TY - JOUR
T1 - Exome chip analyses identify genes affecting mortality after HLA-matched unrelated-donor blood and marrow transplantation
AU - Zhu, Qianqian
AU - Yan, Li
AU - Liu, Qian
AU - Zhang, Chi
AU - Wei, Lei
AU - Hu, Qiang
AU - Preus, Leah
AU - Clay-Gilmour, Alyssa I.
AU - Onel, Kenan
AU - Stram, Daniel O.
AU - Pooler, Loreall
AU - Sheng, Xin
AU - Haiman, Christopher A.
AU - Zhu, Xiaochun
AU - Spellman, Stephen R.
AU - Pasquini, Marcelo
AU - McCarthy, Philip L.
AU - Liu, Song
AU - Hahn, Theresa
AU - Sucheston-Campbell, Lara E.
N1 - Funding Information:
This study was supported by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) (R01 HL102278; principal investigators, T.H. and L.E.S.-C.). This work was also supported by National Cancer Institute (NCI) grant P30CA016056, involving the use of the Roswell Park Cancer Institute Bioinformatics and Biostatistics shared resources. The Center for International Blood and Marrow Transplant Research is supported by public health service grant/cooperative agreement 5U24-CA076518 from the NCI, NHLBI, and the National Institute of Allergy and Infectious Diseases; grant/ cooperative agreement 5U10HL069294 from the NHLBI and NCI; contract HHSH250201200016C with the Health Resources and Services Administration (HRSA)/Department of Health and Human Services; 2 grants (N00014-15-1-0848 and N00014-16-1-2020) from the Office of Naval Research; and support from Alexion, Amgen, Inc.*; an anonymous donation to the Medical College of Wisconsin; Astellas Pharma US; AstraZeneca; Be the Match Foundation; Bluebird Bio, Inc.*; Bristol-Myers Squibb Oncology*; Celgene Corporation*; Cellular Dynamics International, Inc.; Chimerix, Inc.*; Fred Hutchinson Cancer Research Center; Gamida Cell Ltd.; Genentech, Inc.; Genzyme Corporation; Gilead Sciences, Inc.*; Health Research, Inc.; Roswell Park Cancer Institute; HistoGenetics, Inc.; Incyte Corporation; Janssen Scientific Affairs, LLC; Jazz Pharmaceuticals, Inc.*; Jeff Gordon Children’s Foundation; The Leukemia & Lymphoma Society; Medac, GmbH; MedImmune; The Medical College of Wisconsin; Merck & Co, Inc.*; Mesoblast; MesoScale Diagnostics, Inc.; Miltenyi Biotec, Inc.*; National Marrow Donor Program; Neovii Biotech NA, Inc.; Novartis Pharmaceuticals Corporation; Onyx Pharmaceuticals; Optum Healthcare Solutions, Inc.; Otsuka America Pharmaceutical, Inc.; Otsuka Pharmaceutical Co, Ltd. Japan; Patient-Centered Outcomes Research Institute; Perkin Elmer, Inc.; Pfizer, Inc; Sanofi US*; Seattle Genetics*; Spectrum Pharmaceuticals, Inc.*; St. Baldrick’s Foundation; Sunesis Pharmaceuticals, Inc.*; Swedish Orphan Biovitrum, Inc.; Takeda Oncology; Telomere Diagnostics, Inc.; University of Minnesota; and Wellpoint, Inc.* *Corporate members.
Publisher Copyright:
© 2018 by The American Society of Hematology
PY - 2018/5/31
Y1 - 2018/5/31
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2017-11-817973
DO - 10.1182/blood-2017-11-817973
M3 - Article
C2 - 29610366
AN - SCOPUS:85048119147
SN - 0006-4971
VL - 131
SP - 2490
EP - 2499
JO - Blood
JF - Blood
IS - 22
ER -