Elucidation of the mechanism of development and progression of IgA nephropathy

阐明IgA肾病发生、发展的机制

• 批准号: 11671032
• 负责人: NARITA Ichiei
• 金额: $ 2.37万
• 依托单位: NIIGATA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11671032/
• 关键词: IgA nephropathy; Genetic polymorphism; Hypertension; Angiotensinogen; Fcα receptor; Polymeric immunoglobulin receptor; Uteroglobin; α-adducin; Polymeric immunoglobulin receptor; Fcα receptor; Uteroglobin; α-Adducin; アンジオテンシンノーゲン; IFN-γ; gene

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

免疫球蛋白A肾病（IgAN）是原发性肾小球肾炎最常见的形式之一，是终末期肾衰竭的主要过程。该疾病具有可变的临床病程，并且三分之一的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IgAN的易感性以及肾功能不全的进展，但肾小球系膜伊加沉积的发病机制和疾病进展速率的个体间差异机制仍不清楚。本研究旨在探讨IgA肾病发生发展的遗传背景，以及伊加受体（如多聚免疫球蛋白受体（plgR）、Fcα受体（FcαR）和去唾液酸糖蛋白受体（AGPR））的遗传多态性与IgA肾病发生发展的可能关系。我们已经报道 ...更多信息 （2）FcαR基因启动子区和5' UTR区基因多态性与IgAN的发病风险无关。为了阐明IgAN的发病机制，本文分析了血浆中肾素-血管紧张素系统、Sa、α-内收蛋白、TGF-β1、应用多因素考克斯比例风险回归模型分析MCP-1等在IgAN患者进展为ESRD中的作用。血管紧张素原基因A-20 C多态性C等位基因是终末期肾病的独立危险因素。我们还发现子宫珠蛋白基因多态性与高血压和重蛋白尿的IgAN患者的疾病进展有关，我们已开始进一步研究，通过微卫星标记和单核苷酸多态性的全基因组连锁和关联分析来探索致病基因。少

项目成果

Ichiei Narita: "Association of gene polymorphism of polymeric immunoglobulin receptor and IgA nephropathy"Internal Medicine. Vol 40. 867-872 (2001)

成田一荣：《聚合免疫球蛋白受体基因多态性与IgA肾病的关联》内科。

Ichiei Narita et al.: "Genetic polymorphism in angiotensinogen promotor region affects progression of IgA nephropathy"Nephrology. 6(in press). (2001)

Ichiei Narita 等人：“血管紧张素原启动子区的基因多态性影响 IgA 肾病的进展”肾脏病学。

Minoru Skatsume,et al.: "Down-regulation of IFNg-signaling by gene transfer of Stat1-mutant in mesangial cells"Kidney International. 57. 455-463 (2000)

Minoru Skatsume 等人：“系膜细胞中 Stat1 突变体的基因转移下调 IFNg 信号转导”肾脏国际。

Ichiei Narita,et al.: "Gene polymorphism of polymeric immunoglobulin receptor (plgR), TGFbeta-1, MCP-1 and RAA system in patients with IgA nephropathy"Nephrology. (in press). (2000)

Ichiei Narita 等：“IgA 肾病患者的聚合免疫球蛋白受体 (plgR)、TGFbeta-1、MCP-1 和 RAA 系统的基因多态性”肾病学。

Narita Ichiei et al.: "Role of uteroglobin G38A polymorphism in the progression of IgA nephropathy in Japanese patients"Kidney International. 61. 1853-1858 (2002)

Narita Ichiei 等人：“子宫珠蛋白 G38A 多态性在日本患者 IgA 肾病进展中的作用”肾脏国际。