Exome chip analyses identify genes affecting mortality after HLA-matched unrelated-donor blood and marrow transplantation. Blood 2018 May 31;131(22):2490-2499
Date
04/04/2018Pubmed ID
29610366Pubmed Central ID
PMC5981168DOI
10.1182/blood-2017-11-817973Scopus ID
2-s2.0-85048119147 (requires institutional sign-in at Scopus site) 17 CitationsAbstract
Although survival outcomes have significantly improved, up to 40% of patients die within 1 year of HLA-matched unrelated-donor blood and marrow transplantation (BMT). To identify non-HLA genetic contributors to mortality after BMT, we performed the first exome-wide association study in the DISCOVeRY-BMT cohorts using the Illumina HumanExome BeadChip. This study includes 2473 patients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome and 2221 10/10 HLA-matched donors treated from 2000 to 2011. Single-variant and gene-level analyses were performed on overall survival (OS), transplantation-related mortality (TRM), and disease-related mortality (DRM). Genotype mismatches between recipients and donors in a rare nonsynonymous variant of testis-expressed gene TEX38 significantly increased risk of TRM, which was more dramatic when either the recipient or donor was female. Using the SKAT-O test to evaluate gene-level effects, variant genotypes of OR51D1 in recipients were significantly associated with OS and TRM. In donors, 4 (ALPP, EMID1, SLC44A5, LRP1), 1 (HHAT), and 2 genes (LYZL4, NT5E) were significantly associated with OS, TRM, and DRM, respectively. Inspection of NT5E crystal structures showed 4 of the associated variants affected the enzyme structure and likely decreased the catalytic efficiency of the enzyme. Further confirmation of these findings and additional functional studies may provide individualized risk prediction and prognosis, as well as alternative donor selection strategies.
Author List
Zhu Q, Yan L, Liu Q, Zhang C, Wei L, Hu Q, Preus L, Clay-Gilmour AI, Onel K, Stram DO, Pooler L, Sheng X, Haiman CA, Zhu X, Spellman SR, Pasquini M, McCarthy PL, Liu S, Hahn T, Sucheston-Campbell LEAuthor
Marcelo C. Pasquini MD, MS Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
5'-NucleotidaseAdolescent
Adult
Bone Marrow Transplantation
Exome
Female
GPI-Linked Proteins
Genotype
Histocompatibility Testing
Humans
Leukemia, Myeloid, Acute
Male
Middle Aged
Models, Molecular
Myelodysplastic Syndromes
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Transplantation, Homologous
Treatment Outcome
Unrelated Donors
Young Adult
