EPIGENETIC DYSREGULATION OF RISK GENES MEDIATES SUSCEPTIBILITY TO PRIMARY MEMBRANOUS NEPHROPATHY

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EPIGENETIC DYSREGULATION OF RISK GENES MEDIATES SUSCEPTIBILITY TO PRIMARY MEMBRANOUS NEPHROPATHY

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Co-author 1

Hong CHU joycechu0201@163.com Peking University First Hospital Department of Nephrology Beijing China *

Co-author 2

Yuting WANG ytwang@pku.edu.cn Peking University Department of Occupational and Environmental Health Sciences, School of Public Health Beijing China -

Co-author 3

Zhao CUI cuizhao@bjmu.edu.cn Peking University First Hospital Department of Nephrology Beijing China -

Co-author 4

Xue Gao xu.gao@pku.edu.cn Peking University Department of Occupational and Environmental Health Sciences, School of Public Health Beijing China -

Co-author 5

Luxia Zhang zhanglx@bjmu.edu.cn Peking University First Hospital Department of Nephrology Beijing China - Peking University National Institute of Health Data Science at Peking University Beijing China

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Introduction

Primary membranous nephropathy (MN) is the leading cause of adult nephrotic syndrome. The M-type phospholipase A2 receptor (PLA2R) serves as the primary target antigen on glomerular podocytes in MN, and its blood antibody titer correlates with disease activity and progression.

Methods

We performed genome-wide DNA methylation profiling using the Infinium MethylationEPIC BeadChip on peripheral blood cells from 44 MN patients and 32 healthy controls. Differential methylation analysis of several specific genes was conducted using linear mixed-effects models. Target genes focused on: 1) established MN risk genes from genome-wide association studies (PLA2R1, HLA class II genes, NFKB1, IRF4); 2) transcription factors implicated in PLA2R regulation (SP1, c-JUN, FOS, TP53, PU.1); and 3) the proinflammatory cytokine IL1B, which is involved in PLA2R signaling activation.

Results

We identified several significantly differentially methylated CpG sites, including three in NFKB1, two in SP1, two in FOS, and four in HLA-DRB1. No significant methylation changes were found in the PLA2R1 gene. A prominent differentially methylated region (DMR), located in exon 2 of HLA-DRB1, was hypomethylated in MN patients (e.g., cg09139047, β=-0.38, p=0.0016; cg15982117, β=-0.25, p=0.0085; cg16514085, β=-0.33, p=0.0029). Given that DRB1*15:01 and DRB1*03:01 alleles of HLA-DRB1 are independent genetic risk factors for MN, we compared methylation levels between carriers and non-carriers. Homozygous carriers of DRB1*15:01, DRB1*03:01, or both alleles exhibited lower DNA methylation levels at the HLA-DRB1 DMR compared to heterozygous carriers and non-carriers.

Conclusion

Our findings suggest that genetic risk variants may contribute to MN susceptibility by altering the DNA methylation landscape, potentially modulating PLA2R protein expression and antigen presentation pathways.

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