Recipients Receiving Better HLA-Matched Hematopoietic Cell Transplantation Grafts, Uncovered by a Novel HLA Typing Method, Have Superior Survival: A Retrospective Study

Abstract

HLA matching at an allelic-level resolution for volunteer unrelated donor (VUD) hematopoietic cell transplantation (HCT) results in improved survival and fewer post-transplant complications. Limitations in typing technologies used for the hyperpolymorphic HLA genes have meant that variations outside of the antigen recognition domain (ARD) have not been previously characterized in HCT. Our aim was to explore the extent of diversity outside of the ARD and determine the impact of this diversity on transplant outcome. Eight hundred ninety-one VUD-HCT donors and their recipients transplanted for a hematologic malignancy in the United Kingdom were retrospectively HLA typed at an ultra-high resolution (UHR) for HLA-A,-B,-C,-DRB1,-DQB1, and-DPB1 using nextgeneration sequencing technology. Matching was determined at full gene level for HLA class I and at a coding DNA sequence level for HLA class II genes. The HLA matching status changed in 29.1% of pairs after UHR HLA typing. The 12/12 UHR HLA matched patients had significantly improved 5-year overall survival when compared with those believed to be 12/12 HLA matches based on their original HLA typing but were found to be mismatched after UHR HLA typing (54.8% versus 30.1%, P = .022). Survival was also significantly better in 12/12 UHR HLAmatched patients when compared with those with any degree of mismatch at this level of resolution (55.1% versus 40.1%, P = .005). This study shows that better HLA matching, found when typing is done at UHR that includes exons outside of the ARD, introns, and untranslated regions, can significantly improve outcomes for recipients of a VUD-HCT for a hematologic malignancy and should be prospectively performed at donor selection.

Evaluation of the AllType kit for HLA typing using the Ion Torrent S5 XL platform

“…Determining the sequence of HLA proteins expressed by a recipient or donor by exon typing without ambiguity in the second field is considered sufficient for current clinical practice . However, our understanding of the impact of polymorphisms in coding positions out of the peptide‐binding groove, in non‐coding regions on HLA expression, disease susceptibility, and transplantation outcomes is continuing to evolve, and new perspectives in terms of NGS applications are emerging . Moreover, nucleotide substitutions, insertions, and deletions in the enhancer–promoter, intron, and 3′‐UTR regions can result in null alleles requiring identification in clinical settings …”

“…7 However, our understanding of the impact of polymorphisms in coding positions out of the peptide-binding groove, in non-coding regions on HLA expression, disease susceptibility, and transplantation outcomes is continuing to evolve, and new perspectives in terms of NGS applications are emerging. [9][10][11][12] Moreover, nucleotide substitutions, insertions, and deletions in the enhancer-promoter, intron, and 3 0 -UTR regions can result in null alleles requiring identification in clinical settings. 13 NGS methods are based principally on the following steps: immobilization of the DNA sample onto a solid support, cyclic sequencing reactions at the clonal level using automated fluidic devices, and detection of millions of simultaneous molecular events.…”

Review article: the genetics of the human leucocyte antigen region in inflammatory bowel disease

“…Researchers have now demonstrated that typing HLA to the fourth field reveals previously “hidden” haplotypes, such as B*07:02:01~C*07:02:01:03, B*07:06:01~07:02:01:01 . With the ability to determine variation to this level of resolution, more distinct HLA associations and additional variation that is of clinical relevance, may become apparent . In addition, there is a lack of replication of results, in part due to the very large, genotyped, cohorts required to conduct accurate and robust GWAS studies.…”

“…116 With the ability to determine variation to this level of resolution, more distinct HLA associations and additional variation that is of clinical relevance, may become apparent. 116,117 In addition, there is a lack of replication of results, in part due to the very large, genotyped, cohorts required to conduct accurate and robust GWAS studies. Beyond this there have been concerns raised over the ability of GWAS studies to identify biologically important genes/genotypes due to complex genomic interactions, something highly relevant to the HLA region.…”

A Diploid Assembly-based Benchmark for Variants in the Major Histocompatibility Complex

“…The current state-of-the-art methods use next generation sequencing (NGS) to sequence a subset of exons in several HLA genes and result in a high-resolution "HLA type" that specifies the sequence in these exons. 1 Recently, a new method to characterize the HLA at even higher resolution was shown to have the potential to improve outcomes in transplantation in a retrospective study 2 . Other genes in the MHC are also important for transplantation 3 , HIV infection 4 , and many other diseases 5 .…”