Abstract
BackgroundIgA nephropathy (IgAN) is a complex syndrome characterized by deposition of IgA and IgA containing immune complexes (ICs) composed of IgG and complement C3 proteins in the mesangial area of glomeruli. The low-affinity receptors for the Fc region of IgG (FcγRs) are involved in autoantibody/immune complex-induced organ injury as well as ICs clearance. The aim of the study was to associate multiple polymorphisms within FCGR gene locus with IgAN in a large Chinese cohort.Patients and Methods60 single nucleotide polymorphisms (SNPs) spanning a 400 kb range within FCGR gene locus were analyzed in 2100 DNA samples from patients with biopsy proven IgAN and healthy age- and sex-matched controls from the same population in Chinese.ResultsAmong the 60 SNPs investigated, 15 gene polymorphisms within FCGR gene locus (25%) were associated with susceptibility to IgAN. The most significantly associated SNPs within individual genes were FCGR2B rs12118043 (p = 8.74*10−3, OR 0.76, 95% CI 0.62–0.93), and FCRLB rs4657093 (p = 2.28*10−3, OR 0.77, 95% CI 0.65–0.91). Both conditional analysis and linkage disequilibrium analysis suggested they were independent signals associated with IgAN. Associations between FCGR2B rs12118043 and proteinuria (p = 3.65×10−2) as well as gross hematuria (p = 4.53×10−2), between FCRLB rs4657093 and levels of serum creatinine (p = 2.67×10−2) as well as eGFR (p = 5.41*10−3) were also observed. Electronic cis-expression quantative trait loci analysis supported their possible functional significance, with protective genotypes correlating lower gene expressions.ConclusionOur data from genetic associations and expression associations revealed potentially pathogenic roles of Fc receptor gene polymorphisms in IgAN.
Highlights
IgA nephropathy (IgAN) was described histologically for the first time in 1968 by Berger and Hinglais as les depots intercapillaires d’IgAIgG[1]
The most significantly associated SNPs within individual genes were FCGR2B rs12118043 (p = 8.74*1023, Odd ratio (OR) 0.76, 95% CI 0.62–0.93), and FCRLB rs4657093 (p = 2.28*1023, OR 0.77, 95% CI 0.65–0.91)
Current data indicates that at least four hits contribute to development of IgA nephropathy: aberrant glycosylation of IgA1, synthesis of antibodies directed against galactose-deficient IgA1, binding of the galactose-deficient IgA1 by the anti-glycan/ glycopeptides antibodies to form immune complexes (ICs), and accumulation of these complexes in the glomerular mesangium to initiate renal injury[2]
Summary
IgA nephropathy (IgAN) was described histologically for the first time in 1968 by Berger and Hinglais as les depots intercapillaires d’IgAIgG (intercapillary deposits of IgA-IgG)[1]. It was characterized by the deposition of IgA in the mesangial area of glomeruli, and proliferation of the glomerular mesangium with deposition of immune complexes composed of IgG and complement C3 proteins. IgA nephropathy (IgAN) is a complex syndrome characterized by deposition of IgA and IgA containing immune complexes (ICs) composed of IgG and complement C3 proteins in the mesangial area of glomeruli. The aim of the study was to associate multiple polymorphisms within FCGR gene locus with IgAN in a large Chinese cohort
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