Analysis of single nucleotide polymorphisms in the gamma block of the major histocompatibility complex in association with clinical outcomes of hematopoietic cell transplantation: A Center for International Blood and Marrow Transplant Research study Journal Article
| Authors: | Askar, M.; Sayer, D.; Wang, T.; Haagenson, M.; Spellman, S. R.; Lee, S. J.; Madbouly, A.; Fleischhauer, K.; Hsu, K. C.; Verneris, M. R.; Thomas, D.; Zhang, A.; Sobecks, R. M.; Majhail, N. S.; on behalf of the Center for International Blood and Marrow Transplant Research Immunology Working Committee |
| Article Title: | Analysis of single nucleotide polymorphisms in the gamma block of the major histocompatibility complex in association with clinical outcomes of hematopoietic cell transplantation: A Center for International Blood and Marrow Transplant Research study |
| Abstract: | HLA haplotype mismatches have been associated with an elevated risk of acute graft-versus-host disease (aGVHD) in patients undergoing HLA-matched unrelated donor (URD) hematopoietic cell transplantation (HCT). The gamma block (GB) is located in the central MHC region between beta and delta blocks (encoding HLA-B and -C and HLA-DQ and -DR antigens, respectively) and contains numerous inflammatory and immune regulatory genes, including Bf, C2, and C4 genes. A single-center study showed that mismatches in SNPs c.2918+98G, c.3316C, and c.4385C in the GB block (C4 SNPs) were associated with higher risk of grade III-IV aGVHD. We investigated the association of GB SNP (GBS) mismatches with outcomes after 10/10 and 9/10 URD HCT (n = 714). The primary outcome was acute GVHD. Overall survival, disease-free survival, transplantation-related mortality, relapse, chronic GVHD, and engraftment were also analyzed. DNA samples were GBS genotyped by identifying 338 SNPs across 20 kb using the Illumina NGS platform. The overall 100-day incidence of aGVHD grade II-IV and II-IV were 41% and 17%, respectively. The overall incidence of matching at all GBSs tested and at the C4 SNPs were 23% and 81%, respectively. Neither being matched across all GB SNPs tested (versus mismatched) nor having a higher number of GBS mismatches was associated with transplantation outcomes. There was no association between C4 SNP mismatches and outcomes except for an unexpected significant association between having 2 C4 SNP mismatches and a higher hazard ratio (HR) for relapse (association seen in 15 patients only; HR, 3.38, 95% confidence interval, 1.75 to 6.53; P =.0003). These data do not support the hypothesis that mismatching at GB is associated with outcomes after HCT. © 2018 |
| Keywords: | adult; controlled study; aged; human cell; major clinical study; overall survival; single nucleotide polymorphism; mortality; disease free survival; methotrexate; genetic analysis; disease association; genetic association; genotype; gene frequency; relapse; hematopoietic stem cell transplantation; transplantation; acute lymphoblastic leukemia; haplotype; acute graft versus host disease; chronic graft versus host disease; engraftment; hla matching; myeloablative conditioning; myelodysplastic syndrome; peripheral blood stem cell; gene identification; hazard ratio; major histocompatibility complex; calcineurin inhibitor; tacrolimus; dna determination; cyclosporine; genomic dna; clinical outcome; acute myeloid leukemia; mycophenolate mofetil; human; male; female; article; overlapping gene; gamma block; mismatched unrelated donor |
| Journal Title: | Biology of Blood and Marrow Transplantation |
| Volume: | 25 |
| Issue: | 4 |
| ISSN: | 1083-8791 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2019-04-01 |
| Start Page: | 664 |
| End Page: | 672 |
| Language: | English |
| DOI: | 10.1016/j.bbmt.2018.12.008 |
| PUBMED: | 30537553 |
| PROVIDER: | scopus |
| PMCID: | PMC6453713 |
| DOI/URL: | |
| Notes: | Source: Scopus |
