The association between variants in

Background: Both Genome-wide associations and our previous study have shown that single nucleotide polymorphisms (SNPs) of M-type phospholipase A2 receptor (PLA2R) and human leukocyte antigen complex class II HLA-DQαchain 1 (HLA-DQA1) gene were identified to be associated with primary membranous nephropathy (PMN). However, whether these SNPs affect clinical manifestation and renal outcome for PMN patients is poorly defined. Here, we evaluated whether there is an association between these SNPs and clinical manifestations and renal outcomes of PMN in a western Chinese cohort. Methods: Seven SNPs within PLA2R and one SNP in HLA-DQA1 were selected in our study. Clinical data from 314 patients with PMN were collected and the relationship between the genotype and phenotype was evaluated. A total of 186 patients had follow-up data. We assessed the treatment responses and renal outcomes between patients with these gene polymorphisms after a median follow-up of 18.6 months. Results: Eight SNPs were not associated with clinical manifestations of PMN patients (Pc < 0.05). rs3828323 T allele was marginally significantly associated with hypertension (P = 0.008, Pc = 0.064, OR = 1.821). After treatment for PMN, the SR group (including CR and PR) had lower serum creatinine level (68.4 ± 18.8 μmol/L vs. 122.8 ± 126.6 μmol/L, P < 0.001), urea (5.5 ± 1.9 mmol/L vs. 8.0 ± 4.0 mmol/L, P < 0.001), uric acid (358.5 ± 95.1 μmol/L vs. 392.8 ± 118.1 μmol/L, P = 0.037) and urinary protein (0.23 (0.76,1.05) g/d vs. 3.01 (2.06,7.95) g/d, P < 0.001), higher eGFR (100.0 ± 20.1 ml/min/1.73m vs. 77.1 ± 35.3 ml/min/1.73m, P < 0.001) and albumin (41.1 ± 5.1 g/L vs.30.4 ± 8.2 g/L, P < 0.001). We also identified that PMN patients with CT/TT genotype for rs3828323 achieved higher cumulative survival rate than patients with CC genotype. Conclusions: Rs3828323 may influence hypertension and renal outcome in patients with PMN. Further research is needed to explore the mechanism for this genotype-disease phenotype association. © The Author(s) 2021, corrected publication 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Open Access *Correspondence: awang@georgeinstitute.org.au; wwei958@163.com 1 Department of Nephrology and Institute of Nephrology, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, Chengdu 610072, China 2 The Renal and Metabolic Division, The George Institute for Global Health, University of NSW, Sydney, Australia Full list of author information is available at the end of the article Page 2 of 10 Fan et al. BMC Med Genomics (2021) 14:123 Background Primary membranous nephropathy (PMN) is one of the most common causes for nephrotic syndrome for adult. Its typical pathological features are diffuse thickening of glomerular capillary basement membrane and deposition of subepithelial immune complexes [1, 2]. In recent years, its incidence is increasing. It is the second most common type of primary glomerulonephritis in China [3, 4]. PMN is a typical kidney disease caused by antigen– antibody reaction. Antigen–antibody binding forms immune complex, then activates complement system, resulting in injury of podocytes and glomerular basement membrane, and eventually leading to kidney injury [5, 6]. The production of circulating PLA2R antibodies may be the main pathogenic mechanism of the disease [7]. The anti-PLA2R antibody has high specificity and good sensitivity. PLA2R antibody are positive in 70–80% of patients with PMN [8]. The higher the antibody titer is, the higher the risk of deterioration of renal function is [9, 10]. It is reported that some clinical factors are related to the progress of the disease, including severe proteinuria, hypertension, and renal dysfunction at diagnosis [11, 12]. In Caucasian population, genome-wide association studies have confirmed the susceptibility of PLA2R and HLA-DQA1 gene with PMN [13]. Multiple loci in PLA2R and HLA-DQA1 were closely related to PMN in various ethnicities, but the results of different regions and ethnic groups were not entirely consistent [8, 13–18]. To verify the previous findings in Western China, in our previous study we selected eight SNPs reported in the literatures and found that two SNPs (rs2715918, rs4665143) within PLA2R, 1 SNP in HLA-DQA1 (rs2187668) were associated with primary membranous nephropathy [19]. The interactions of rs2715918, rs4665143 and rs2187668 were associated with an increased risk of the development of PMN by10.61-fold. Patients carrying risk alleles confer a predisposition to anti-PLA2R autoantibody generation [19]. In a Spanish study, Bullich et al. found that PMN patients with two SNP risk alleles, rs2187668 and rs4664308, had better response to immunosuppressive therapy and slower progression of chronic kidney disease [17]. Wang et al. found that PMN Patients with HLADRB1*1502 had worse kidney outcomes in Han Chinese [20]. To evaluate whether these SNPs are associated with clinical manifestations and renal outcomes of PMN patients, clinical data from 314 patients with PMN were collected and the relationship between the genotype and phenotype was evaluated. We performed a retrospective cohort study of 186 patients who had follow-up data to assess the relationship between genetic polymorphisms and renal outcome.