Variants in the Promoter Region of HLA-DQA1 were Associated with Idiopathic Membranous Nephropathy in a Chinese Han Population

Abstract

Background:Idiopathic membranous nephropathy (IMN) is an autoimmune disease and the leading cause of adult nephritic syndrome. HLA-DQA1 had been identified to be associated with IMN in Europeans and the result was replicated in Chinese Han population. In this study, six single nucleotide polymorphisms (SNPs) in the promoter of HLA-DQA1 and other two SNPs with IgA nephropathy were included for the association analysis.Methods:The SNPs were genotyped in 509 patients and 601 controls by the MassArray iPLEX. The quantification of anti-phospholipase A2 receptor (PLA2R) antibodies in sera of IMN patients was performed by anti-PLA2R ELISA (IgG) kit.Results:After analysis, four SNPs were significantly associated with IMN, with rs2187668 and rs28383345 as the top two signals (P = 8.42×10-5 and 2.48×10-5, respectively). Even under dominant model, the two SNPs were still significantly associated with IMN (P = 3.50×10-3 for rs28383345 and P = 6.55×10-5 for rs2187668). After conditional study with rs2187668, rs28383345 was the only variant significantly correlated with IMN after Bonferroni correction (P = 0.016). The minor alleles of the two SNPs were also mutually exclusive in our cohort. This indicated that the two SNPs were independently associated with IMN in Chinese Han population. Levels of anti-PLA2R autoantibodies were correlated with the genotypes of the two SNPs, but not significantly (P>0.05).Conclusions:Our results revealed that a novel independent variant in the promoter of HLA-DQA1 was associated with IMN in Chinese Han population. The locus possessed regulatory role according to the data of RegulomeDB. The exact role of the SNPs on the expression of HLA-DQA1 needs further investigation.

Association of 10 Polymorphisms in PLA2R1 and HLA DQA1 Genes with Primary Membranous Nephropathy Risk: A Meta-Analysis and a Meta-Regression

“…Overall, 27 studies with a total of 5353 PMN cases and 10,777 controls were included in the present study. 13 – 35 The characteristics of included studies are summarized in Table 1 . Genotyping data of cases and controls are depicted in Supplemental Tables S1–S10 .…”

Association between PLA2R1 rs4664308 and susceptibility to idiopathic membranous nephropathy

“…The HLA-DQA1 allele on chromosome 6p21 is closely related to IMN, mainly in Caucasian populations, and this allele may promote autoimmune responses to targets, which include PLA2R1 variants. [ 32 ] HLA-DQA1 rs2187668 is known to be associated with IMN, and carriers of the major allele of HLA-DQA1 rs2187668 have a higher probability of harboring PLA2R1 rs4664308 major allele to increase the IMN risk. However, studies have shown Asians are less likely to exhibit PLA2R1 genetic variations to increase IMN risk.…”