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

• Published in: Genes and immunity Vol. 11; no. 5; pp. 432 - 438
• Main Authors: Gestermann, N, Mekinian, A, Comets, E, Loiseau, P, Puechal, X, Hachulla, E, Gottenberg, J-E, Mariette, X, Miceli-Richard, C
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2010; Nature Publishing Group
• Subjects: 631/208/457/649; 631/250/516; 631/45/612/822; 692/699/249/1313/498; Alleles; Antigens, Differentiation; Biomedical and Life Sciences; Biomedicine; Cancer Research; Case-Control Studies; Cohort Studies; Confidence intervals; Cytokines; eIF-2 Kinase - metabolism; Exocrine glands; Gene Expression; Gene polymorphism; Genes; Genetic aspects; Genetic Predisposition to Disease - genetics; Genome-Wide Association Study; GTP-Binding Proteins - metabolism; Human Genetics; Humans; Immunology; Interferon; Interleukin 12; Kinases; Leukocytes (mononuclear); Leukocytes, Mononuclear - immunology; Lupus; Membrane Proteins - metabolism; Myxovirus Resistance Proteins; Odds Ratio; original-article; Peripheral blood mononuclear cells; Physiological aspects; Polymorphism; Polymorphism, Single Nucleotide - genetics; Risk factors; Signal Transduction - genetics; Signal Transduction - immunology; Sjogren's syndrome; Sjogren's Syndrome - genetics; Stat1 protein; Stat4 protein; STAT4 Transcription Factor - genetics; Transcription factors; France; Paris France; STAT4; promoter; Sjögren's syndrome; genetic polymorphism
• ISSN: 1466-4879; 1476-5470; 1476-5470
• DOI: 10.1038/gene.2010.29

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.