Genome-wide Association Study Identifies HLA-DPB1 as a Significant Risk Factor for Severe Aplastic Anemia

Sharon A. Savage; Mathias Viard; Colm O’hUigin; Weiyin Zhou; Meredith Yeager; Shengchao Alfred Li; Tao Wang; Veron Ramsuran; Nicolas Vince; Aurelie Vogt; Belynda Hicks; Laurie Burdett; Charles Chung; Michael Dean; Kelvin C. de Andrade; Neal D. Freedman; Sonja I. Berndt; Nathaniel Rothman; Qing Lan; James R. Cerhan; Susan L. Slager; Yawei Zhang; Lauren R. Teras; Michael Haagenson; Stephen J. Chanock; Stephen R. Spellman; Youjin Wang; Amanda Willis; Medhat Askar; Stephanie J. Lee; Mary Carrington; Shahinaz M. Gadalla

doi:10.1016/j.ajhg.2020.01.004

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Genome-wide Association Study Identifies HLA-DPB1 as a Significant Risk Factor for Severe Aplastic Anemia

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Genome-wide Association Study Identifies HLA-DPB1 as a Significant Risk Factor for Severe Aplastic Anemia

Sharon A. Savage, Mathias Viard, Colm O’hUigin, Weiyin Zhou, Meredith Yeager, Shengchao Alfred Li, Tao Wang, Veron Ramsuran, Nicolas Vince, Aurelie Vogt, …

American journal of human genetics, Vol.106(2), pp.264-271

02/06/2020

DOI: 10.1016/j.ajhg.2020.01.004

PMCID: PMC7010969

PMID: 32004448

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Abstract

Severe aplastic anemia (SAA) is a rare disorder characterized by hypoplastic bone marrow and progressive pancytopenia. The etiology of acquired SAA is not understood but is likely related to abnormal immune responses and environmental exposures. We conducted a genome-wide association study of individuals with SAA genetically matched to healthy controls in discovery (359 cases, 1,396 controls) and validation sets (175 cases, 1,059 controls). Combined analyses identified linked SNPs in distinct blocks within the major histocompatibility complex on 6p21. The top SNP encodes p.Met76Val in the P4 binding pocket of the HLA class II gene HLA-DPB1 (rs1042151A>G, odds ratio [OR] 1.75, 95% confidence interval [CI] 1.50–2.03, p = 1.94 × 10−13) and was associated with HLA-DP cell surface expression in healthy individuals (p = 2.04 × 10−6). Phylogenetic analyses indicate that Val76 is not monophyletic and likely occurs in conjunction with different HLA-DP binding groove conformations. Imputation of HLA-DPB1 alleles revealed increased risk of SAA associated with Val76-encoding alleles DPB1∗03:01, (OR 1.66, p = 1.52 × 10−7), DPB1∗10:01 (OR 2.12, p = 0.0003), and DPB1∗01:01 (OR 1.60, p = 0.0008). A second SNP near HLA-B, rs28367832G>A, reached genome-wide significance (OR 1.49, 95% CI 1.22–1.78, p = 7.27 × 10−9) in combined analyses; the association remained significant after excluding cases with clonal copy-neutral loss-of-heterozygosity affecting class I HLA genes (8.6% of cases and 0% of controls). SNPs in the HLA class II gene HLA-DPB1 and possibly class I (HLA-B) are associated with SAA. The replacement of Met76 to Val76 in certain HLA-DPB1 alleles might influence risk of SAA through mechanisms involving DP peptide binding specificity, expression, and/or other factors affecting DP function.

Etiology

aplastic anemia

bone marrow failure

genome-wide association study

GWAS

hematpoietic cell transplantation

HLA

HLA-DP

Details

Title: Subtitle: Genome-wide Association Study Identifies HLA-DPB1 as a Significant Risk Factor for Severe Aplastic Anemia
Creators: Sharon A. Savage - National Cancer Institute
Mathias Viard - Frederick National Laboratory for Cancer Research
Colm O’hUigin - Frederick National Laboratory for Cancer Research
Weiyin Zhou - Leidos Biomedical Research Inc.
Meredith Yeager - Leidos Biomedical Research Inc.
Shengchao Alfred Li - Leidos Biomedical Research Inc.
Tao Wang - Medical College of Wisconsin
Veron Ramsuran - University of KwaZulu-Natal
Nicolas Vince - Nantes Université
Aurelie Vogt - Leidos Biomedical Research Inc.
Belynda Hicks - Frederick National Laboratory for Cancer Research
Laurie Burdett - Leidos Biomedical Research Inc.
Charles Chung - Frederick National Laboratory for Cancer Research
Michael Dean - National Cancer Institute
Kelvin C. de Andrade - National Cancer Institute
Neal D. Freedman - National Cancer Institute
Sonja I. Berndt - National Cancer Institute
Nathaniel Rothman - National Cancer Institute
Qing Lan - National Cancer Institute
James R. Cerhan - Mayo Clinic
Susan L. Slager - Mayo Clinic
Yawei Zhang - Yale University
Lauren R. Teras - American Cancer Society
Michael Haagenson - Medical College of Wisconsin
Stephen J. Chanock - National Cancer Institute
Stephen R. Spellman - Medical College of Wisconsin
Youjin Wang - National Cancer Institute
Amanda Willis - Baylor University Medical Center
Medhat Askar - Baylor University Medical Center
Stephanie J. Lee - Fred Hutch Cancer Center
Mary Carrington - Ragon Institute of MGH, MIT and Harvard
Shahinaz M. Gadalla - National Cancer Institute
Resource Type: Journal article
Publication Details: American journal of human genetics, Vol.106(2), pp.264-271
Publisher: Elsevier Inc
DOI: 10.1016/j.ajhg.2020.01.004
PMID: 32004448
PMCID: PMC7010969
ISSN: 0002-9297
eISSN: 1537-6605
Grant note: DOI: 10.13039/100000006, name: Office of Naval Research; DOI: 10.13039/100000050, name: National Heart, Lung, and Blood Institute; DOI: 10.13039/100007197, name: U.S. Public Health Service; DOI: 10.13039/100000102, name: Health Resources and Services Administration; DOI: 10.13039/100012728, name: Frederick National Laboratory for Cancer Research; DOI: 10.13039/100000054, name: National Cancer Institute; DOI: 10.13039/100000054, name: National Cancer Institute
Language: English
Date published: 02/06/2020
Academic Unit: Epidemiology
Record Identifier: 9984368218202771

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