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HLA-D and PLA2R1 risk alleles associate with recurrent primary membranous nephropathy in kidney transplant recipients.

Lena Berchtold 1, 2 Eric Letouzé 3 Mariam Priya Alexander 4 Guillaume Canaud 5, 6 Anne-Els van De Logt 7 Patrick Hamilton 8 Christiane Mousson 9 Vincent Vuiblet 10, 11 Ann Moyer 4 Sylvain Guibert Petra Mrázová Charlène Levi 12 Valérie Dubois 13 Josep Maria Cruzado 14, 15 Armando Torres 16 Manish Gandhi 4 Nadhir Yousfi 1 Vladimir Tesar 17 Ondrej Viklický 18 Maryvonne Hourmant 19 Bruno Moulin 20, 21 Philippe Rieu 22 Gabriel Choukroun 23 Christophe Legendre 24 Jack Wetzels 7 Paul Brenchley 8 José Aurelio Ballarín Castan Hanna Debiec 1 Pierre Ronco 1, 25
Abstract : 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 the genetic testing in donor selection.
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Lena Berchtold, Eric Letouzé, Mariam Priya Alexander, Guillaume Canaud, Anne-Els van De Logt, et al.. HLA-D and PLA2R1 risk alleles associate with recurrent primary membranous nephropathy in kidney transplant recipients.. Kidney International, Nature Publishing Group, 2020, ⟨10.1016/j.kint.2020.08.007⟩. ⟨hal-02935575⟩

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