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STAT4 Associates with SLE through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk
  1. Anna-Karin Abelson (anna-karin.abelson{at}genpat.uu.se)
  1. Department of Genetics and Pathology, Uppsala University, Sweden
    1. Angélica Maria Delgado-Vega (angelica.delgado{at}genpat.uu.se)
    1. Department of Genetics and Pathology, Uppsala University, Sweden
      1. Sergey V Kozyrev (sergey.kozyrev{at}genpat.uu.se)
      1. Department of Genetics and Pathology, Uppsala University, Sweden
        1. Elena Sánchez (elena{at}ipb.csic.es)
        1. Instituto de Biomedicina y Parasitología “López-Neyra”, Spain
          1. Rafael Velázquez-Cruz (rvelazquez{at}inmegen.gob.mx)
          1. Instituto Nacional de Medicina Genómica, Mexico
            1. Niclas Eriksson (niclas.eriksson{at}ucr.uu.se)
            1. Uppsala Clinical Research Center, Uppsala University, Sweden
              1. Jerome Wojcik (jerome.wojcik{at}merckserono.net)
              1. Merck Serono, Chemin des Mines, Switzerland
                1. Prasad Linga Reddy (mlingareddy{at}mail.mcg.edu)
                1. Department of Genetics and Pathology, Uppsala University, Sweden
                  1. Guadalupe Lima
                  1. Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán&rdqu, Mexico
                    1. Sandra D’Alfonso
                    1. Department of Medical Sciences and IRCAD, University of Eastern Piedmont, Italy
                      1. Sergio Migliaresi
                      1. Rheumatology Unit, Second University of Naples, Italy
                        1. Vicente Baca
                        1. Department of Rheumatology, Pediatric Hospital, Centro Medico Nacional Siglo XXI, IMSS, Mexico
                          1. Lorena Orozco
                          1. Instituto Nacional de Medicina Genómica, Mexico
                            1. Torsten Witte
                            1. Medical School Hannover, Germany
                              1. Norberto Ortego-Centeno
                              1. Department of Internal Medicine, Hospital Clínico San Cecilio, Spain
                                1. Hadi Abderrahim
                                1. Merck Serono, Chemin des Mines, Switzerland
                                  1. Bernardo A Pons-Estel
                                  1. Sanatorio Parque, Argentina
                                    1. Carmen Gutiérrez
                                    1. Hospital Universitario Central de Asturias, Universidad de Oviedo, Spain
                                      1. Ana Suárez (anasua{at}uniovi.es)
                                      1. Hospital Universitario Central de Asturias, Universidad de Oviedo, Spain
                                        1. Maria Francisca González-Escribano
                                        1. Department of Immunology, Hospital Virgen del Rocío, Spain
                                          1. Javier Martin (martin{at}ipb.csic.es)
                                          1. Instituto de Biomedicina Lopez-Neyra. CSIC, Spain
                                            1. Marta E Alarcón-Riquelme (marta.alarcon{at}genpat.uu.se)
                                            1. Department of Genetics and Pathology, Uppsala University, Sweden

                                              Abstract

                                              Objectives: To confirm and define the genetic association of STAT4 and systemic lupus erythematosus, investigate the possibility of correlations with differential splicing and/or expression levels, and genetic interaction with IRF5.

                                              Methods: 30 tag SNPs were genotyped in an independent set of Spanish cases and controls. SNPs surviving correction for multiple tests were genotyped in 5 new sets of cases and controls for replication. STAT4 cDNA was analyzed by 5'-RACE PCR and sequencing. Expression levels were measured by quantitative PCR.

                                              Results: In the fine-mapping, four SNPs were significant after correction for multiple testing, with rs3821236 and rs3024866 as the strongest signals, followed by the previously associated rs7574865, and by rs1467199. Association was replicated in all cohorts. After conditional regression analyses, two major independent signals represented by SNPs rs3821236 and rs7574865, remained significant across the sets. These SNPs belong to separate haplotype blocks. High levels of STAT4 expression correlated with SNPs rs3821236, rs3024866 (both in the same haplotype block) and rs7574865 but not with other SNPs. We also detected transcription of alternative tissue-specific exons 1, indicating presence of tissue-specific promoters of potential importance in the expression of STAT4. No interaction with associated SNPs of IRF5 was observed using regression analysis.

                                              Conclusions: These data confirm STAT4 as a susceptibility gene for SLE and suggest the presence of at least two functional variants affecting levels of STAT4. Our results also indicate that both genes STAT4 and IRF5 act additively to increase risk for SLE.

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