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The associations of single nucleotide polymorphisms (SNPs) in  PLA2R1  and  HLA-DQA1 , as well as  HLA-DRB1*15:01-DQB1*06:02  haplotype with idiopathic membranous nephropathy (IMN) is well known. However, the primary associations of these loci still need to be determined. We used Japanese-specific SNP genotyping array and imputation using 2,048 sequenced Japanese samples to fine-map  PLA2R1  region in 98 patients and 413 controls. The most significant SNPs were replicated in a separate sample set of 130 patients and 288 controls. A two-SNP haplotype of intronic and missense SNPs showed the strongest association. The intronic SNP is strongly associated with  PLA2R1  expression in the Genotype-Tissue Expression (GTEx) database, and the missense SNP is predicted to alter peptide binding with HLA-DRB1*15:01 by the Immune Epitope Database (IEDB). In  HLA  region, we performed relative predispositional effect (RPE) tests and identified additional risk alleles in both  HLA-DRB1  and  HLA-DQB1 . We collapsed the risk alleles in each of  HLA-DRB1  and  HLA-DQB1  into single risk alleles. Reciprocal conditioning of these collapsed risk alleles showed more residual significance for  HLA-DRB1  collapsed risk than  HLA-DQB1  collapsed risk. These results indicate that changes in the expression levels of structurally different PLA2R protein confer risk for IMN in the presence of risk  HLA-DRB1  alleles.

Identification of a two-SNP PLA2R1 Haplotype and HLA-DRB1 Alleles as Primary Risk Associations in Idiopathic Membranous Nephropathy