Genome-Wide Association Analyses Identify Variants in IRF4 Associated With Acute Myeloid Leukemia and Myelodysplastic Syndrome Susceptibility
Year: 2021
Type: article
Study design: Observational Study
Abstract: ABSTRACT 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 (2309 cases and 2814 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, P meta =2.8×10 -12 ) in patients carrying the T allele at rs12203592 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, P meta =1.0×10 -7 ). The identification of IRF4 by both GWAS and TWAS contributes valuable insight on the role of genetic variation in AML and MDS susceptibility.
Source: Frontiers in Genetics
Authors: Junke Wang, Alyssa I. Clay-Gilmour, Ezgi Karaesmen, Abbas Rizvi, Qianqian Zhu, Li Yan, Leah Preus, Song Liu, Yiwen Wang, Elizabeth Griffiths, Daniel O. Stram, Loreall Pooler, Xin Sheng, Christopher Haiman, David Van Den Berg, Amy Webb, Guy Brock, Stephen Spellman, Marcelo Pasquini, Philip McCarthy, James Allan, Friedrich Stölzel, Kenan Onel, Theresa Hahn, Lara E. Sucheston-Campbell
Institutions: The Ohio State University, Mayo Clinic, University of South Carolina, Roswell Park Comprehensive Cancer Center, University of Southern California, Medical College of Wisconsin, Newcastle University, University Hospital Carl Gustav Carus, Technische Universität Dresden, Mount Sinai Medical Center
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,950
Funders: U.S. Department of Defense, U.S. Department of Health and Human Services, Be The Match Foundation, Amgen, Bristol-Myers Squibb, Pfizer, Astellas Pharma US, AstraZeneca, Sanofi, WellPoint, Gilead Sciences, Health Research, Patient-Centered Outcomes Research Institute, Alexion Pharmaceuticals, Spectrum Pharmaceuticals, Celgene, HistoGenetics, Ohio State University, University of Minnesota, Novartis Pharmaceuticals Corporation, Medical College of Wisconsin, Jazz Pharmaceuticals, Sunesis, Pelotonia, bluebird bio, Chimerix, Telomere Diagnostics, Janssen Scientific Affairs, Incyte, Otsuka America, Astellas Pharma, Otsuka Pharmaceutical, Swedish Orphan Biovitrum, Medac, Health Resources and Services Administration, Genentech, Onyx Pharmaceuticals, U.S. Navy, Takeda Oncology, National Heart, Lung, and Blood Institute, Office of Naval Research, National Cancer Institute, National Institute of Allergy and Infectious Diseases
Awards: G1384772222, G1626132361, G1769371581, G1770367129, Genetic susceptibility to unrelated donor stem cell transplant-related mortality, G226656, G2814340220, G3564874410, G3816434386, G3847019374, G4298420724, G4373273904, G4414605889, G4930744573, G5214925129, G5442330786, G5706912026, Genetic susceptibility to acute lymphocytic and myeloid leukemia, G6771248800, G6850693576, G7506463667, Blood & Marrow Transplant Clinical Trials Network Data Coordinating Center, G8649229721, G8876996369, A Data Resource for Blood and Marrow Transplants and Adoptive Cellular Therapy Research
OpenAlex ID: W3173600570