Epitopes as characterized by antibody-verified eplet mismatches determine risk of kidney transplant loss.

To optimize strategies that mitigate the risk of graft loss associated with HLA incompatibility, we evaluated whether sequence defined HLA targets (eplets) that result in donor-specific antibodies are associated with transplant outcomes. To define this, we fit multivariable Cox proportional hazard models in a cohort of 118 382 United States first kidney transplant recipients to assess risk of death-censored graft failure by increments of ten antibody-verified eplet mismatches. To verify robustness of our findings, we conducted sensitivity analysis in this United States cohort and assessed the role of antibody-verified eplet mismatches as autonomous predictors of transplant glomerulopathy in an independent Canadian cohort. Antibody-verified eplet mismatches were found to be independent predictors of death-censored graft failure with hazard ratios of 1.231 [95% confidence interval 1.195, 1. 268], 1.268 [1.231, 1.305] and 1.411 [1.331, 1.495] for Class I (HLA-A, B, and C), -DRB1 and -DQB1 loci, respectively. To address linkage disequilibrium between HLA-DRB1 and -DQB1, we fit models in a subcohort without HLA-DQB1 eplet mismatches and found hazard ratios for death-censored graft failure of 1.384 [1.293, 1.480] for each additional antibody-verified HLA-DRB1 eplet mismatch. In a subcohort without HLA-DRB1 mismatches, the hazard ratio was 1.384 [1.072, 1.791] for each additional HLA-DQB1 mismatch. In the Canadian cohort, antibody-verified eplet mismatches were independent predictors of transplant glomerulopathy with hazard ratios of 5.511 [1.442, 21.080] for HLA-DRB1 and 3.640 [1.574, 8.416] for -DRB1/3/4/5. Thus, donor-recipient matching for specific HLA eplets appears to be a feasible and clinically justifiable strategy to mitigate risk of graft loss.

Performance of an allele-level multi-locus HLA genotype imputation tool in hematopoietic stem cell donors from Quebec.

INTRODUCTION: Donor-recipient HLA compatibility is an important determinant of transplant outcomes. Allele-group to allele-level imputations help assign HLA genotypes when allele-level genotypes are not available during donor selection. METHODS: We evaluated the performance of HaploStats, an allele-level multi-locus HLA genotype imputation tool from the National Marrow Donor Program, in a cross-sectional study including hematopoietic stem cell donors (HSCD) from Quebec, Canada. A total of 144 self-identified Caucasian HSCD genotyped at the allele-group and allele-level for HLA-A, -B, -C, -DRB1, and -DQB1 loci were studied. We compared allele-level genotypes imputed by HaploStats to those obtained by the reference standard, sequenced-based typing (SBT). RESULTS: Imputation performance, determined by allele-level genotype recall (fraction of matching imputed and sequenced genotypes) was 97%, 96%, 95%, 84%, and 81% for HLA-A, -B, -C, -DRB1, and -DQB1 loci, respectively. Our sample deviated from Hardy-Weinberg equilibrium only at the HLA-DRB1 locus. Residual ambiguity, determined by typing resolution scores (TRS), was greatest for HLA class II loci (average TRS 0.65 and 0.80 for DRB1 and DQB1, respectively). In contrast, average TRS of 0.88, 0.84, and 0.92 was observed for HLA-A, -B, and -C, respectively. CONCLUSIONS: HLA allele imputation from ambiguous genotypes demonstrate satisfactory prediction accuracy for HLA class I but modest prediction accuracy for HLA class II loci in self-identified Caucasian HSCD from Quebec. While consideration of high-resolution allele and haplotype frequencies in the Quebec population may improve the performance of available allele-level multi-locus genotype imputation tools in Quebec, this study suggests that genotyping at the first two field level should be conducted whenever possible.