Podocyte autophagy is activated in lupus-prone mice and patients with lupus nephritis. Increased autophagy is cytoprotective against antibody and interferon-α induced podocyte injury.
Objectives
Recent genome-wide association studies have identified several novel susceptibility genes for systemic lupus erythematosus (SLE) and IgA nephropathy (IgAN). Since both lupus nephritis (LN) and IgAN are autoimmune kidney diseases, they may share common disease mechanisms that overlap with genetic susceptibility. To test this hypothesis, we sought to identify genetic variants associated with IgAN in LN.
Methods
In the first stage, 500 LN patients, 240 SLE patients without LN, and 500 healthy controls were enrolled. Fifteen reported SNPs with top association signals with IgAN were selected for further testing in LN. Three independent cohorts from Beijing, Shanghai and Hong Kong were included as replicates. We also analyzed the functional significance of identified non-coding variants on regulatory motifs and gene expression.
Results
Except for associations with HLA gene polymorphisms, genetic variants of MTMR3 in 22q12 showed associations with LN (rs9983A with P = 2.07×10−3; OR 1.61; 95% CI 1.19–2.19) compared to healthy controls in the first stage. In replications, associations were replicated and reinforced with northern (LN vs. non-LN patients, P = 0.01) but not southern Han Chinese, although significant genetic heterogeneity was observed. In silico analyses predicted conservative and regulatory features of rs9983. In expression analysis, we observed lower MTMR3 transcription levels in blood samples with rs9983A and renal biopsies from LN and IgAN.
Conclusions
Our results suggested that the MTMR3 gene was shared between IgAN and LN in the northern Chinese, further highlighting the role of autophagy in SLE. However, widespread replication of these experiments, fine mapping, and functional assays are required to establish this connection.
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.
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