补体活化影响IgA肾病(IgAN)的肾损及预后。近期全基因组关联分析 (GWAS)揭示补体调节蛋白基因:H因子相关蛋白1(CFHR1)与IgAN发病易感。申请者前期研究证实CFHR1基因缺失通过影响IgA启动的补体活化参与IgAN发病。进一步预实验发现CFHR1编码区遗传变异(CFHR1*A/CFHR1*B)与IgAN的遗传关联。最近研究阐明CFHR1的补体活化去调节功能，即与补体H因子(CFH)竞争结合C3b，进而抑制CFH对补体活化的负调控，最终促进补体活化。基于CFHR1的功能发现及与IgAN的关联，申请者提出假设：CFHR1*A有较CFHR1*B蛋白更强的补体活化去调节功能，引起更显著的补体活化；携带CFHR1*A个体，在致病性IgA分子激发下，致更显著的补体活化和肾损，进而参与IgAN发病。本研究拟明确CFHR1基因编码区遗传变异参与IgAN的机制，并进一步在IgAN患者中验证。

IgA nephropathy is the most common primary glomerulonephritis. Complement activation is common in patients with IgAN and further associated with disease severity and prognosis. Our recent IgAN-GWAS identified complement factor H related protein 1 gene (CFHR1), which encoded a complement regulatory protein, to be associated with IgAN susceptibility. Our previous study indicated that genetic deletion of CFHR1 regulated pathogenic IgA1 induced complement activation, and therefore contributed to IgAN susceptibility. Furthermore, our preliminary experiment observed the genetic association between the coding variants in CFHR1 (CFHR1*A/CFHR1*B) and IgA nephropathy. Recent important discovery of CFHR1 revealed its function of complement deregulation, induced by its competition binding to C3b with complement factor H (CFH), a complement inhibitor, and at last resulted in up-regulation of complement activation. Based on the deregulation function of CFHR1, as well as its genetic association with IgAN, we proposed the following pathogenic hypothesis of IgA nephropathy: compared to CFHR1*B, CFHR1*A has stronger function of complement deregulation (induced by more competition to CFH, therefore weakened the complement inhibition function of CFH), and resulted in more powerful complement activation. Therefore, under the challenge of pathogenic IgA molecules, individuals bearing the allele of CFHR1*A would be presented with more powerful complement activation and severer kidney injury, both of which contributed to the susceptibility of IgAN.