Exome Sequencing and Prediction of Long-Term Kidney Allograft Function

Abstract

Current strategies to improve graft outcome following kidney transplantation consider information at the human leukocyte antigen (HLA) loci. Cell surface antigens, in addition to HLA, may serve as the stimuli as well as the targets for the anti-allograft immune response and influence long-term graft outcomes. We therefore performed exome sequencing of DNA from kidney graft recipients and their living donors and estimated all possible cell surface antigens mismatches for a given donor/recipient pair by computing the number of amino acid mismatches in trans-membrane proteins. We designated this tally as the allogenomics mismatch score (AMS). We examined the association between the AMS and post-transplant estimated glomerular filtration rate (eGFR) using mixed models, considering transplants from three independent cohorts (a total of 53 donor-recipient pairs, 106 exomes, and 239 eGFR measurements). We found that the AMS has a significant effect on eGFR (mixed model, effect size across the entire range of the score: -19.4 [-37.7, -1.1], P = 0.0042, χ2 = 8.1919, d.f. = 1) that is independent of the HLA-A, B, DR matching, donor age, and time post-transplantation. The AMS effect is consistent across the three independent cohorts studied and similar to the strong effect size of donor age. Taken together, these results show that the AMS, a novel tool to quantify amino acid mismatches in trans-membrane proteins in individual donor/recipient pair, is a strong, robust predictor of long-term graft function in kidney transplant recipients.

Novel Non-Histocompatibility Antigen Mismatched Variants Improve the Ability to Predict Antibody-Mediated Rejection Risk in Kidney Transplant

“…Further analysis of the 94 variants significantly associated with an increased risk of post-tx AMR located in 72 unique genes are enriched in immune-related function, supporting their role in the rejection process; in addition, these variants also map to genes that are more likely to be expressed on the cell-surface, suggesting that changes in the expression/function of these genes are more likely to be recognized by the recipients’ immune system, and support the possible generation of antibody responses to nHLA targets. These results are supported by a previous study ( 15 ), where a cohort with a small number of acute rejections was used to generate an allogenomic mismatch score that associated with transmembrane proteins predicted long-term graft function in kidney transplantation. In this study, we examine a larger number of acute rejections and also stratify risk further by considering both types of acute rejection, AMR and CMR.…”

“…Population-based assessments suggest a familial component to rejection-free tx course ( 13 ) and a recent GWAS study ( 14 ) identified two loci (PTPRO and CCDC67) as associates with a specific phenotype of CMR. In addition, amino acid mismatches in transmembrane proteins in D/R pairs ( 15 ) were identified to be a predictor of long-term graft function in kidney tx recipients, further highlighting the critical role of nHLA immunogenic epitopes in the organ tx. There have been no published studies that have systematically identified D/R nHLA epitopes that can be predictive of risk of AMR and CMR after tx.…”

Novel insights into non‐HLA alloimmunity in kidney transplantation

“…The high number of potential genome‐wide mismatches suggests that each donor and recipient pair caries a unique set of mismatched genetic variations. Mesnard et al were the first to quantify genome‐wide mismatches outside of the HLA region and developed the allogenomics mismatch score (AMS). Exome sequencing was performed in 53 living donor and recipient pairs, and the number of predicted amino acid mismatches in transmembrane proteins was calculated.…”

23rd Nantes Actualités Transplantation: “Genomics and Immunogenetics of Kidney and Inflammatory Diseases—Lessons for Transplantation”

“…56 In the field of transplantation matching, Laurent Mesnard's (Inserm UMR 1155, Paris, France) research group aimed at summarizing non-HLA-coding differences between D/R into an allogenomics mismatch score. 57 This score compares minor antigens (amino-acid mismatches) between D/R from whole-exome data and was shown to correlate with graft dysfunction. If the results have yet to be confirmed and synergized with HLA data, this very promising strategy opens the avenue for personalized medicine and development of innovative transplantomic strategies.…”