Biol Blood Marrow Transplant. 2018 Dec 8. pii: S1083-8791(18)30805-X. doi: 10.1016/j.bbmt.2018.12.006. [Epub ahead of print]
Direct HLA Genetic Comparisons Identify Highly Matched Unrelated Donor/Recipient Pairs with Improved Transplant Outcome.
Vazirabad I1, Chhabra S2, Nytes J1, Mehra V1, Narra RK2, Szabo A3, Jerkins JH2, Dhakal B2, Hari P2, Anderson MW4.
HLA matching by allele-level genotyping is largely based on genetic similarity between a few exons which encode the antigen recognition domain (ARD) of the HLA protein. Next-generation sequencing (NGS) can identify HLA genetic polymorphisms in non-ARD encoding exons, introns, and untranslated regions, but the impact of these polymorphisms on hematopoietic cell transplant (HCT) outcomes is unclear. We performed NGS-based sequencing of eleven HLA loci on a well-characterized retrospective cohort of 166 unrelated donor/recipient HCT pairs. Genetic differences between HCT pairs were identified and visualized using a novel bioinformatics approach which directly compares phased full-length HLA sequences. Our approach was able to correctly classify HCT pairs without known HLA allele-level mismatches, and also identify a subset of HLA-allele matched HCT pairs with very few to no genetic differences in the sequenced HLA regions. This highly HLA genetically matched unrelated HCT group shows improved overall survival and reduced acute GVHD when compared to HCT pairs with HLA-allele level mismatches. These results suggest that direct genetic matching of HLA loci may offer an additional means of HCT donor selection beyond traditional HLA allele comparisons and suggests that genetic similarity as defined by HLA sequencing may have a novel role in unrelated HCT donor selection. Finally, our approach can enable larger cohort studies with adequate power to detect differences in other HCT outcomes based on genetic similarity within the HLA loci.
Allogeneic transplantation; HLA; Next-generation sequencing; Unrelated donor