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ma=86400 Genetic association of miRNA-146a with systemic lupus erythematosus in Europeans through decreased expression of the gene | Genes & Immunity
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Genetic association of miRNA-146a with systemic lupus erythematosus in Europeans through decreased expression of the gene

Genes & Immunity volume 13, pages 268–274 (2012)Cite this article

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Abstract

A recent genome-wide association study revealed a variant (rs2431697) in an intergenic region, between the pituitary tumor-transforming 1 (PTTG1) and microRNA (miR-146a) genes, associated with systemic lupus erythematosus (SLE) susceptibility. Here, we analyzed with a case–control design this variant and other candidate polymorphisms in this region together with expression analysis in order to clarify to which gene this association is related. The single-nucleotide polymorphisms (SNPs) rs2431697, rs2910164 and rs2277920 were genotyped by TaqMan assays in 1324 SLE patients and 1453 healthy controls of European ancestry. Genetic association was statistically analyzed using Unphased. Gene expression of PTTG1, the miRNAs miR-3142 and primary and mature forms of miR-146a in peripheral blood mononuclear cells (PBMCs) were assessed by quantitative real-time PCR. Of the three variants analyzed, only rs2431697 was genetically associated with SLE in Europeans. Gene expression analysis revealed that this SNP was not associated with PTTG1 expression levels, but with the microRNA-146a, where the risk allele correlates with lower expression of the miRNA. We replicated the genetic association of rs2341697 with SLE in a case–control study in Europeans and demonstrated that the risk allele of this SNP correlates with a downregulation of the miRNA 146a, potentially important in SLE etiology.

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Acknowledgements

We gratefully acknowledge the financial support provided through the BIOLUPUS Research Networking Programme of the European Science Foundation. This work has been supported by the Swedish Research Council to MEAR, the King Gustaf Vth-80th Jubilee Fund to SVK and MEAR, Clas Groschinskys Fund and Olle Engkvist Byggmästare Fund and Marcus Borgström Fund to SVK and the Swedish Association Against Rheumatism to SVK and MEAR. Dr Pons-Estel's work was supported by the Federico Wilhelm Agricola Foundation Research grant. Dr Torsten Witte's work was supported by DFG WI 1031/6-1. We also acknowledge the Instituto de Salud Carlos III (PS09/00129) partly co-financed through European FEDER funds, Spain.

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Author notes

  1. S V Kozyrev and M E Alarcón-Riquelme: These authors contributed equally to this work

Authors and Affiliations

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

    S E Löfgren

  2. Department of Medicine, Karolinska University Hospital, Stockholm, Sweden

    J Frostegård

  3. Department of Laboratory Medicine, Section of M.I.G., Lund University, Lund, Sweden

    L Truedsson

  4. Department of Rheumatology, Sanatorio Parque, Rosario, Argentina

    B A Pons-Estel

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

    S D'Alfonso

  6. Clinic for Immunology and Rheumatology, Hannover Medical School, Hannover, Germany

    T Witte

  7. Rheumatology Department, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium

    B R Lauwerys

  8. Department of Pediatrics and Health Center, University of Szeged, Szeged, Hungary

    E Endreffy

  9. Department of Rheumatology, Albert Szent-Györgyi Clinical Centre, University of Szeged, Szeged, Hungary

    L Kovács

  10. Unidade de Imunologia Clinica and UMIB, Hospital Santo Antonio and ICBAS, Porto, Portugal

    C Vasconcelos

  11. Department of Molecular Pathology and Immunology, UMIB/ICBAS, Immunogenetic, Porto, Portugal

    B Martins da Silva

  12. Department of Medical Biochemistry and Microbiology, BMC, Uppsala University, Uppsala, Sweden

    S V Kozyrev

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

    M E Alarcón-Riquelme

  14. Andalucian Center for Genomics and Oncological Research, Pfizer-University of Granada-Junta de Andalucia, Granada, Spain

    M E Alarcón-Riquelme

Authors
  1. S E Löfgren
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  2. J Frostegård
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  4. B A Pons-Estel
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  5. S D'Alfonso
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  6. T Witte
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  9. L Kovács
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  10. C Vasconcelos
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  11. B Martins da Silva
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Corresponding authors

Correspondence to S V Kozyrev or M E Alarcón-Riquelme.

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APPENDIX

APPENDIX

The list of participants

The Argentine Collaborative Group Participants are Hugo R Scherbarth MD, Pilar C Marino MD, Estela L Motta MD, Servicio de Reumatología, Hospital Interzonal General de Agudos ‘Dr Oscar Alende’, Mar del Plata, Argentina; Susana Gamron MD, Cristina Drenkard MD, Emilia Menso MD, Servicio de Reumatología de la UHMI 1, Hospital Nacional de Clínicas, Universidad Nacional de Córdoba, Córdoba, Argentina; Alberto Allievi MD, Guillermo A Tate MD, Organización Médica de Investigación, Buenos Aires, Argentina; Jose L Presas MD Hospital General de Agudos Dr Juán A Fernandez, Buenos Aires, Argentina; Simon A Palatnik MD, Marcelo Abdala MD, Mariela Bearzotti PhD, Facultad de Ciencias Medicas, 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 Medico de Córdoba, Córdoba, Argentina; Sergio Paira MD, Susana Roverano 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 Medica, 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 Italian collaborative participants are Nadia Barizzone (Department of Medical Sciences, University of Eastern Piedmont, Novara, Italy), Maria Giovanna Danieli (Dipartimento di Scienze Mediche e Chirurgiche, Università Politecnica delle Marche, Ancona, Italy), Gian Domenico Sebastiani (U.O.C. di Reumatologia Ospedale San Camillo, Roma, Italy), Enrica Bozzolo, Maria Grazia Sabbadini (IRCCS San Raffaele Hospital, Milan, Italy), Mauro Galeazzi, (Siena University, Siena, Italy), Sergio Migliaresi, Giovanni La Montagna (Rheumatology Unit Second University of Naples, Naples, Italy).

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Löfgren, S., Frostegård, J., Truedsson, L. et al. Genetic association of miRNA-146a with systemic lupus erythematosus in Europeans through decreased expression of the gene. Genes Immun 13, 268–274 (2012). https://doi.org/10.1038/gene.2011.84

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