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

Year: 2020

Type: article

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.

Source: The American Journal of Human Genetics

DOI: 10.1016/j.ajhg.2020.01.004

Institutions: National Cancer Institute, Division of Cancer Epidemiology and Genetics, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc. (United States), Medical College of Wisconsin, University of KwaZulu-Natal, Inserm, Centre Hospitalier Universitaire de Nantes, Institut de Transplantation Urologie en Nephrologie, Center for Research in Transplantation and Translational Immunology, Université de Nantes, Nantes Université, Mayo Clinic, Yale University, American Cancer Society, Baylor University Medical Center, Fred Hutch Cancer Center, Harvard University, Ragon Institute of MGH, MIT and Harvard

Language: English

Topic: Genetic Associations and Epidemiology

Subfield: Genetics

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $5,000

Funders: Frederick National Laboratory for Cancer Research, Agence Nationale de la Recherche, National Institutes of Health, Health Resources and Services Administration, U.S. Public Health Service, National Heart, Lung, and Blood Institute, Office of Naval Research, National Cancer Institute, National Center for Advancing Translational Sciences

Awards: SURVEILLANCE EPIDEMIOLOGY &END RESULTS PROGRAM, G1044130170, NExT (I-SITE), SURVEILLANCE EPIDEMIOLOGY &END RESULTS PROGRAM, SURVEILLANCE, EPIDEMIOLOGY, AND END RESULTS--SEER, SURVEILLANCE EPIDEMIOLOGY &END RESULTS PROGRAM, G2660289629, G386607036, G4836174358, G5185757912, G5372537626, HAIR DYE USE AND RISK OF NONHODGKINS LYMPHOMA, G5888954722, G6622425196, G6961396861, G777363952, G835684289, A Data Resource for Blood and Marrow Transplants and Adoptive Cellular Therapy Research, Yale Clinical and Translational Science Award

OpenAlex ID: W3003407767