Associations between m-type phospholipase A2 receptor,human leukocyte antigen gene polymorphisms and idiopathic membranous nephropathy

Abstract

Primary membranous nephropathy, also known as idiopathic membranous nephropathy, is an autoimmune disease. As an autoimmune disease, genetic factors are essential in the pathogenesis of IMN. People pay more and more attention to genetics and bioinformatics. With the continuous improvement and development of high-throughput gene sequencing and genotyping technology, it has been confirmed that many genes and their single nucleotide polymorphisms are strongly correlated with IMN disease susceptibility. However, there are few studies on HLA-DQA1 and PLA2R gene polymorphisms and IMN susceptibility in China. The purpose of this study was to investigate whether PLA2R rs2715928 and rs16844715 are related to IMN, the correlation between five SNP loci of PLA2R and HLA-DQA1 and IMN, and the effect of gene-gene interaction among different genotypes of each locus on disease. In this study, 86 patients with IMN confirmed by renal biopsy in the first hospital of Harbin Medical University and 90 healthy controls were selected. All subjects were excluded from secondary membranous nephropathy, pregnant or breastfeeding women, severe primary disease of vital organs, severe infection, major surgery, and severe trauma. Seven selected SNP loci were genotyped using the IMLDR multiple SNP typing kit. Chi-square test and logistic regression were used to analyze the correlation between each SNP and IMN. The general clinical data and laboratory indicators of each subject were recorded, and the relationship between different genotypes and clinical manifestations was analyzed. Among the 7 SNP loci included in the study, except HLA-DQA1 rs2187668, the other 6 loci all met Hardy-Weiberg equilibrium test (P > 0.05). The allele distribution of PLA2R rs2715928 and rs16844715 was significantly different between the IMN group and the healthy control group, and it was closely related to IMN (P < 0.05). There was no statistical difference in the distribution of alleles of rs2715918 between the IMN group and the control group (P* > 0.05), and there was also statistical difference in the distribution of alleles of rs35771982, rs3749117, and rs4664308 between the IMN group and the healthy control group (P < 0.05).The C allele of rs16844715 (OR = 2.03, 95%CI: 1.29-3.19, P* = 0.0140) and the A allele of rs2715928 (OR = 3.18, 95%CI: 1.94-5.24, P* = 3.54E-5), G allele of rs35771982 (OR = 4.07, 95%CI: 2.34-7.08, P* = 4.96E-6), T allele of rs3749117 (OR = 4.07, 95%CI: 2.34-7.08, P* = 4.96E-6), the A allele of rs4664308 (OR = 2.63, 95%CI: 1.54-4.49, P* = 0.0028) was the risk gene of IMN.Through the establishment of different genetic models, we found that,in the additive model, the three SNPs of PLA2R rs2715928 (OR = 5.40, 95%CI: 1.77-16.50, P* = 0.0217) and rs35771982 (OR = 15.15, 95%CI: 2.92-78.48, P* = 0.0084), rs3749117 (OR = 15.15, 95%CI: 2.92-78.48, P* = 0.0084) had a strong correlation with IMN. In the stealth model,homozygous gene risk type of the five SNPs,PLA2R rs16844715 (OR = 2.52, 95%CI: 1.38-4.61, P* = 0.0189) and rs2715928 (OR = 4.30, 95%CI: 2.31-8.03, P* = 3.14E-5), rs35771982 (OR = 4.85, 95%CI: 5.53-9.31, P* = 1.42E-5), rs3749117 (OR = 4.85, 95%CI: 5.53-9.31, P* = 1.42E-5) and rs4664308 (OR = 3.16, 95%CI: 1.67-5.97, P* = 0.0028) had a strong correlation with IMN. The distribution of GT haplotypes and CC haplotypes of rs35771982 and rs3749117 and CA haplotypes and TG haplotypes of rs16844715 and rs4664308 were significantly different between IMN group and control group (P < 0.05). When GMDR software was used to establish a model to analyze the interaction between various SNP sites, it was found that the combination of GG genotype at rs35771982 and AA genotype at rs2715928 was the highest risk of disease. The risk genotypes of rs16844715, rs2715928 and rs4664308 had no effect on the clinical manifestations of IMN (P > 0.05). PLA2R rs2715928 and rs16844715 are associated with susceptibility to IMN. The C allele of rs16844715, the A allele of rs2715928, the G allele of rs35771982, the T allele of rs3749117, and the A allele of rs4664308 are the dangerous genes of IMN. The combination of GG genotype at rs35771982 and AA genotype at rs2715928 poses the greatest risk of disease. Haplotype may affect susceptibility to IMN. The risk genotype had no effect on the clinical manifestations of IMN.

Keywords: HLA DQA1; Idiopathic membranous nephropathy; PLA2R; single nucleotide polymorphism.

Figure 1.

Linkage disequilibrium analysis of PLA2R gene

Figure 2.

Combination of high-risk and low-risk genotypes under the best model