Elucidation of the mechanism of development and progression of IgA nephropathy

免疫球蛋白A肾病(IgAN)是原发性肾小球肾炎最常见的类型之一，是终末期肾功能衰竭的主要病程。该病的临床病程多种多样，三分之一的IgAN患者在发病后10-20年内进展为终末期肾病(ESRD)。尽管越来越多的证据表明遗传因素决定了IgA肾病的易感性和肾功能障碍的进展，但系膜IgA沉积的发病机制和疾病进展速度的个体差异机制仍不清楚。在这项研究中，我们调查了与IgA肾病的发生发展有关的遗传背景，并调查了多聚型免疫球蛋白受体(PLGR)、Fcα受体(FcαR)和去唾液酸糖蛋白受体(AGPR)等IgA受体基因多态性与IgA肾病发生发展的可能关联。我们已经报告了…(2)FcαR基因启动子和5‘端非编码区基因多态性与IgAN的发病风险无关。为了阐明疾病进展的机制，采用多因素COX比例风险回归模型分析了肾素-血管紧张素系统基因、sA、α-内收蛋白、转化生长因子-β-1、单核细胞趋化蛋白-1等基因多态性在终末期肾病发病中的意义。我们已报道血管紧张素原基因A-20C多态的C等位基因是ESRD的独立危险因素。我们还发现子宫红蛋白基因多态性与伴有高血压和大量蛋白尿的IgAN患者的疾病进展有关。我们已经开始利用全基因组的连锁和关联分析，结合微卫星标记和单核苷酸多态性来探索致病基因。较少

Immunoglobulin A nephropathy (IgAN), one of the most prevalent forms of primary glomerulonephritis, is the major course of end-stage renal failure. The disease has a variable clinical course and one third of the patients with IgAN progress to end stage renal disease (ESRD) within 10-20 years of the onset. The pathogenesis of mesangial IgA deposition and the mechanism of inter-individual differences in the rate of disease progression are still unclear, although an accumulating amount of evidence suggests that genetic factors determine the susceptibility to developing IgAN as well as to the progression of renal dysfunction. In this study, we have investigated genetic backgrounds, which are implicated in the development and progression of IgA nephropathy.We surveyed possible associations between the development of IgAN and genetic polymorphisms of IgA receptors, such as polymeric immunoglobulin receptor (plgR), Fcα receptor (FcαR), and asialoglycoprotein receptor (AGPR). We have reported … More that (1) the genotype distribution of plgR was significantly different between the patients with IgAN and those without IgAN and that (2) the genetic polymorphisms in the promoter and 5' UTR region of FcαR were not associated with a risk of IgAN.In order to clarify mechanisms of the disease progression, significances of genetic polymorphisms, including those of renin-angiotensin system, Sa, α-adducin, TGF-β1 , MCP-1, and etc, in progression to ESRD were analyzed in patients with biopsy proven IgAN by using multivariate Cox proportional hazard regression model. We have reported that a C allele of A-20C polymorphism in Angiotensinogen gene was an independent risk factor for ESRD. We have also found that uteroglobin gene polymorphism had an implication for the disease progression in IgAN patients with hypertension and heavy proteinuria.We have started a further investigation to explore the disease-causing gene by using genome-wide linkage and association analysis with microsattelite markers and single nucleotide polymorphisms. Less