Journal
FRONTIERS IN GENETICS
Volume 12, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fgene.2021.554948
Keywords
acute myeloid leukemia; myelodysplastic syndrome; genome-wide association study; blood and marrow transplantation; pleiotropy
Categories
Funding
- National Institute of Health
- Pelotonia Foundation Graduate Student Fellowship
- Pelotonia Fellowship Program
- Mayo Clinic R25 Training Grant [CA9204]
- Public Health Service from the National Cancer Institute (NCI) [5U24-CA076518]
- National Heart, Lung and Blood Institute (NHLBI)
- National Institute of Allergy and Infectious Diseases (NIAID)
- NHLBI [5U10HL069294]
- NCI
- Health Resources and Services Administration (HRSA/DHHS) [HHSH250201200016C]
- Office of Naval Research [N00014-15-1-0848, N00014-16-1-2020]
- Alexion
- Amgen, Inc.
- 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
- Leukemia & Lymphoma Society
- Medac, GmbH
- MedImmune
- 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
- PCORI
- 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
- Wellpoint, Inc.
- [1R01HL102278]
- [1R03CA188733]
Ask authors/readers for more resources
This study identified an increased risk for de novo AML and MDS in patients carrying the T allele at the s12203592 locus in the IRF4 gene, which regulates myeloid and lymphoid hematopoietic differentiation. Additionally, increased IRF4 gene expression was found to be associated with an increased risk of de novo AML and MDS.
The role of common genetic variation in susceptibility to acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS), a group of rare clonal hematologic disorders characterized by dysplastic hematopoiesis and high mortality, remains unclear. We performed AML and MDS genome-wide association studies (GWAS) in the DISCOVeRY-BMT cohorts (2,309 cases and 2,814 controls). Association analysis based on subsets (ASSET) was used to conduct a summary statistics SNP-based analysis of MDS and AML subtypes. For each AML and MDS case and control we used PrediXcan to estimate the component of gene expression determined by their genetic profile and correlate this imputed gene expression level with risk of developing disease in a transcriptome-wide association study (TWAS). ASSET identified an increased risk for de novo AML and MDS (OR = 1.38, 95% CI, 1.26-1.51, Pmeta = 2.8 x 10(-12)) in patients carrying the T allele at s12203592 in Interferon Regulatory Factor 4 (IRF4), a transcription factor which regulates myeloid and lymphoid hematopoietic differentiation. Our TWAS analyses showed increased IRF4 gene expression is associated with increased risk of de novo AML and MDS (OR = 3.90, 95% CI, 2.36-6.44, Pmeta = 1.0 x 10(-7)). The identification of IRF4 by both GWAS and TWAS contributes valuable insight on the role of genetic variation in AML and MDS susceptibility.
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