Recent studies have demonstrated that alleles at single nucleotide polymorphisms (SNPs) rs2187668 and rs4664308 within genes HLA-DQA1 and PLA2R1, respectively, had a significant impact on the susceptibility to idiopathic membranous nephropathy (IMN).
In African Americans, much of the risk for end-stage nondiabetic kidney disease is explained by common variants in the MYH9/APOL1 locus, and in individuals of European descent, variants in HLA-DQA1 and PLA(2)R1 implicate most of the risk for idiopathic membranous nephropathy.
This study validated the association of these HLA-DQA1 and PLA2R1 SNPs with IMN in a Spanish cohort and its increased risk when combining both risk genotypes.
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.
Our recent genome-wide association study showed that genetic variants in an HLA-DQA1 and phospholipase A2 receptor (PLA2R1) allele associate most significantly with biopsy-proven iMN, suggesting that rare genetic variants within the coding region of the PLA2R1 gene may contribute to antibody formation.
The pooled odds ratios (ORs) regarding the association between the HLA-DQA1rs2187668 polymorphism and iMN risk were statistically significant [A vs G: OR = 3.34, 95% confidence interval (CI) = 2.70-4.13; AA vs GA + GG: OR = 8.69, 95% CI = 6.64-11.36; GG vs GA + AA: OR = 0.25, 95% CI = 0.19-0.33;AA vs GG: OR = 12.61, 95% CI = 8.02-19.81; GA vs GG: OR = 3.45, 95% CI = 2.79-4.25].
The incidence of DQA1*0501 was raised in both Greek (96% vs. 66%, OR 9.7, chi 2 6.9, P = 0.009) and British IMN (85% vs. 45%, OR 7.4, chi 2 20, P = 0.00007) patients.
A genome-wide association study has provided further evidence for a highly significant association between PLA2R1 and HLA-DQA1 loci and idiopathic membranous nephropathy in patients of white ancestry.
Furthermore, patients with PLA2R-associated IMN had significantly higher age (with vs without, 54.31 ± 14.03 vs 46.67 ± 13.30 years old; P = .04), proteinuria (4.32 ± 1.84 vs 3.29 ± 1.90 g/d, P = .039), and serum albumin (25.33 ± 9.60 vs 31.38 ± 9.52 g/L, P = .019), but had lower serum immunoglobulin G (6.83 ± 2.89 vs 8.72 ± 2.95 g/L, P = .016) and erythrocyte sedimentation rate (47.31 ± 32.11 vs 26.33 ± 27.94, P = .013), when compared to IMN patients without PLA2R.
The baseline serum creatinine, serum albumin, and urine protein excretion were not significantly different between PLA2R-associated (n = 145) and non-PLA2R-associated iMN patients (n = 41).
The titer of anti-PLA2R antibody was significantly correlated with both TUpro and serum Alb levels of pre- and post-therapeutic values in IMN (P<0.05), but did not have a relationship with Ccr (P>0.05).
Statistical analyses indicated that there were positive correlations between uPLA<sub>2</sub>R-Ab and gPLA<sub>2</sub>R, sPLA<sub>2</sub>R-Ab or urinary protein and negative correlations between uPLA<sub>2</sub>R-Ab and serum albumin in patients with IMN.
Significant differences in systolic blood pressure, serum Cystatin C, serum albumin and estimated glomerular filtration rate (eGFR) were found between the antibody-positive and antibody-negative groups of IMN patients.
Furthermore, CD14<sup>+</sup>CD163<sup>+</sup>CD206<sup>+</sup> M2-like cell counts in the patients with incipient IMN were also positively related with 24 h urinary albumin levels and the values of serum M-type phospholipase A2 receptor (PLA2R).