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STAT4 is a confirmed genetic risk factor for Sjögren's syndrome and could be involved in type 1 interferon pathway signaling

Genes & Immunity volume 11, pages 432–438 (2010)Cite this article

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A Corrigendum to this article was published on 21 July 2010

Abstract

Signal transducer and activator of transcription 4 (STAT4) is a transcription factor mainly activated by interleukin 12, which promotes the secretion of type 2 interferon (IFN) by T-helper 1 cells. We assessed the association of STAT4 gene polymorphism and primary Sjögren's syndrome (pSS) and its functional relevance. We analyzed STAT4 rs7582694 polymorphism in an exploratory cohort of 186 pSS patients and 152 controls, and in a replication cohort of 192 pSS patients and 483 controls, all Caucasian. mRNA levels of STAT4α, STAT4β, STAT1, and the type 1 IFN-induced genes PKR, MX1 and IFITM1 were assessed in peripheral blood mononuclear cells (PBMCs) from 30 pSS patients. STAT4 rs7582694 C allele was associated with pSS in both cohorts (odds ratio (OR) 1.57, 95% confidence interval (CI) 1.27–1.93, P=2.3 × 10−5). The association was increased for homozygous subjects, which suggests a recessive effect of the STAT4 at-risk allele. STAT4α, STAT4β and STAT1 mRNA levels in PBMCs were not significantly associated with rs7582694 genotypes, however the mRNA levels of STAT4α and type 1 IFN-induced genes were strongly correlated: PKR (P=4 × 10−3, r=0.51), MX1 (P=2 × 10−4, r=0.63) and IFITM1 (P=8 × 10−3, r=0.47), suggesting that STAT4 might be involved in not only type 2 IFN production but also in type 1 IFN-mediated effects.

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Acknowledgements

We thank Dr J Benessiano and all staff members of the Bichat Hospital Biological resource Center (Paris) for their help in centralizing and managing biological data collection from the French ASSESS (Atteinte Systémique et Evolution des patients atteints de Syndrome de Sjögren primitive), a prospective cohort of patients with Sjögren's syndrome; and S Gaete from the Unité de recherche Clinique Paris Sud for clinical data collection. We thank all the investigators of the ASSESS cohort who recruited and followed the patients: AL Fauchais (Limoges), S Rist (Orleans), D Sené (Paris–La Pitié-Salpétrière), V Le Guern (Paris–Cochin), G Hayem (Paris–Bichat), J Sibilia (Strasbourg), J Morel (Montpellier), E Hachulla (Lille), A Saraux (Brest), A Perdriger (Rennes), X Puechal (Le Mans), V Goeb (Rouen) and JJ Dubost (Clermont-Ferrand). We thank Dr Patricia Lienard from DNAvision SA (Belgium) for conducting DNA sample genotyping. We thank P Dieudé, Y Allanore and C Boileau, and l’Association des Sclérodermiques de France for their contribution in the collection and genotyping of DNA samples from French controls, supported by a grant from Agence Nationale pour la Recherche (Grant number R07094KS). This work was supported by Agence Nationale pour la Recherche (ANR-06-PHYSIO-033-01), Société Française de Rhumatologie and Program Hospitalier de Recherche Clinique (AOM06133–P060228)

Author contributions: CMR and XM designed and directed the study. NG and AM conducted STAT4α, STAT4β, STAT1, MX1, PKR and IFITM1 mRNA expression experiments. CMR, NG, AM and XM conducted data analysis. EC conducted statistical analysis. PL was involved in control sample data collection. XP, EH and JEG were involved in patient sample data collection.

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Author notes

  1. X Mariette and C Miceli-Richard: These authors contributed equally to this work.

Authors and Affiliations

  1. Rhumatologie, Institut Pour la Santé et la Recherche Médicale (INSERM) U802, Université Paris-Sud 11, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris (AP-HP), Le Kremlin Bicêtre, France

    N Gestermann, A Mekinian, X Mariette & C Miceli-Richard

  2. INSERM U738, Université Paris 7, Paris, France

    E Comets

  3. INSERM U396, Immunologie et Histocompatibilité, Hôpital Saint-Louis, AP-HP, Paris, France

    P Loiseau

  4. Rhumatologie, Hôpital du Mans, Le Mans, France

    X Puechal

  5. Médecine Interne, Hôpital Claude Huriez, Lille, France

    E Hachulla

  6. Rhumatologie, Hôpital De Hautepierre, Strasbourg, France

    J-E Gottenberg

  7. Pharmacologie, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris (AP-HP), Le Kremlin Bicêtre, France

    N Gestermann, A Mekinian, E Comets, P Loiseau, X Puechal, E Hachulla, J-E Gottenberg, X Mariette & C Miceli-Richard

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  1. N Gestermann
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Correspondence to X Mariette or C Miceli-Richard.

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Gestermann, N., Mekinian, A., Comets, E. et al. STAT4 is a confirmed genetic risk factor for Sjögren's syndrome and could be involved in type 1 interferon pathway signaling. Genes Immun 11, 432–438 (2010). https://doi.org/10.1038/gene.2010.29

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  • DOI: https://doi.org/10.1038/gene.2010.29

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