Berchtold Lena, Letouzé Eric, Alexander Mariam Priya, Canaud Guillaume, Logt Anne-Els van de, Hamilton Patrick, Mousson Christiane, Vuiblet Vincent, Moyer Ann M, Guibert Sylvain, Mrázová Petra, Levi Charlène, Dubois Valérie, Cruzado Josep Maria, Torres Armando, Gandhi Manish J, Yousfi Nadhir, Tesar Vladimir, Hourmant Maryvonne, Moulin Bruno, Rieu Philippe, Choukroun Gabriel, Legendre Christophe, Wetzels Jack, Brenchley Paul, Ballarín Castan José Aurelio, Debiec Hanna, Ronco Pierre
Sorbonne Université, Université Pierre et Marie Curie Paris 06, Paris, France; Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S1155, Paris, France; Division of Nephrology, Department of Internal Medicine Specialties, University Hospital of Geneva, Geneva, Switzerland.
Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, France; Functional Genomics of Solid Tumor, Labex Immuno-Oncology, Equipe Labellisée Ligue Contre le Cancer, Université Paris 13, Paris, France.
Kidney Int. 2021 Mar;99(3):671-685. doi: 10.1016/j.kint.2020.08.007. Epub 2020 Sep 2.
Recurrence of primary membranous nephropathy after transplantation occurs in up to 44% of patients and is driven by PLA2R antibody. Here, we asked whether genetic determinants could improve risk prediction. First, we sequenced PLA2R1 and HLA-D loci in 248 patients with primary membranous nephropathy and identified two independent single nucleotide polymorphisms (SNPs) at risk for primary membranous nephropathy at each locus. These were rs9271188 (intergenic between HLA-DRB1 and HLA-DQA1,) and rs9275086 (intergenic between HLA-DQB1 and HLA-DQA2) at the HLA-D locus along with rs6726925 and rs13018963 at the PLA2R1 locus. Then we investigated whether primary membranous nephropathy at-risk variants were associated with recurrence in a retrospective cohort of 105 donor-recipient pairs and a replication cohort of 40 pairs. Seven SNPs located between HLA-DRB1 and HLA-DQA1 in linkage disequilibrium with rs9271188, and three SNPs in the PLA2R1 region predicted recurrence when presented by the donor, but not when presented by the recipient. The two SNPs in the HLA-D region most strongly associated with recurrence (rs9271705 and rs9271550) were confirmed in the replication cohort. A genetic risk score based on the two best predictors at each locus (rs9271705, rs9271550, rs17830558, and rs3828323) identified a group of patients with high risk of recurrence. Thus, our results suggest that the graft contributes to recurrence of primary membranous nephropathy through the disease susceptibility HLA-D and PLA2R1 SNPs in an autoimmune milieu. Further studies are needed before implementation of genetic testing for these in donor selection.
移植后原发性膜性肾病的复发率高达44%的患者，且由PLA2R抗体驱动。在此，我们探讨遗传因素是否能改善风险预测。首先，我们对248例原发性膜性肾病患者的PLA2R1和HLA - D基因座进行测序，在每个基因座上鉴定出两个与原发性膜性肾病风险相关的独立单核苷酸多态性（SNP）。这些分别是HLA - D基因座上的rs9271188（位于HLA - DRB1和HLA - DQA1之间的基因间区域）和rs9275086（位于HLA - DQB1和HLA - DQA2之间的基因间区域），以及PLA2R1基因座上的rs6726925和rs13018963。然后，我们在一个包含105对供体 - 受体对的回顾性队列和一个包含40对的复制队列中，研究原发性膜性肾病风险变异与复发之间的关联。与rs9271188处于连锁不平衡状态的位于HLA - DRB1和HLA - DQA1之间的7个SNP，以及PLA2R1区域的3个SNP，当由供体传递时可预测复发，但由受体传递时则不能。在复制队列中证实了HLA - D区域中与复发最密切相关的两个SNP（rs9271705和rs9271550）。基于每个基因座上两个最佳预测指标（rs9271705、rs9271550、rs17830558和rs3828323）构建的遗传风险评分，识别出一组复发风险高的患者。因此，我们的结果表明，在自身免疫环境中，移植物通过疾病易感性HLA - D和PLA2R1基因座的SNP促成原发性膜性肾病的复发。在将这些基因检测用于供体选择之前，还需要进一步研究。
