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. CerhanSusan 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

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


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 DPB103:01, (OR 1.66, p = 1.52 × 10−7), DPB110:01 (OR 2.12, p = 0.0003), and DPB101:01 (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.

Original languageEnglish (US)
Pages (from-to)264-271
Number of pages8
JournalAmerican journal of human genetics
Issue number2
StatePublished - Feb 6 2020


  • GWAS
  • HLA
  • HLA-DP
  • aplastic anemia
  • bone marrow failure
  • etiology
  • genome-wide association study
  • hematpoietic cell transplantation

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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