STAT4 is a confirmed genetic risk factor for Sjögren's syndrome and could be involved in type 1 interferon pathway signaling.
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 STAT4alpha, STAT4beta, 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 x 10(-5)). The association was increased for homozygous subjects, which suggests a recessive effect of the STAT4 at-risk allele. STAT4alpha, STAT4beta and STAT1 mRNA levels in PBMCs were not significantly associated with rs7582694 genotypes, however the mRNA levels of STAT4alpha and type 1 IFN-induced genes were strongly correlated: PKR (P=4 x 10(-3), r=0.51), MX1 (P=2 x 10(-4), r=0.63) and IFITM1 (P=8 x 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.
Gestermann
N
N
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.
Mekinian
A
A
Comets
E
E
Loiseau
P
P
Puechal
X
X
Hachulla
E
E
Gottenberg
J-E
JE
Mariette
X
X
Miceli-Richard
C
C
D000943:Antigens, Differentiation; D016022:Case-Control Studies; D015331:Cohort Studies; D019204:GTP-Binding Proteins / Q000378:metabolism; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008565:Membrane Proteins / Q000378:metabolism; D064547:Myxovirus Resistance Proteins; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D050797:STAT4 Transcription Factor / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology; D012859:Sjogren's Syndrome / Q000235:genetics*; D019892:eIF-2 Kinase / Q000378:metabolism
D000943:Antigens, Differentiation; D008565:Membrane Proteins; D064547:Myxovirus Resistance Proteins; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; C062010:leu-13 antigen; D019892:eIF-2 Kinase; D019204:GTP-Binding Proteins