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Replication of the TNFSF4 (OX40L) promoter region association with systemic lupus erythematosus

Genes & Immunity volume 10, pages 248–253 (2009)Cite this article

Abstract

The tumor necrosis factor ligand superfamily member 4 gene (TNFSF4) encodes the OX40 ligand (OX40L), a costimulatory molecule involved in T-cell activation. A recent study demonstrated the association of TNFSF4 haplotypes located in the upstream region with risk for or protection from systemic lupus erythematosus (SLE). To replicate this association, five single nucleotide polymorphisms (SNPs) tagging the previously associated haplotypes and passing the proper quality-control filters were tested in 1312 cases and 1801 controls from Germany, Italy, Spain and Argentina. The association of TNFSF4 with SLE was replicated in all the sets except Spain. There was a unique risk haplotype tagged by the minor alleles of the SNPs rs1234317 (pooled odds ratio (OR)=1.39, P=0.0009) and rs12039904 (pooled OR=1.38, P=0.0012). We did not observe association to a single protective marker (rs844644) or haplotype as the first study reported; instead, we observed different protective haplotypes, all carrying the major alleles of both SNPs rs1234317 and rs12039904. Association analysis conditioning on the haplotypic background confirmed that these two SNPs explain the entire haplotype effect. This first replication study confirms the association of genetic variation in the upstream region of TNFSF4 with susceptibility to SLE.

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Acknowledgements

This work was supported by the Swedish Research Council, the Gustav-Ve-80-year Jubilee Foundation, the Torsten and Ragnar Söderbegs Foundation, the Marcus Borgströms Foundation and the Swedish Association Against Rheumatism. MEAR is supported by an award from the Knut and Alice Wallenberg Foundation through the Royal Swedish Academy of Sciences. This work was also partially supported by PRIN Project (MIUR, Rome), Compagnia di San Paolo (Turin), Regione Piemonte (Ricerca Sanitaria Finalizzata Project and Ricerca Sanitaria Applicata-CIPE Project), Fondazione Monte dei Paschi di Siena, the BMBF Kompetenznetz Rheuma C2.12 (Germany), Plan Nacional de I+D (Spain, SAF06-00398) and Grant CTS1880 (Junta de Andalucía, Spain). We thank Adriana I Scollo, Armando M Perichon and Mariano CR Tenaglia (CEDIM, Diagnóstico Molecular y Forense SRL, Rosario, Argentina), for their help in preparing the Argentinean samples.

The Argentine collaborative group participants: Hugo R Scherbarth MD, Jorge A Lopez MD, Estela L Motta MD Servicio de Reumatología, Hospital Interzonal General de Agudos ‘Dr Oscar Alende’, Mar del Plata, Argentina; Susana Gamron MD, Sandra Buliubasich MD, Emilia Menso MD Servicio de Reumatología de la UHMI 1, Hospital Nacional de Clínicas, Universidad Nacional de Córdoba, Córdoba, Argentina; Alberto Allievi MD, Jose L Presas MD Hospital General de Agudos Dr Juán A Fernandez, Buenos Aires, Argentina; Guillermo A Tate MD Organización Médica de Investigación, Buenos Aires, Argentina; Simon A Palatnik MD, Mariela Bearzotti PhD Facultad de Ciencias Médicas, Universidad Nacional de Rosario y Hospital Provincial del Centenario, Rosario, Argentina; Alejandro Alvarellos MD, Francisco Caeiro MD, Ana Bertoli MD Servicio de Reumatología, Hospital Privado, Centro Médico de Córdoba, Córdoba, Argentina; Sergio Paira MD, Susana Roverano MD, Carlos Louteiro MD Hospital José M Cullen, Santa Fe, Argentina; Cesar E Graf MD, Estela Bertero PhD Hospital San Martín, Paraná; Cesar Caprarulo MD, Griselda Buchanan PhD Hospital Felipe Heras, Concordia, Entre Ríos, Argentina; Carolina Guillerón MD, Sebastian Grimaudo PhD, Jorge Manni MD Departamento de Inmunología, Instituto de Investigaciones Médicas ‘Alfredo Lanari’, Buenos Aires, Argentina; Luis J Catoggio MD, Enrique R Soriano MD, Carlos D Santos MD Sección Reumatología, Servicio de Clínica Médica, Hospital Italiano de Buenos Aires y Fundación Dr Pedro M Catoggio para el Progreso de la Reumatología, Buenos Aires, Argentina; Cristina Prigione MD, Fernando A Ramos MD, Sandra M Navarro MD Servicio de Reumatología, Hospital Provincial de Rosario, Rosario, Argentina; Guillermo A Berbotto MD, Marisa Jorfen MD, Elisa J Romero PhD Servicio de Reumatología Hospital Escuela Eva Perón Granadero Baigorria, Rosario, Argentina; Mercedes A Garcia MD, Juan C Marcos MD, Ana I Marcos MD Servicio de Reumatología, Hospital Interzonal General de Agudos General San Martín, La Plata; Carlos E Perandones MD, Alicia Eimon MD Centro de Educación Médica e Investigaciones Clínicas (CEMIC), Buenos Aires, Argentina; Cristina G Battagliotti MD Hospital de Niños Dr Orlando Alassia, Santa Fe, Argentina.

The German collaborative group participants: K Armadi-Simab, MD, Wolfgang L Gross, MD, Abteilung Rheumatologie und Immunologie, University Hospital of Schleswig-Holstein, Campus Luebeck, Rheumaklinik Bad Bramstedt, Luebeck, Germany, Erika Gromnica-Ihle, MD, Rheumaklinik Berlin-Buch, Berlin, Germany, Hans-Hartmut Peter, MD, Medizinische Universitaetsklinik, Abteilung Rheumatologie und Klinische Immunologie, Freiburg, Germany, Karin Manger, MD, Medizinische Klinik III derFAU Erlangen-Nuernberg, Erlangen, Germany, Sebastian Schnarr, MD, Henning Zeidler, MD, Abteilung Rheumatologie, Medizinische Hochschule Hannover, Hannover, Germany, Reinhold E Schmidt, MD, Klinik fuer Immunologie und Rheumatologies, Medizinische Hochschule Hannover, Hannover, Germany.

The Spanish collaborative group participants: Norberto Ortego, Servicio Medicina Interna, Hospital Clínico San Cecilio, Granada, Enrique de Ramón, Servicio de Medicina Interna, Hospital Carlos Haya, Málaga, Juan Jiménez-Alonso, Servicio de Medicina Interna, Hospital Virgen de las Nieves, Granada, Julio Sánchez-Román, Servicio de Medicina Interna, Hospital Virgen del Rocío, Sevilla, and Miguel ángel López-Nevot, Servicio de Inmunología, Hospital Virgen de las Nieves, Granada.

The Italian collaborative group participants: Maria Giovanna Danieli and Armando Gabrielli (Clinica Medica, Dipartimento di Scienze Mediche e Chirurgiche, Università Politecnica delle Marche, Ancona, Italy), Gian Domenico Sebastiani (UOC di Reumatologia Ospedale San Camillo, Roma – Italy), Patrizia Rovere Querini (IRCCS San Raffaele Scientific Institute, Milan, Italy), Sergio Migliaresi (Rheumatology Unit Second University of Naples, Naples, Italy).

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Author notes

  1. T Witte, S D'Alfonso, J Jiménez-Alonso and B A Pons-Estel: Other clinical collaborators who provided samples are listed in the acknowledgements.

  2. B A Pons-Estel: Bernardo Pons-Estel is the coordinator of the Argentine Collaborative Group

  3. J Martin and M E Alarcón-Riquelme: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Genetics and Pathology, Unit of Medical Genetics, Rudbeck Laboratory, University of Uppsala, Uppsala, Sweden

    A M Delgado-Vega, A-K Abelson & M E Alarcón-Riquelme

  2. Instituto de Biomedicina ‘L,

    E Sánchez & J Martin

  3. ó,

    E Sánchez & J Martin

  4. pez-Neyra’, CSIC, Granada, Spain

    E Sánchez & J Martin

  5. Department of Medicine, Medical School Hannover, Hannover, Germany

    T Witte

  6. Department of Medical Sciences and IRCAD, University of Eastern Piedmont, Novara, Italy

    S D'Alfonso

  7. Department of Clinical Medicine, Rheumatology Unit, Siena University, Siena, Italy

    M Galeazzi

  8. Servicio Medicina Interna, Hospital Virgen de las Nieves, Granada, Spain

    J Jiménez-Alonso

  9. Sanatorio Parque, Rosario, Argentina

    B A Pons-Estel

  10. Arthritis and Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA

    M E Alarcón-Riquelme

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  1. A M Delgado-Vega
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  2. A-K Abelson
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  3. E Sánchez
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  4. T Witte
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Correspondence to M E Alarcón-Riquelme.

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Supplementary Information accompanies the paper on Genes and Immunity website (http://www.nature.com/gene)

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Delgado-Vega, A., Abelson, AK., Sánchez, E. et al. Replication of the TNFSF4 (OX40L) promoter region association with systemic lupus erythematosus. Genes Immun 10, 248–253 (2009). https://doi.org/10.1038/gene.2008.95

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