ATC Abstracts

American Transplant Congress abstracts

HLA-DRB1 and DQB1 Amino Acid Mismatches as Determinants of Kidney Allograft Failure

1Tulane Cancer Center, Tulane University, New Orleans, LA, 2Arbor Research Collaborative for Health, Ann Arbor, MI, 3Tulane University, New Orleans, LA, 4University of Pennsylvania, Philadelphia, PA

Meeting: 2022 American Transplant Congress

Abstract number: 935

Keywords: , , ,

Topic: Basic Science » Basic Science » 11 - Histocompatibility and Immunogenetics

Session Information

Session Name: Histocompatibility and Immunogenetics

Session Type: Poster Abstract

Date: Sunday, June 5, 2022

Session Time: 7:00pm-8:00pm

 Presentation Time: 7:00pm-8:00pm

Location: Hynes Halls C & D

*Purpose: It was previously reported that HLA-DRB1 amino acid (AA) mismatches (MMs) at peptide-binding pockets of this molecule account for significant incremental risk of kidney graft failure (GF), independent of the long-established association of HLA ABDR antigen (Ag) MMs with GF. We expanded on this prior work by separately examining the incremental risk of graft failure associated with HLA-DRB1 and DQB1 AA MMs beyond that of Ag-level MMs.

*Methods: Data on 141,588 adult-recipient deceased-donor kidney-alone transplants (TXPs) performed between 2000 and 2017 were obtained from the Scientific Registry of Transplant Recipients. We computed DQ Ag MM covering the 2013-2017 TXP period. HLA-A, B, C, DRB1, and DQB1 alleles and corresponding AA polymorphisms were imputed from antigenic specificities using high resolution haplotype frequency data. GF risk was evaluated using Cox proportional-hazards regression models adjusted for covariates including patient and donor risk factors and HLA Ag-level ABDR MMs. Regression results from 10 separate realizations of AA MMs were combined using Rubin’s rules for multiple imputation.

*Results: The impact of HLA-DR Ag MM on GF was replicated; however, HLA-DQ Ag MM was not associated with GF risk after adjusting for ABDR Ag MM (not shown). In contrast, both DRB1 and DQB1 AAMM improved risk stratification after adjusting for ABDR Ag MM. Associations between AAMM and risk of GF are shown during the first year after TXP (Table 1) and after the first year (Table 2), conditional on function at 1 year. DRB1 and DQB1 AAMMs had higher adjusted hazard ratios (HR) during the first year after TXP [DRB1 AA HR 1.12 (1.03-1.21) and DQB1 AA HR 1.08 (95% CI 1.02-1.14)] compared with after the first year after TXP, [DRB1 AA HR 1.03 (0.98-1.08) and DQB1 AA HR 1.04 (1.01-1.08)].

Table 1: GF risk by AAMM (all loci in each model) censored at 1 year after transplant
<1 yr Covariate-adjusted Covariate- and HLA antigen MM-adjusted
HR (per AAMM) 95% CI t and p HR (per AAMM) 95% CI t and p
A 1.00 0.95-1.05 -0.02 and 0.9812 0.97 0.91-1.03 -1.06 and 0.2883
B 0.99 0.93-1.05 -0.33 and 0.7423 0.94 0.88-1.01 -1.66 and 0.0964
C 0.97 0.90-1.03 -0.98 and 0.3262 0.99 0.92-1.06 -0.41 and 0.68
DRB1 1.12 1.04-1.21 2.97 and 0.003 1.12 1.03-1.21 2.56 and 0.0106
DQB1 1.07 1.01-1.14 2.38 and 0.0175 1.08 1.02-1.14 2.51 and 0.0121
Data is with and without adjustment for HLA-A, B and DR antigen-level MMs. Kidney-alone transplants between 2000-2017 with follow-up censored at November 2018.
Table 2: GF risk by AAMM (all loci included in each model) after first year after transplant
1+ yr Covariate-adjusted Covariate- and HLA antigen MM-adjusted
HR (per AAMM) 95% CI t and p HR (per AAMM) 95% CI t and p
A 1.03 1.00-1.06 1.91 and 0.0567 1.00 0.97-1.04 0.08 and 0.9368
B 1.00 0.97-1.03 -0.07 and 0.9414 0.96 0.93-1.00 -2.02 and 0.0435
C 0.96 0.93-1.00 -2.11 and 0.0352 0.99 0.95-1.02 -0.76 and 0.446
DRB1 1.06 1.02-1.11 2.92 and 0.0035 1.03 0.98-1.08 1.23 and 0.2185
DQB1 1.04 1.01-1.08 2.38 and 0.0175 1.04 1.01-1.08 2.38 and 0.0174
Data is with and without adjustment for HLA-A, B and DR antigen-level MMs. Kidney-alone transplants between between 2000-2017 with follow-up censored at November 2018.

*Conclusions: This study of SRTR data shows that during the first year after TXP, both DRB1 and DQB1 AA MMs increase risk of GF, with DRB1 AA MMs having the stronger effect. Discovery of AA MM associations should be validated in future studies based on high resolution genotyping.

To cite this abstract in AMA style:

Gragert L, McCullough KP, Wager GL, Urbanowicz R, Merion RM, Kamoun M. HLA-DRB1 and DQB1 Amino Acid Mismatches as Determinants of Kidney Allograft Failure [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/hla-drb1-and-dqb1-amino-acid-mismatches-as-determinants-of-kidney-allograft-failure/. Accessed November 21, 2024.

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