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

• Main Authors: Khun Zaw Latt, Kenjiro Honda, Myo Thiri, Yuki Hitomi, Yosuke Omae, Hiromi Sawai, Yosuke Kawai, Shunsuke Teraguchi, Kazuko Ueno, Masao Nagasaki, Akihiko Mabuchi, Hajime Kaga, Atsushi Komatsuda, Katsushi Tokunaga, Eisei Noiri
• Format: Article
• Language: English
• Published: Nature Publishing Group 2018-10-01
• Series: Scientific Reports
• Subjects: Idiopathic Membranous Nephropathy; Phospholipase A2 Receptor (PLA2R); Missense SNPs; Single Nucleotide Polymorphisms (SNPs); Additional Risk Allele
• Online Access: https://doi.org/10.1038/s41598-018-33612-7

Abstract 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.