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Analysis of the functional relevance of a putative regulatory SNP of PDCD1, PD1.3, associated with systemic lupus erythematosus

Genes & Immunity volume 9, pages 309–315 (2008)Cite this article

Abstract

This study aimed to test the functional effects of the PD1.3 single nucleotide polymorphism (SNP) (rs11568821), which were proposed based on its association to systemic lupus erythematosus (SLE) susceptibility and in electrophoretic mobility shift assays (EMSA) results. We analysed transcriptional effects of the PD1.3 locus by enhancer reporter assays. Results were against the hypothesis that the PD1.3 locus acts as enhancer in transcriptional regulation of PDCD1. In addition, they excluded a differential effect of the PD1.3 alleles. EMSA results confirmed that oligonucleotides with the PD1.3 G allele bind RUNX1 but not those with the A allele. However, binding to PD1.3 G oligonucleotides was much lower than binding to positive control oligonucleotides. Criss-cross experiments showed that this was due to flanking nucleotides in the PD1.3 sequence that negatively affect RUNX1 binding. These results cast doubts on the functional relevance of the PD1.3 SNP and, together with the lack of association in several studies, put into question its role as an SLE susceptibility factor. Investigation of other PDCD1 polymorphisms is needed to uncover the possible effect of this gene on SLE susceptibility.

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References

  1. Prokunina L, Castillejo-Lopez C, Oberg F, Gunnarsson I, Berg L, Magnusson V et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet 2002; 32: 666–669.

    Article  CAS  Google Scholar 

  2. Velazquez-Cruz R, Orozco L, Espinosa-Rosales F, Carreno-Manjarrez R, Solis-Vallejo E, Lopez-Lara ND et al. Association of PDCD1 polymorphisms with childhood-onset systemic lupus erythematosus. Eur J Hum Genet 2007; 15: 336–341.

    Article  CAS  Google Scholar 

  3. Thorburn CM, Prokunina-Olsson L, Sterba KA, Lum RF, Seldin MF, Alarcon-Riquelme ME et al. Association of PDCD1 genetic variation with risk and clinical manifestations of systemic lupus erythematosus in a multiethnic cohort. Genes Immun 2007; 8: 279–287.

    Article  CAS  Google Scholar 

  4. Sigurdsson S, Nordmark G, Goring HH, Lindroos K, Wiman AC, Sturfelt G et al. Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am J Hum Genet 2005; 76: 528–537.

    Article  CAS  Google Scholar 

  5. Ferreiros-Vidal I, D’Alfonso S, Papasteriades C, Skopouli FN, Marchini M, Scorza R et al. Bias in association studies of systemic lupus erythematosus susceptibility due to geographical variation in the frequency of a programmed cell death 1 polymorphism across Europe. Genes Immun 2007; 8: 138–146.

    Article  CAS  Google Scholar 

  6. Nielsen C, Laustrup H, Voss A, Junker P, Husby S, Lillevang ST et al. A putative regulatory polymorphism in PD-1 is associated with nephropathy in a population-based cohort of systemic lupus erythematosus patients. Lupus 2004; 13: 510–516.

    Article  CAS  Google Scholar 

  7. Sanghera DK, Manzi S, Bontempo F, Nestlerode C, Kamboh MI . Role of an intronic polymorphism in the PDCD1 gene with the risk of sporadic systemic lupus erythematosus and the occurrence of antiphospholipid antibodies. Hum Genet 2004; 115: 393–398.

    Article  CAS  Google Scholar 

  8. Johansson M, Arlestig L, Moller B, Rantapaa-Dahlqvist S . Association of a PDCD1 polymorphism with renal manifestations in systemic lupus erythematosus. Arthritis Rheum 2005; 52: 1665–1669.

    Article  CAS  Google Scholar 

  9. Ferreiros-Vidal I, Gomez-Reino JJ, Barros F, Carracedo A, Carreira P, Gonzalez-Escribano F et al. Association of PDCD1 with susceptibility to systemic lupus erythematosus: evidence of population-specific effects. Arthritis Rheum 2004; 50: 2590–2597.

    Article  CAS  Google Scholar 

  10. Ferreiro-Neira I, Calaza M, Alonso-Perez E, Marchini M, Scorza R, Sebastiani GD et al. Opposed independent effects and epistasis in the complex association of IRF5 to SLE. Genes Immun 2007; 8: 429–439.

    Article  CAS  Google Scholar 

  11. Nath SK, Kilpatrick J, Harley JB . Genetics of human systemic lupus erythematosus: the emerging picture. Curr Opin Immunol 2004; 16: 794–800.

    Article  CAS  Google Scholar 

  12. Keir ME, Francisco LM, Sharpe AH . PD-1 and its ligands in T-cell immunity. Curr Opin Immunol 2007; 19: 309–314.

    Article  CAS  Google Scholar 

  13. Gotsman I, Grabie N, Dacosta R, Sukhova G, Sharpe A, Lichtman AH et al. Proatherogenic immune responses are regulated by the PD-1/PD-L pathway in mice. J Clin Invest 2007; 117: 2974–2982.

    Article  CAS  Google Scholar 

  14. Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 2006; 443: 350–354.

    Article  CAS  Google Scholar 

  15. Urbani S, Amadei B, Tola D, Massari M, Schivazappa S, Missale G et al. PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion. J Virol 2006; 80: 11398–11403.

    Article  CAS  Google Scholar 

  16. Meyers S, Downing JR, Hiebert SW . Identification of AML-1 and the (8;21) translocation protein (AML-1/ETO) as sequence-specific DNA-binding proteins: the runt homology domain is required for DNA binding and protein-protein interactions. Mol Cell Biol 1993; 13: 6336–6345.

    Article  CAS  Google Scholar 

  17. Otto F, Lubbert M, Stock M . Upstream and downstream targets of RUNX proteins. J Cell Biochem 2003; 89: 9–18.

    Article  CAS  Google Scholar 

  18. Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM et al. The human genome browser at UCSC. Genome Res 2002; 12: 996–1006.

    Article  CAS  Google Scholar 

  19. Benson G . Tandem repeats finder: a program to analyze DNA sequences. Nucleic Acids Res 1999; 27: 573–580.

    Article  CAS  Google Scholar 

  20. Hubbard TJ, Aken BL, Beal K, Ballester B, Caccamo M, Chen Y et al. Ensembl 2007. Nucleic Acids Res 2007; 35: D610–D617.

    Article  CAS  Google Scholar 

  21. Miller W, Rosenbloom K, Hardison RC, Hou M, Taylor J, Raney B et al. 28-Way vertebrate alignment and conservation track in the UCSC Genome Browser. Genome Res 2007; 17: 1797–1808.

    Article  CAS  Google Scholar 

  22. Puig-Kroger A, Lopez-Rodriguez C, Relloso M, Sanchez-Elsner T, Nueda A, Munoz E et al. Polyomavirus enhancer-binding protein 2/core binding factor/acute myeloid leukemia factors contribute to the cell type-specific activity of the CD11a integrin gene promoter. J Biol Chem 2000; 275: 28507–28512.

    Article  CAS  Google Scholar 

  23. Rahmann S, Muller T, Vingron M . On the power of profiles for transcription factor binding site detection. Stat Appl Genet Mol Biol 2003; 2: Article7.

    Article  Google Scholar 

  24. Collas P, Dahl JA . Chop it, ChIP it, check it: the current status of chromatin immunoprecipitation. Front Biosci 2008; 13: 929–943.

    Article  CAS  Google Scholar 

  25. Hollenhorst PC, Shah AA, Hopkins C, Graves BJ . Genome-wide analyses reveal properties of redundant and specific promoter occupancy within the ETS gene family. Genes Dev 2007; 21: 1882–1894.

    Article  CAS  Google Scholar 

  26. Yochum GS, McWeeney S, Rajaraman V, Cleland R, Peters S, Goodman RH et al. Serial analysis of chromatin occupancy identifies beta-catenin target genes in colorectal carcinoma cells. Proc Natl Acad Sci USA 2007; 104: 3324–3329.

    Article  CAS  Google Scholar 

  27. MacKenzie A, Quinn J . A serotonin transporter gene intron 2 polymorphic region, correlated with affective disorders, has allele-dependent differential enhancer-like properties in the mouse embryo. Proc Natl Acad Sci USA 1999; 96: 15251–15255.

    Article  CAS  Google Scholar 

  28. Giambra V, Fruscalzo A, Giufre’ M, Martinez-Labarga C, Favaro M, Rocchi M et al. Evolution of human IgH3′EC duplicated structures: both enhancers HS1,2 are polymorphic with variation of transcription factor's consensus sites. Gene 2005; 346: 105–114.

    Article  CAS  Google Scholar 

  29. Bellizzi D, Rose G, Cavalcante P, Covello G, Dato S, De Rango F et al. A novel VNTR enhancer within the SIRT3 gene, a human homologue of SIR2, is associated with survival at oldest ages. Genomics 2005; 85: 258–263.

    Article  CAS  Google Scholar 

  30. Thornell A, Hallberg B, Grundstrom T . Binding of SL3-3 enhancer factor 1 transcriptional activators to viral and chromosomal enhancer sequences. J Virol 1991; 65: 42–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Mori M, Yamada R, Kobayashi K, Kawaida R, Yamamoto K . Ethnic differences in allele frequency of autoimmune-disease-associated SNPs. J Hum Genet 2005; 50: 264–266.

    Article  Google Scholar 

  32. Kristjansdottir H, Steinsson K, Gunnarsson I, Thorsteinsdottir T, Alarcon-Riquelme ME . Lower Expression Levels of the PD1 Immunoreceptor in SLE Patients and Lower Frequency of CD25+ CD4 T-cells. Arthritis Rheum 2007; 56: S746 (Abs. 1952).

    Google Scholar 

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Acknowledgements

We thank Samuel Seoane-Ruzo (University of Santiago) for help with luciferase assays and Miguel A Iñiguez-Peña (Centro de Biologia Molecular, Madrid) for providing us with a working protocol for Jurkat cell transfection. This work was supported by two Grants, PI04/1615 and PI06/0620, from the Instituto de Salud Carlos III (ISCIII, Spanish Health Ministry), which included funds from the FEDER programme of the European Union. MAS-G is the recipient of a pre-doctoral bursary from the Spanish Ministry of Education and Culture. IF-V is the recipient of an ISCIII pre-doctoral bursary. AG has been the recipient of a Research contract from the ISCIII.

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Author notes

  1. M Suarez-Gestal and I Ferreiros-Vidal: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratorio de Investigacion 2 and Rheumatology Unit, Hospital Clinico Universitario de Santiago, Santiago de Compostela, Spain

    M Suarez-Gestal, I Ferreiros-Vidal, J J Gomez-Reino & A Gonzalez

  2. Departamento de BiologĂ­a Molecular, Instituto Bernabeu, Alicante, Spain

    J A Ortiz

  3. Department of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain

    J J Gomez-Reino

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  1. M Suarez-Gestal
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  2. I Ferreiros-Vidal
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  3. J A Ortiz
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  4. J J Gomez-Reino
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  5. A Gonzalez
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Corresponding author

Correspondence to A Gonzalez.

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Suarez-Gestal, M., Ferreiros-Vidal, I., Ortiz, J. et al. Analysis of the functional relevance of a putative regulatory SNP of PDCD1, PD1.3, associated with systemic lupus erythematosus. Genes Immun 9, 309–315 (2008). https://doi.org/10.1038/gene.2008.19

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