充。二、AS相关工作：1）AS-GWAS的研究：采用Omni-Zhonghua芯片技术对2000 例AS病例和3104例健康正常对照的900,015个SNP位点进行了全基因组基因分型基础上，另外显子区域位点的CoreExome芯片技术，6000例中国AS患者和3975例健康对照的547,644个遗传变异进行基因分型，目前已完成了所有对照标本和部分病例标本的基因分型和数据分析。1）在国际上率先在汉族人中发现对强直性脊柱炎有保护作用的IL-23R基因的罕见变异体，再次证实了IL-23R在AS发病机制中所起的关键作用，IL-23R成为治疗强直性脊柱炎的潜在靶点。相关结果发表在Arthritis Rheum. 2013; 65: 1747-52。3).探讨调节性T细胞在AS中发病机制：已完成Foxp3+ T细胞亚群的表型及基因型及功能测定，并评估其与AS临床指标、疾病活动度的相关性；相关结果发表在Immunology and Cell Biology. 2016;94:293-305。4).AS基因型及表型的相关性研究：已开展一项比较英夫利西单抗和传统疗法治疗 16-40 岁(包含)髋关节受累 AS 受试者的疗效的多中心、观察性、前瞻性研究。已入组69例髋关节受累的患者，其中4例患者已完成随访。5）AS宏基因组研究：完成了116例AS患者及85例健康对照的外周血、血清、尿液及粪便标本的收集，并进行宏基因组测序，共鉴定出68种肠道细菌及53种细菌信号通路与AS相关。

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