IgA肾病（IgAN）机制不明。最近发现糖化缺陷IgA1（Gd-IgA1）和补体旁路途径异常活化与IgAN密切相关，同时一项全基因组关联分析将IgAN易感基因定位于1q31补体调节区域（RCA）。为探索这两项重要机制的遗传学基础，本课题组已应用QTL连锁分析成功将Gd-IgA1的易感基因定位在5个独立区段，并采用MLPA和Taqman探针方法建立RCA拷贝数变异（CNV）的检测方法。课题组拟采用外显子组测序，对上述易感区段进行精细定位，并在其他高Gd-IgA1家系及散发患者中验证候选基因。同时，拟对大组IgAN患者和正常人进行RCA区域CNV检测，通过关联分析明确候选基因CNV与IgAN之间的相关性，通过对患者血、尿、肾组织补体相关因子的检测阐明其生物学功能。识别出的致病基因通过基因敲除小鼠以及细胞模型验证其功能。本研究对揭示IgAN遗传机制有重要意义。

The pathogenesis of IgAN is incompletely understood yet. Recently it has been found that the disease is correlated with Galactose-Deficient IgA1 and aberrant activation of alternative pathway of complement system. A recent extended whole genome wide association study identified one susceptible locus at 1q31 region which cover the regulator complement activation region (RCA). We have successfully identified 5 independent susceptible loci of Gd-IgA1 and established the methods for testing copy number variation (CNV) of RCA by MLPA and Taqman methods. To carry out fine mapping, we plan to perform exome sequencing to identify candidate genes. Replication study will be conducted in new recruited families as well as sporadic IgAN patients with high Gd-IgA1 levels. We are further about to test the CNV of RCA region in both IgAN patients and healthy controls from an extended cohort, analyze the correlation between RCA CNV and IgAN via association analysis approach and study the biological function of CNV in RCA region through blood, urine and renal tissue complement component testing. The function of candidate variations will be further confirmed by cell model or knock-out mice model. Our study is very important to clarify genetic mechanism of IgAN.