Volume 94, Issue 5, Pages 974-982 (November 2018) HLA class II alleles differing by a single amino acid associate with clinical phenotype and outcome in patients with primary membranous nephropathy  Huai-yu Wang, Zhao Cui, Li-jun Xie, Li-jie Zhang, Zhi-Yong Pei, Fang-jin Chen, Zhen Qu, Jing Huang, Yi-miao Zhang, Xin Wang, Fang Wang, Li-qiang Meng, Xu-yang Cheng, Gang Liu, Xu-jie Zhou, Hong Zhang, Hanna Debiec, Pierre Ronco, Ming-hui Zhao  Kidney International  Volume 94, Issue 5, Pages 974-982 (November 2018) DOI: 10.1016/j.kint.2018.06.005 Copyright © 2018 International Society of Nephrology Terms and Conditions

Kidney International 2018 94, 974-982DOI: (10.1016/j.kint.2018.06.005) Copyright © 2018 International Society of Nephrology Terms and Conditions

Figure 1 Flowchart of the main findings of the genotype–phenotype analysis in primary membranous nephropathy (pMN) patients. eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; PLA2R, M-type phospholipase A2 receptor. Kidney International 2018 94, 974-982DOI: (10.1016/j.kint.2018.06.005) Copyright © 2018 International Society of Nephrology Terms and Conditions

Figure 2 Comparison of chronic kidney disease (CKD) stages in primary membranous nephropathy patients with versus without the human leukocyte antigen class II allele DRB1*1502. Kidney International 2018 94, 974-982DOI: (10.1016/j.kint.2018.06.005) Copyright © 2018 International Society of Nephrology Terms and Conditions

Figure 3 Analysis of gene–gene interaction: odds ratios for anti-M-type phospholipase A2 receptor (PLA2R) antibody levels, for human leukocyte antigen DRB1*1502 and DRB1*0301 combinations (a) and DRB1*1502 and DRB1*1501 combinations (b). The combination of DRB1*0301 and DRB1*1502 confers a 5.45-fold greater risk of higher anti-PLA2R antibody level, using both negative alleles as a reference (P = 0.049). No gene–gene interaction was found with the combination of DRB1*1501 and DRB1*1502 (P = 0.150). Kidney International 2018 94, 974-982DOI: (10.1016/j.kint.2018.06.005) Copyright © 2018 International Society of Nephrology Terms and Conditions

Figure 4 Kaplan–Meier renal survival curves (end-stage renal disease) in primary membranous nephropathy patients. Patients with human leukocyte antigen DRB1*1502 had worse kidney outcomes during follow-up (P = 0.013). Kidney International 2018 94, 974-982DOI: (10.1016/j.kint.2018.06.005) Copyright © 2018 International Society of Nephrology Terms and Conditions

Figure 5 Structure models of pocket 1 of DRB1*1501 and DRB1*1502. Sheet and spiral structures are shown by purple and cyan, respectively. Key amino acids are highligted in green. Oxygen and nitrogen are shown in red and dark blue, respectively. In pocket 1 of the DRB1*1501 molecule, the side chain of valine on position 86 is isopropyl; the greater steric hindrance of this side chain leads to a smaller pocket (a). In pocket 1 of the DRB1*1502 molecule, the side chain of glycine on position 86 is hydrogen; the lower level of steric hindrance of this side chain leads to a larger pocket (b). GLY, glycine; PHE, phenylalanine; VAL, valine. Kidney International 2018 94, 974-982DOI: (10.1016/j.kint.2018.06.005) Copyright © 2018 International Society of Nephrology Terms and Conditions

Figure 6 Structure models of the DRB1*1502 molecule and the M-type phospholipase A2 receptor (PLA2R) CLTD4-FKVFHSEKV peptide. The peptide is shown by yellow. The DRB1*1502 molecule is shown by purple and blue. Overall structure of peptide CLTD4-FKVFHSEKV and the DRB1*1502 molecule (a). Pockets of the DRB1*1502 molecule are highlighted in green. Lysine679 of the peptide could be presented by pocket 4. The nitrogen of glutamine70 in pocket 4 could then form a hydrogen bond with the oxygen of lysine679 of the peptide. The distance between these 2 atoms is 3.9 Å (b). Lysine679 of the peptide could be presented by pocket 6 and pocket 7. The oxygen of tyrosine30 in pocket 6 could form a hydrogen bond with the hydrogen of lysine679 of the peptide. The distance between these 2 atoms is 2.9 Å. The oxygen of aspartic28 in pocket 7 could form a hydrogen bond with the nitrogen of lysine679 of the peptide. The distance between these 2 atoms is 2.5 Å (c). Phenylalanine678 of the peptide could be presented by pocket 9. The oxygen of tyrosine60 in pocket 9 could form a hydrogen bond with the nitrogen of phenylalanine678 of the peptide. The distance between these 2 atoms is 2.5 Å (d). ASP, aspartate; GLN, glycine; LYS, lysine; PHE, phenylalanine; TYR, tyrosine. Kidney International 2018 94, 974-982DOI: (10.1016/j.kint.2018.06.005) Copyright © 2018 International Society of Nephrology Terms and Conditions

Figure S1 Comparisons of serum anti- M-type phospholipase A2 receptor (PLA2R) antibody levels in primary membranous nephropathy (pMN) patients with versus without the following: human leukocyte antigen (HLA)-DRB1*0301 (A); DRB1*1502 (B); the combination of DRB1*1502 and DRB1*0301 (C); DRB1*0701 (D); DRB1*0201 (E); and DQB1*0202 (F). Kidney International 2018 94, 974-982DOI: (10.1016/j.kint.2018.06.005) Copyright © 2018 International Society of Nephrology Terms and Conditions