Trends and the Role of Gene-Environment Interactions in Idiopathic Membranous Nephropathy in Northern China

Introduction: Idiopathic membranous nephropathy (iMN) has become one of the most prevalent primary glomerular diseases, with a marked increase in prevalence over the past two decades in northern China. Fine particulate matter (PM2.5) is considered to be associated with this rising prevalence. In this study, we aim to evaluate the trends of iMN in relation to improved air quality and conduct a cross-sectional study in Hebei province (northern China, near Beijing) to investigate the role of gene-environment interactions in its development. Methods: This study established two cohorts. Cohort 1 included 22,937 pathology reports from Peking University First Hospital (2002-2021) to assess iMN prevalence. Cohort 2 comprised 5,635 iMN patients from 11 cities in Hebei Province (2009-2013). DNA samples from 374 iMN patients and 1,259 controls were genotyped for SNPs rs4664608 (PLA2R1) and rs2187668 (HLA-DQA1). Patients were stratified by air pollution risk levels. The annual percentage change (APC) and average annual percentage change (AAPC) were estimated using a join-point regression model. Gene-environment interactions were analyzed using logistic regression and epinet-calculation. Results: In Cohort 1, 5,586 patients with iMN were identified, representing 24.3% of the 22,937 patients from 2002 to 2021. The general population showed a significant increase in iMN proportion with an APC of +12.7% per year from 2002 to 2014 (95% CI: 10.3 to 17.5, p < 0.001), followed by a decline with an APC of -5.6% per year from 2014 to 2021 (95% CI: -9.6 to -2.6, p < 0.001).In Hebei Province, the iMN frequency rose significantly with an APC of +17.6% per year from 2002 to 2016 (95% CI: 14.5 to 28.6, p < 0.001), peaking at 60%, and then declined with an APC of -5.5% per year from 2016 to 2021 (95% CI: -13.1 to -1.2, p = 0.02). Cohort 2 highlighted significant regional variation in iMN incidence across Hebei Province. Geographic exposure to pollution was identified as an independent risk factor for iMN (RR 1.49, 95% CI 1.38–1.56, p<0.001). Gene-environment interaction analysis revealed that patients with risk alleles in the PLA2R1 gene and exposure to risk environments had a markedly increased risk of developing iMN (OR=38.72, 95% CI 11.95-125.46, p<0.01). Conclusion: The annual growth rate of iMN in northern China appears to be slowing down. Gene-environment interactions may have contributed to the previously observed increase in iMN prevalence.