Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter to the Editor
  • Published:

HLA polymorphism and risk of multiple myeloma

Leukemia volume 30, pages 2260–2264 (2016)Cite this article

Subjects

The two- to threefold increased risk of multiple myeloma (MM) within families, and among African Americans vs Whites support a role of genetic factors in disease development.1, 2 Human leukocyte antigen (HLA) proteins initiate immune surveillance through peptide presentation to T-cell receptors.3 Each HLA allele has the capability of presenting a differing limited repertoire of peptides derived from self and non-self proteins, therefore HLA polymorphim has been associated with numerous immune-mediated diseases.4

A genome-wide association study (GWAS) of MM identified a risk variant within the major histocompatibility complex (MHC), but the associated single-nucleotide polymorphism (SNP; rs228580) was not directly characterized with classical HLA typing.5 GWAS has identified loci in the major histocompatibility region as the strong associations in other B-cell malignancies, with P-values of up to 10−60.6 Previous MM association studies with HLA are limited by sample size.7 Building on work in chronic lymphocytic leukemia (CLL), where a similar analysis identified several HLA alleles associated with susceptibility,8 we comprehensively analyzed HLA associations with MM risk among White, African American, Hispanic and Asian US populations.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

References

  1. Vachon CM, Kyle RA, Therneau TM, Foreman BJ, Larson DR, Colby CL et al. Increased risk of monoclonal gammopathy in first-degree relatives of patients with multiple myeloma or monoclonal gammopathy of undetermined significance. Blood 2009; 114: 785–790.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Landgren O, Gridley G, Turesson I, Caporaso NE, Goldin LR, Baris D et al. Risk of monoclonal gammopathy of undetermined significance (MGUS) and subsequent multiple myeloma among African American and white veterans in the United States. Blood 2006; 107: 904–906.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Wang JH, Reinherz EL . Structural basis of T cell recognition of peptides bound to MHC molecules. Mol Immunol 2002; 38: 1039–1049.

    Article  CAS  PubMed  Google Scholar 

  4. Trowsdale J, Knight JC . Major histocompatibility complex genomics and human disease. Annu Rev Genomics Hum Genet 2013; 14: 301–323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chubb D, Weinhold N, Broderick P, Chen B, Johnson DC, Forsti A et al. Common variation at 3q26.2, 6p21.33, 17p11.2 and 22q13.1 influences multiple myeloma risk. Nat Genet 2013; 45: 1221–1225.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Smedby KE, Foo JN, Skibola CF, Darabi H, Conde L, Hjalgrim H et al. GWAS of follicular lymphoma reveals allelic heterogeneity at 6p21.32 and suggests shared genetic susceptibility with diffuse large B-cell lymphoma. PLoS Genet 2011; 7: e1001378.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ludwig H, Mayr W . Genetic aspects of susceptibility to multiple myeloma. Blood 1982; 59: 1286–1291.

    CAS  PubMed  Google Scholar 

  8. Gragert L, Fingerson S, Albrecht M, Maiers M, Kalaycio M, Hill BT . Fine-mapping of HLA associations with chronic lymphocytic leukemia in US populations. Blood 2014; 124: 2657–2665.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Erlich H . HLA DNA typing: past, present, and future. Tissue Antigens 2012; 80: 1–11.

    Article  CAS  PubMed  Google Scholar 

  10. Gragert L, Madbouly A, Freeman J, Maiers M . Six-locus high resolution HLA haplotype frequencies derived from mixed-resolution DNA typing for the entire US donor registry. Human Immunol 2013; 74: 1313–1320.

    Article  CAS  Google Scholar 

  11. Fabrigar LR, Wegener DT . Exploratory Factor Analysis (Understanding Statistics). Oxford University Press, 2011.

    Book  Google Scholar 

  12. Benjamini Y, Hochberg Y . Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Series B (Methodological) 1995; 57: 289–300.

    Article  Google Scholar 

  13. Kulkarni S, Savan R, Qi Y, Gao X, Yuki Y, Bass SE et al. Differential microRNA regulation of HLA-C expression and its association with HIV control. Nature 2011; 472: 495–498.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Naumova E, Mihaylova A, Stoitchkov K, Ivanova M, Quin L, Toneva M . Genetic polymorphism of NK receptors and their ligands in melanoma patients: prevalence of inhibitory over activating signals. Cancer Immunol Immunother 2005; 54: 172–178.

    Article  CAS  PubMed  Google Scholar 

  15. Alcoceba M, Sebastian E, Marin L, Balanzategui A, Sarasquete ME, Chillon MC et al. HLA specificities are related to development and prognosis of diffuse large B-cell lymphoma. Blood 2013; 122: 1448–1454.

    Article  CAS  PubMed  Google Scholar 

  16. Wang SS, Abdou AM, Morton LM, Thomas R, Cerhan JR, Gao X et al. Human leukocyte antigen class I and II alleles in non-Hodgkin lymphoma etiology. Blood 2010; 115: 4820–4823.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Preuss KD, Pfreundschuh M, Fadle N, Regitz E, Raudies S, Murwaski N et al. Hyperphosphorylation of autoantigenic targets of paraproteins is due to inactivation of PP2A. Blood 2011; 118: 3340–3346.

    Article  CAS  PubMed  Google Scholar 

  18. Preuss KD, Pfreundschuh M, Weigert M, Fadle N, Regitz E, Kubuschok B . Sumoylated HSP90 is a dominantly inherited plasma cell dyscrasias risk factor. J Clin Invest 2015; 125: 2179.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Nair S, Branagan AR, Liu J, Boddupalli CS, Mistry PK, Dhodapkar MV . Clonal Immunoglobulin against Lysolipids in the Origin of Myeloma. N Engl J Med 2016; 374: 555–561.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sarkar S, van Gelder M, Noort W, Xu Y, Rouschop KM, Groen R et al. Optimal selection of natural killer cells to kill myeloma: the role of HLA-E and NKG2A. Cancer Immunol Immunother 2015; 64: 951–963.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Dr Beksac’s work was supported by the Turkish Academy of Sciences. The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 from the National Cancer Institute (NCI), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U01HL069294 from NHLBI and NCI; a contract HHSH234200637015C with Health Resources and Services Administration (HRSA/DHHS); two Grants N00014-06-1-0704 and N00014-08-1-0058 from the Office of Naval Research; and grants from Allos, Inc.; Amgen, Inc.; Angioblast; Anonymous donation to the Medical College of Wisconsin; Ariad; Be the Match Foundation; Blue Cross and Blue Shield Association; Buchanan Family Foundation; CaridianBCT; Celgene Corporation; CellGenix, GmbH; Children’s Leukemia Research Association; Fresenius-Biotech North America, Inc.; Gamida Cell Teva Joint Venture Ltd; Genentech, Inc.; Genzyme Corporation; GlaxoSmithKline; HistoGenetics, Inc.; Kiadis Pharma; The Leukemia & Lymphoma Society; The Medical College of Wisconsin; Merck & Co, Inc.; Millennium: The Takeda Oncology Co.; Milliman USA, Inc.; Miltenyi Biotec, Inc.; National Marrow Donor Program; Optum Healthcare Solutions, Inc.; Osiris Therapeutics, Inc.; Otsuka America Pharmaceutical, Inc.; RemedyMD; Sanofi; Seattle Genetics; Sigma-Tau Pharmaceuticals; Soligenix, Inc.; StemCyte, A Global Cord Blood Therapeutics Co.; Stemsoft Software, Inc.; Swedish Orphan Biovitrum; Tarix Pharmaceuticals; Teva Neuroscience, Inc.; THERAKOS, Inc.; and Wellpoint, Inc. The views expressed in this article do not reflect the official policy or position of the National Institute of Health, the Department of the Navy, the Department of Defense or any other agency of the US Government. Dr Cozen’s work was supported by the following grants: 2P50CA100707-06, 1R01CA134786-02 and N01-CP-67010, HHSN261201000035C.

Author contributions

All authors participated and co-wrote the manuscript. In addition, MB and PH designed the study, analyzed the data and interpreted the results. LG, SF, MM, MA, XZ and MZ designed the methods for analysis and analyzed the data. WC, AD and SL interpreted the results, and reviewed and edited the paper. MB and LG’s contributions to the manuscript were equal.

Author information

Author notes

  1. M Beksac and L Gragert: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Tissue Typing Laboratories and Donor Registry, Ankara University, Ankara, Turkey

    M Beksac

  2. Bioinformatics Research, National Marrow Donor Program/Be The Match, Minneapolis, MN, USA

    L Gragert, S Fingerson, M Maiers & M Albrecht

  3. Department of Pathology and Laboratory Medicine, Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, USA

    L Gragert, S Fingerson, M Maiers & M Albrecht

  4. Department of Medicine, Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI, USA

    M-J Zhang, X Zhong & P Hari

  5. Division of Biostatistics, Institute for Health and Society, Medical College of Wisconsin, Milwaukee, WI, USA

    M-J Zhang

  6. Departments of Preventive Medicine and Pathology and Norris Comprehensive Cancer Center, USC Keck School of Medicine, Los Angeles, CA, USA

    W Cozen

  7. Department of Medicine, Mayo Clinic, Rochester, MN, USA

    A Dispenzieri

  8. Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA

    S Lonial

Authors
  1. M Beksac
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L Gragert
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Fingerson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Maiers
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M-J Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Albrecht
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. X Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. W Cozen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A Dispenzieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S Lonial
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. P Hari
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P Hari.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Beksac, M., Gragert, L., Fingerson, S. et al. HLA polymorphism and risk of multiple myeloma. Leukemia 30, 2260–2264 (2016). https://doi.org/10.1038/leu.2016.199

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2016.199

This article is cited by

Search

Advanced search

Quick links