强直性脊柱炎不同临床表型的遗传基因差异研究

Ankylosing Spondylitis (AS) is one of the most common inflammatory arthritis and also one of incurable diseases. In addition to its high prevalence and increased disability, this condition causes substantial cost to the community. However, the pathogenesis of AS is poorly understood. To date genetics research has provided important information as to the aetiopathogenesis of AS and its medical imaging diversification, while MRI findings of sacroiliac joints play a vital role in the diagnosis and treatment of AS. Previous studies are limited by either sample size of AS population, especially a large AS population of sacroiliac joints’ MRI imaging, or genetic research methods not covering the rare variants with minor allele frequency less than 1%. Therefore, association study of genetic determining medical imaging severity of AS is extremely urgent to be conducted. The current proposal is aiming to address the details in AS immunogenetics by whole exome sequencing and to find out how genetics determines the medical imaging severity of AS. The significance of this project is not only to identify variants which are associated with the development of diseases, but also will have a major impact to clinical practice, such as informing drug development, improving early diagnosis, prognosis and treatment.

强直性脊柱炎（Ankylosing Spondylitis, AS）是一种致病机理不明的疑难杂症之一，AS发病率、致残率高、治疗费用高，造成这“三高”的根本原因在于致病机制不清。目前认为遗传基因的变异是决定AS影像学进展的重要因素，而骶髂关节炎的MRI影像学发现对于AS的诊断和治疗至关重要。已有的研究受限于AS研究人群样本量，尤其是难于获得较大样本AS人群的骶髂关节MRI影像学表型，以及采用的基因研究手段未覆盖频率低于1%的疾病相关的罕见变异，因此，AS遗传变异决定不同临床表型的相关性研究迫在眉睫。本项目拟在中国汉族人群中，利用全外显子组测序技术进一步研究和挖掘中国汉族人群AS患者的精细遗传背景及罕见遗传变异，阐明遗传背景与疾病临床表型尤其是影像学进展的相关性，从而完成对AS从遗传学到临床表型研究的衔接，为AS的精准医疗提供新的线索和指导。

强直性脊柱炎是一种致病机理不明的疑难杂症之一，AS发病率、致残率高、治疗费用高，造成这“三高”的根本原因在于致病机制不清。我们在前期工作的基础上，在中国汉族AS人群中进行全外显子组测序，发现中国汉族AS疾病的易感基因，并在中国汉族人群中进行验证；同时总结中国汉族AS的患病特点，对AS患者骶髂关节MRI进行分级，结合临床表型如钙卫蛋白、骨密度等数据，并将临床表型包括影像学表型与易感基因进行关联分析。我们发现，人类白细胞抗原基因（定义为位于6号染色体上27-34Mb内的SNP）显示出与疾病的最强关联（p=10^-16）。同时也发现了在HLA之外的60个最重要的关联基因。HLA区域以外最重要的发现是位于PPP1R12B基因外显子区域1号染色体上的exm2277017。第二个重要发现是位于USP8基因15号染色体上的exm1161045，编码泛素羧基末端水解酶8，在AS中具有很强的保护作用。在对AS患者骶髂关节MRI资料与临床数据、基因检测结果分析中，我们发现骶髂关节SPACC评分和性别、HLA-B27呈正相关，而与CRP、ESR、BASFI及BASDAI呈显示负相关。相比较其他参数而言，骶髂关节SPACC评分与HLA-B27、BASFI及BASDAI相关性较强，同时与基因数据结合分析未发现与SPACC评分显著相关的基因位点。一方面可能是标本数量受限导致遗传统计效力不足，另一方面也说明骶髂关节MRI炎症受累表型相比较其他AS临床表现如虹膜睫状体炎、炎症性肠病等，不存在显著的易感基因型，但不排除低频率罕见或新型的遗传变异。本项目进一步研究和挖掘中国汉族人群AS患者的精细遗传背景，阐明遗传背景与疾病临床表型尤其是影像学进展的相关性，从而完成对AS从遗传学到临床表型研究的衔接，为AS的精准医疗提供新的线索和指导。