Abstract
Although recent studies showed anti-PLA2R antibody plays a crucial role in idiopathic membranous nephropathy (IMN), detailed HLA mapping and interaction between the HLA genes and PLA2R1 have not been investigated in IMN. We genotyped across the PLA2R1 gene and the HLA region, using 183 IMN patients and 811 healthy controls. Five SNPs around the PLA2R1 gene were significantly associated with IMN. In addition to the two SNPs previously reported to be strongly associated with IMN, rs3749119 and rs35771982 (OR 3.02 and 2.93, P = 3.24E-14 and 4.64E-14, respectively), two novel intronic SNPs (rs2715928 and rs16844715) were also identified as IMN-associated SNPs (OR = 2.30 and 2.51, P = 3.15E-10 and 5.66E-13, respectively). In the HLA gene analysis, DRB1*1501 and DQB1*0602 were strongly associated with IMN (P = 1.14E-11 and 1.25E-11, respectively). The interaction was strongest between HLA-DRB1*15:01 - HLA-DQB1*06:02 and the intronic SNP rs2715928 (OR = 17.53, P = 4.26E-26). Furthermore, positive interaction was also observed between HLA-DRB1*15:01 - HLA-DQB1*06:02 and the missense SNP rs35771982 (OR = 15.91, P = 2.76E-29), which is in strong linkage disequilibrium with 5′UTR SNP rs3749119, and intronic SNP rs16844715 (OR = 15.91, P = 2.30E-26) for IMN. Neither HLA-DRB1*15:01 nor HLA-DQB1*06:02 was associated with steroid responsiveness, overall survival and renal survival during the observation period of mean 11 years though limited number of analysis.
Highlights
Recent studies showed anti-phospholipase A2 receptor (PLA2R) antibody plays a crucial role in idiopathic membranous nephropathy (IMN), detailed HLA mapping and interaction between the HLA genes and PLA2R1 have not been investigated in IMN
Of the[13] SNPs included in the association analysis, we found 9 SNPs significantly associated with IMN (P < 0.05)
The genetic association of PLA2R1 and HLA-DQA1 risk alleles with IMN in the Caucasian populations was reported by a genome-wide association studies (GWAS) that included three independent GWAS in three populations[4]
Summary
Recent studies showed anti-PLA2R antibody plays a crucial role in idiopathic membranous nephropathy (IMN), detailed HLA mapping and interaction between the HLA genes and PLA2R1 have not been investigated in IMN. In the HLA gene analysis, DRB1*1501 and DQB1*0602 were strongly associated with IMN (P = 1.14E-11 and 1.25E-11, respectively). Stanescu et al reported a strong genetic interaction of risk alleles at both the HLA and PLA2R1 regions, relatively modest risk of IMN was identified at each locus. Association of HLA-DQA1 and PLA2R1 with IMN was reported by case-control candidate gene studies in Korea, Taiwan and China[5,6,7]. Previous studies have reported the effect of single locus and the genetic interaction of SNPs in PLA2R1 and HLA-DQA1, no study has performed the high-density association mapping of both the PLA2R1 gene and HLA genes to date for identifying the primary polymorphisms and it is still not known the interaction effect of PLA2R1 risk variants and fully detailed analysis of HLA-gene alleles
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