The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis Jingyuan Xie et al. # Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1
Epitopes of phospholipase A2 receptor (PLA2R), the target antigen in idiopathic membranous nephropathy (iMN), must be presented by the HLA-encoded MHC class II molecules to stimulate autoantibody production. A genome-wide association study identified risk alleles at HLA and PLA2R loci, with the top variant rs2187668 within HLA-DQA1 showing a risk effect greater than that of the top variant rs4664308 within PLA2R1. How the HLA risk alleles affect epitope presentation by MHC class II molecules in iMN is unknown. Here, we genotyped 261 patients with iMN and 599 healthy controls at the HLA-DRB1, HLA-DQA1, HLA-DQB1, and HLA-DPB1 loci with four-digit resolution and extracted the encoded amino acid sequences from the IMGT/HLA database. We predicted T cell epitopes of PLA2R and constructed MHC-DR molecule-PLA2R peptide-T cell receptor structures using Modeler. We identified DRB1*1501 (odds ratio, 4.65; 95% confidence interval [95% CI], 3.39 to 6.41; <0.001) and DRB1*0301 (odds ratio, 3.96; 95% CI, 2.61 to 6.05; <0.001) as independent risk alleles for iMN and associated with circulating anti-PLA2R antibodies. Strong gene-gene interaction was noted between rs4664308(AA) and HLA-DRB1*1501/DRB1*0301. Amino acid positions 13 (<0.001) and 71 (<0.001) in the MHC-DR1 chain independently associated with iMN. Structural models showed that arginine13 and alanine71, encoded by DRB1*1501, and lysine71, encoded by DRB1*0301, facilitate interactions with T cell epitopes of PLA2R. In conclusion, we identified two risk alleles of HLA class II genes and three amino acid residues on positions 13 and 71 of the MHC-DR1 chain that may confer susceptibility to iMN by presenting T cell epitopes on PLA2R.
In this study, we measured soluble urokinase receptor levels, a possible permeability factor, in the plasma of patients with primary focal segmental glomerulosclerosis (FSGS) and determined their association with clinical and pathological data in 74 patients with primary FSGS. Healthy donors and patients with minimal change disease, membranous nephropathy, and secondary FSGS were used as controls. The plasma-soluble urokinase receptor levels, measured by commercial ELISA kits, of patients with primary FSGS (median: 2923, interquartile range 2205-4360 pg/ml) were significantly higher than those of patients with minimal change disease (median 2050 pg/ml), membranous nephropathy (median 2029 pg/ml), and normal individuals (median 1739 pg/ml). There was no significant difference in plasma-soluble urokinase receptor levels between the 74 patients with primary and 14 patients with secondary FSGS. The soluble urokinase receptor levels increased in the order of tip variant, to a not otherwise specified variant and a cellular variant. The soluble urokinase receptor levels were significantly but negatively correlated with creatinine clearance at presentation but positively correlated with crescent formation in patients with primary FSGS. During follow-up, receptor levels decreased significantly in patients with complete remission. Thus, plasma-soluble urokinase receptor levels did not differentiate primary and secondary FSGS, and although significantly elevated in FSGS, they showed considerable overlap with other glomerular diseases.
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