系统性红斑狼疮中国人群特异性遗传标记物TACI的验证和功能研究

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by abnormal regulation of immune cells. Existing therapies could not further reduce disease mortality and improve quality of life for SLE patients. Population differences for SLE have been well-documented. Disease onset for SLE patients in China is much earlier than patients of European origin, and patients in China show much severer clinical manifestations. However, the diagnostic criteria for SLE and drugs intended for the disease are mainly based on studies in European population. Through comparing the difference between GWAS datasets derived from both Asian and European ancestries (9,212 cases and 18,186 controls), we identified a novel SLE susceptibility locus. Interesting, the novel locus is associated with SLE particularly in Asian populations but not in Europeans. We identified a putative causal variant in the region using fine-mapping algorithm, which is a nonsynonymous mutation in the gene TNFRSF13B. The gene TNFRSF13B encodes transmembrane activator and CAML interactor (TACI), which is a membrane receptor expressed in B lymphocytes. Following Bioinformatic analyses suggest that the putative causal variant may affect binding affinities between TACI and cytokines (BAFF and APRIL) and immune globulin level, probably due to the coding change induced by the variant. In this study, we are planning to examine the hypotheses through 1) confirming the association between TACI and SLE in Chinese population; 2) performing functional assays to examine whether/how the variant affects TACI in expression and protein level, and whether/how it affects binding affinities between TACI and cytokines; 3) investigating the role of variant in the downstream changes of immune globulin level. This study would help understand the Chinese-specific disease mechanism and provide new insight to modify the diagnostic criteria for SLE in China and develop more efficient drug for SLE patient in China.

系统性红斑狼疮 (SLE)是一种典型的自身免疫性病，涉及多种免疫细胞的异常调控。现有疗法难以降低患者的死亡率和提高患者的生活质量。和欧洲人群相比，我国SLE患者发病年龄更早，临床表现更严重。然而现有的诊断标准和药物多是基于欧洲人群的研究。前期研究通过比较SLE大规模全基因组关联数据在东亚和欧洲人群的不同（9212患者和18186对照），发现了一个东亚人群特异的SLE相关位点，位于B细胞的重要受体蛋白TACI。生物信息学分析表明，该致病突变体可能改变TACI的氨基酸编码，调节其对细胞因子的亲和力，导致下游免疫球蛋白的异常调控。本课题将对该假设进行系统验证：1）验证TACI在中国人群与SLE的特异相关性；2）探索潜在致病突变体对TACI在基因和蛋白水平的调控，及其对细胞因子亲和力的影响；3）研究致病突变体对下游免疫球蛋白代谢水平的影响。本课题将为建立我国特异的SLE诊断标准及药物开发提供线索。

系统性红斑狼疮(Systemic Lupus Erythematosus, SLE)是一类经典的自身免疫性疾病，该疾病可累及心脏、脑、肾、关节、皮肤以及中枢神经系统等全身多个重要器官，且好发于年轻女性。和欧洲人群相比，我国的SLE患者发病年龄更早，临床表现更严重。SLE在临床表现上的人群异质性，预示着在亚洲人群中可能存在不同于欧洲人群的致病机制。然后现有的SLE诊断和药物开发多是基于欧洲人群的研究。因此，挖掘这一现象背后的分子机制，有助于制订和开发更适合我国SLE患者的诊疗方法。基于先前的研究，我们发现了一个潜在的我国人群中相较欧洲人群特有的SLE遗传标记物rs34562254，位于TNFRSF13B基因座上。本课题验证了该位点为中国人群中特有的SLE相关位点。通过对公共数据库的生物信息学挖掘，细胞模型实验和定量分析SLE病人的抗体水平，我们发现遗传位点rs34562254可通过调控TNFRSF13B基因表达，激活B细胞的I型干扰素通路，并促使抗体过量表达，从而导致疾病发生。基因TNFRSF13B编码蛋白TACI，是B细胞表面的重要受体。这一发现或可为靶向TACI的药物治疗SLE患者提供遗传学论证，并为该类药物将来的精准使用提供生物标记物。此外，我们系统地比较了132个已知的SLE相关位点在中国和欧洲GWAS队列中的异同，找到了包括TNFRSF13B基因座在内的9个人群不同的SLE相关位点。基因富集分析显示这些人群不同的SLE易感基因富集在和抗体水平调控相关的通路上。结合分子进化特征分析，结果表明这些群体差异的相关位点可能是基因与不同环境相互作用的结果。最后，我们构建一个基于中国人群的SLE遗传风险多基因预测模型（Polygenic Risk Score, PRS），该模型将来或可辅助SLE的诊断和早期筛查。课题负责人在课题开展期间合计发表SCI论文7篇，包括4篇第一（含共同）作者论文（其中2篇论文发表在影响因子大于10的学术期刊上）。