title: HLA Amino Acid Polymorphisms and Kidney Allograft Survival.
abstract: The association of HLA mismatching with kidney allograft survival has been well established. We examined whether amino acid (AA) mismatches (MMs) at the antigen recognition site of HLA molecules represent independent and incremental risk factors for kidney graft failure (GF) beyond those MMs assessed at the antigenic (2-digit) specificity.
  
  
  
  Data on 240 024 kidney transplants performed between 1987 and 2009 were obtained from the Scientific Registry of Transplant Recipients. We imputed HLA-A, -B, and -DRB1 alleles and corresponding AA polymorphisms from antigenic specificity through the application of statistical and population genetics inferences. GF risk was evaluated using Cox proportional-hazards regression models adjusted for covariates including patient and donor risk factors and HLA antigen MMs.
  
  
  
  We show that estimated AA MMs at particular positions in the peptide-binding pockets of HLA-DRB1 molecule account for a significant incremental risk that was independent of the well-known association of HLA antigen MMs with graft survival. A statistically significant linear relationship between the estimated number of AA MMs and risk of GF was observed for HLA-DRB1 in deceased donor and living donor transplants. This relationship was strongest during the first 12 months after transplantation (hazard ratio, 1.30 per 15 DRB1 AA MM; P < 0.0001).
  
  
  
  This study shows that independent of the well-known association of HLA antigen (2-digit specificity) MMs with kidney graft survival, estimated AA MMs at peptide-binding sites of the HLA-DRB1 molecule account for an important incremental risk of GF.
authors.affiliation: 1 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA. 2 Arbor Research Collaborative for Health, Ann Arbor, MI. 3 National Marrow Donor Program, Minneapolis, MN. 4 Department of Pathology, Stanford University, Palo Alto, CA. 5 Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA.
authors.forename: Malek
authors.initials: M
authors.lastname: Kamoun
authors.forename: Keith P
authors.initials: KP
authors.lastname: McCullough
authors.forename: Martin
authors.initials: M
authors.lastname: Maiers
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Fernandez Vina
authors.forename: Hongzhe
authors.initials: H
authors.lastname: Li
authors.forename: Valerie
authors.initials: V
authors.lastname: Teal
authors.forename: Alan B
authors.initials: AB
authors.lastname: Leichtman
authors.forename: Robert M
authors.initials: RM
authors.lastname: Merion
mesh_terms: D005500:Follow-Up Studies; D005819:Genetic Markers; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology*; D006680:HLA Antigens / Q000235:genetics* / Q000276:immunology; D006801:Humans; D016030:Kidney Transplantation; D016014:Linear Models; D011110:Polymorphism, Genetic; D016016:Proportional Hazards Models
chemical_list: D005819:Genetic Markers; D006680:HLA Antigens