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

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.

Advances of the experimental models of idiopathic membranous nephropathy (Review)

“…among untreated patients, approximately one third undergo spontaneous remission, one-third progress to end-stage renal disease over 10 years and the remainder develop non-progressive cKd. in short, approximately two-thirds of cases progress to cKd (12)(13)(14)(15). Thus far, no curative therapies have been achieved for cKd or iMn (16,17), which may be attributed to unclear mechanisms.…”

Mutational analysis on predicting the impact of high-risk SNPs in human secretary phospholipase A2 receptor (PLA2R1)

“…The authors 10 have reported the SNPs rs3749119, rs3749117, rs35771982, rs3828323, and rs4664308 as crucial for causing Nephropathy. Further 11 , have identified the two SNPs rs3749117 and rs35771982 that are causing protein level changes to the protein hence effecting its function. The experimental analysis carried out by 12 showed that rs6757188 and rs3577198 are highly associated with idiopathic membranous nephropathy (IMN) and that's maybe the underlying cause of IMN.…”

The association between variants in PLA2R and HLA-DQA1 and renal outcomes in patients with primary membranous nephropathy in Western China

“…In Caucasian population, genome-wide association studies have confirmed the susceptibility of PLA2R and HLA-DQA1 gene with PMN [ 13 ]. Multiple loci in PLA2R and HLA-DQA1 were closely related to PMN in various ethnicities, but the results of different regions and ethnic groups were not entirely consistent [ 8 , 13 – 18 ]. To verify the previous findings in Western China, in our previous study we selected eight SNPs reported in the literatures and found that two SNPs (rs2715918, rs4665143) within PLA2R , 1 SNP in HLA-DQA1 (rs2187668) were associated with primary membranous nephropathy [ 19 ].…”