Elucidation of the mechanism of development and progression of IgA nephropathy

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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