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.

  • Short Communication
  • Published:

Follicular lymphoma-protective HLA class II variants correlate with increased HLA-DQB1 protein expression

Genes & Immunity volume 15, pages 133–136 (2014)Cite this article

Subjects

Abstract

Multiple follicular lymphoma (FL) susceptibility single-nucleotide polymorphisms in the human leukocyte antigen (HLA) class I and II regions have been identified, including rs6457327, rs3117222, rs2647012, rs10484561, rs9268853 and rs2621416. Here we validated previous expression quantitative trait loci results with real-time reverse transcription quantitative PCR and investigated protein expression in B-lymphoblastoid cell lines and primary dendritic cells using flow cytometry, cell-based enzyme-linked immunosorbent assay and western blotting. We confirmed that FL-protective rs2647012-linked variants, in high linkage disequilibrium with the extended haplotype DRB1*15:01-DQA1*01:02-DQB1*06:02, correlate with increased HLA-DQB1 expression. This association remained significant at the protein level and was reproducible across different cell types. We also found that differences in HLA-DQB1 expression were not related to changes in activation markers or class II, major histocompatibility complex, transactivator expression, suggesting the role of an alternative regulatory mechanism. However, functional analysis using RegulomeDB did not reveal any relevant regulatory candidates. Future studies should focus on the clinical relevance of increased HLA-DQB1 protein expression facilitating tumor cell removal through increased immune surveillance.

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

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

Similar content being viewed by others

References

  1. Cerhan JR . Host genetics in follicular lymphoma. Best Pract Res Clin Haematol 2011; 24: 121–134.

    Article  CAS  Google Scholar 

  2. Skibola CF, Bracci PM, Halperin E, Conde L, Craig DW, Agana L et al. Genetic variants at 6p21.33 are associated with susceptibility to follicular lymphoma. Nat Genet 2009; 41: 873–875.

    Article  CAS  Google Scholar 

  3. Conde L, Halperin E, Akers NK, Brown KM, Smedby KE, Rothman N et al. Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32. Nat Genet 2010; 42: 661–664.

    Article  CAS  Google Scholar 

  4. 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  Google Scholar 

  5. Skibola CF, Conde L, Foo JN, Riby J, Humphreys K, Sille FC et al. A meta-analysis of genome-wide association studies of follicular lymphoma. BMC Genomics 2012; 13: 516.

    Article  CAS  Google Scholar 

  6. Vijai J, Kirchhoff T, Schrader KA, Brown J, Dutra-Clarke AV, Manschreck C et al. Susceptibility loci associated with specific and shared subtypes of lymphoid malignancies. PLoS Genet 2013; 9: e1003220.

    Article  CAS  Google Scholar 

  7. Conde L, Bracci PM, Richardson R, Montgomery SB, Skibola CF . Integrating GWAS and expression data for functional characterization of disease-associated SNPs: an application to follicular lymphoma. Am J Hum Genet 2013; 92: 126–130.

    Article  CAS  Google Scholar 

  8. Skibola CF, Akers NK, Conde L, Ladner M, Hawbecker SK, Cohen F et al. Multi-locus HLA class I and II allele and haplotype associations with follicular lymphoma. Tissue Antigens 2012; 79: 279–286.

    Article  CAS  Google Scholar 

  9. Chang KC, Huang X, Medeiros LJ, Jones D . Germinal centre-like versus undifferentiated stromal immunophenotypes in follicular lymphoma. J Pathol 2003; 201: 404–412.

    Article  Google Scholar 

  10. Jin MK, Hoster E, Dreyling M, Unterhalt M, Hiddemann W, Klapper W . Follicular dendritic cells in follicular lymphoma and types of non-Hodgkin lymphoma show reduced expression of CD23, CD35 and CD54 but no association with clinical outcome. Histopathology 2011; 58: 586–592.

    Article  Google Scholar 

  11. Briata P, Radka SF, Sartoris S, Lee JS . Alternative splicing of HLA-DQB transcripts and secretion of HLA-DQ beta-chain proteins: allelic polymorphism in splicing and polyadenylylation sites. Proc Natl Acad Sci USA 1989; 86: 1003–1007.

    Article  CAS  Google Scholar 

  12. Královicová J, Vorechovsky I . Position-dependent repression and promotion of DQB1 intron 3 splicing by GGGG motifs. J Immunol 2006; 176: 2381–2388.

    Article  Google Scholar 

  13. Kralovicova J, Houngninou-Molango S, Kramer A, Vorechovsky I . Branch site haplotypes that control alternative splicing. Hum Mol Genet 2004; 13: 3189–3202.

    Article  CAS  Google Scholar 

  14. Britten AC, Mijovic CH, Barnett AH, Kelly MA . Differential expression of HLA-DQ alleles in peripheral blood mononuclear cells: alleles associated with susceptibility to and protection from autoimmune type 1 diabetes. Int J Immunogenet 2009; 36: 47–57.

    Article  CAS  Google Scholar 

  15. Wang H, Wang Q, Pape UJ, Shen B, Huang J, Wu B et al. Systematic investigation of global coordination among mRNA and protein in cellular society. BMC Genomics 2010; 11: 364.

    Article  Google Scholar 

  16. Greenbaum D, Colangelo C, Williams K, Gerstein M . Comparing protein abundance and mRNA expression levels on a genomic scale. Genome Biol 2003; 4: 117.

    Article  Google Scholar 

  17. Van Gool SW, Vandenberghe P, de Boer M, Ceuppens JL . CD80, CD86 and CD40 provide accessory signals in a multiple-step T-cell activation model. Immunol Rev 1996; 153: 47–83.

    Article  CAS  Google Scholar 

  18. Krawczyk M, Peyraud N, Rybtsova N, Masternak K, Bucher P, Barras E et al. Long distance control of MHC class II expression by multiple distal enhancers regulated by regulatory factor X complex and CIITA. J Immunol 2004; 173: 6200–6210.

    Article  CAS  Google Scholar 

  19. Prod'homme T, Drenou B, De Ruyffelaere C, Barbieri G, Wiszniewski W, Bastard C et al. Defective class II transactivator expression in a B lymphoma cell line. Leukemia 2004; 18: 832–840.

    Article  CAS  Google Scholar 

  20. Fairfax BP, Makino S, Radhakrishnan J, Plant K, Leslie S, Dilthey A et al. Genetics of gene expression in primary immune cells identifies cell type-specific master regulators and roles of HLA alleles. Nat Genet 2012; 44: 502–510.

    Article  CAS  Google Scholar 

  21. Boyle AP, Hong EL, Hariharan M, Cheng Y, Schaub MA, Kasowski M et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res 2012; 22: 1790–1797.

    Article  CAS  Google Scholar 

  22. Doran G . The short and the long of UTRs. J RNAi Gene Silencing 2008; 4: 264–265.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Halvorsen M, Martin JS, Broadaway S, Laederach A . Disease-associated mutations that alter the RNA structural ensemble. PLoS Genetics 2010; 6: e1001074.

    Article  Google Scholar 

  24. Alcina A, Abad-Grau Mdel M, Fedetz M, Izquierdo G, Lucas M, Fernandez O et al. Multiple sclerosis risk variant HLA-DRB1*1501 associates with high expression of DRB1 gene in different human populations. PLoS One 2012; 7: e29819.

    Article  CAS  Google Scholar 

  25. Akers NK, Curry JD, Conde L, Bracci PM, Smith MT, Skibola CF . Association of HLA-DQB1 alleles with risk of follicular lymphoma. Leuk Lymphoma 2011; 52: 53–58.

    Article  CAS  Google Scholar 

  26. Foo JN, Smedby KE, Akers NK, Berglund M, Irwan ID, Jia X et al. Coding variants at hexa-allelic amino acid 13 of HLA-DRB1 explain independent SNP associations with follicular lymphoma risk. Am J Hum Genet 2013; 93: 167–172.

    Article  CAS  Google Scholar 

  27. Skibola CF, Nieters A, Bracci PM, Curry JD, Agana L, Skibola DR et al. A functional TNFRSF5 gene variant is associated with risk of lymphoma. Blood 2008; 111: 4348–4354.

    Article  CAS  Google Scholar 

  28. Grubbs FE . Procedures for detecting outlying observations in samples. Technometrics 1969; 11: 1–21.

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by National Institutes of Health grants CA154643 and CA104682 (CFS).

Author contributions

CFS obtained financial support for the study; FCMS, LC and CFS designed the study; FCMS, JZ, NKA, SS and JM, performed experiments; FCMS and LC analyzed data; FCMS, LC and CFS wrote the manuscript; All authors contributed to the final manuscript and approved its content.

Author information

Authors and Affiliations

  1. Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA, USA

    F C M Sillé, N K Akers, S Sanchez, J Maltbaek & M T Smith

  2. Department of Epidemiology, Comprehensive Cancer Center, University of Alabama, Birmingham, AL, USA

    L Conde, J Zhang, J E Riby & C F Skibola

Authors
  1. F C M Sillé
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. L Conde
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. N K Akers
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S Sanchez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Maltbaek
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J E Riby
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M T Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. C F Skibola
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C F Skibola.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on Genes and Immunity website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sillé, F., Conde, L., Zhang, J. et al. Follicular lymphoma-protective HLA class II variants correlate with increased HLA-DQB1 protein expression. Genes Immun 15, 133–136 (2014). https://doi.org/10.1038/gene.2013.64

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gene.2013.64

Keywords

This article is cited by

Search

Advanced search

Quick links