IgA血管炎(IgAV)是IgA小血管壁沉积为特征性表现的系统性血管炎，累及肾脏为IgA血管炎肾损害(IgAVN)。成人IgAV肾脏受累率高，预后不良。申请者前期成人IgAVN的全基因组关联分析(GWAS)发现FCAR调控区遗传变异与IgAVN发病相关，还与肾小球毛细血管壁IgA沉积、内皮增生病变相关。FCAR编码IgA Fc受体(FcαR)，主要表达在中性粒细胞表面，被证实与IgA复合物结合并促进中性粒细胞活化并与内皮细胞粘附。因此申请者提出科学假设：FCAR调控区危险型遗传变异上调中性粒细胞FcαR表达并与致病性IgA复合物结合，致中性粒细胞活化，促内皮细胞粘附，导致IgAVN中IgA血管壁沉积和内皮细胞损伤。本研究拟探讨FCAR调控区遗传变异影响FcαR表达的机制；并检测FCAR基因型对中性粒细胞结合致病IgA复合物、损伤内皮细胞的影响，明确FCAR参与IgAVN发病的分子遗传机制。

IgA vasculitis (IgAV) is a systemic vasculitis with IgA-dominant immune deposits, affecting small vessels. IgAV patients with nephritis are called IgAVN. Adult IgAV patients have more frequent renal involvement and poor prognosis. We previously performed a genome-wide association study in adult IgAVN patients and identified FCAR as an IgAVN susceptible gene. In addition, regulatory variants in FCAR were found to be associated with the phenotype of IgA deposits on the glomerular capillary walls, as well as glomerular endothelial cells proliferation. FCAR gene encodes a receptor for the Fc region of IgA (FcαR), which is a transmembrane glycoprotein present on the surface of myeloid lineage cells, mainly neutrophils. It has been proved that multimeric IgA immune complexes trigger several activation responses in neutrophils after binding to FcaRI, including acceleration its adherence to endothelial cells. Based on these clues, we proposed the following pathogenic hypothesis for IgAVN: the regulatory risk variants in FCAR gene up-regulate the expression of FcαR on the surface of neutrophils; after binding with its ligand IgA complex, FcαR would induce the activation of neutrophils, and facilitate its adherence to endothelial cells, which results in IgA deposits on the glomerular capillary walls and glomerular endothelial cells proliferation in IgAVN. In the present research project, we plan to investigate the mechanism of variants in FCAR regarding its regulation to FcαR expression, as well as its influence to IgA small vessels deposition and endothelial cells injury in IgAVN.