title: The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype.
abstract: The aim of this study was to investigate the possible role of STAT4 gene in the genetic predisposition to systemic sclerosis (SSc) susceptibility or clinical phenotype. A total of 1317 SSc patients [896 with limited cutaneous SSc (lcSSc) and 421 with diffuse cutaneous SSc (dcSSc)] and 3113 healthy controls, from an initial case-control set of Spanish Caucasian ancestry and five independent cohorts of European ancestry (The Netherlands, Germany, Sweden, Italy and USA), were included in the study. The rs7574865 polymorphism was selected as STAT4 genetic marker. We observed that the rs7574865 T allele was significantly associated with susceptibility to lcSSc in the Spanish population [P = 1.9 x 10(-5) odds ratio (OR) 1.61 95% confidence intervals (CI) 1.29-1.99], but not with dcSSc (P = 0.41 OR 0.84 95% CI 0.59-1.21). Additionally, a dosage effect was observed showing individuals with rs7574865 TT genotype higher risk for lcSSc (OR 3.34, P = 1.02 x 10(-7) 95% CI 2.11-5.31). The association of the rs7574865 T allele with lcSSc was confirmed in all the replication cohorts with different effect sizes (OR ranging between 1.15 and 1.86), as well as the lack of association of STAT4 with dcSSc. A meta-analysis to test the overall effect of the rs7574865 polymorphism showed a strong risk effect of the T allele for lcSSc susceptibility (pooled OR 1.54 95% CI 1.36-1.74; P < 0.0001). Our data show a strong and reproducible association of the STAT4 gene with the genetic predisposition to lcSSc suggesting that this gene seems to be one of the genetic markers influencing SSc phenotype.
authors.affiliation: Instituto de Parasitologia y Biomedicina Lopez-Neyra (CSIC), Granada, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Rueda
authors.forename: J
authors.initials: J
authors.lastname: Broen
authors.forename: C
authors.initials: C
authors.lastname: Simeon
authors.forename: R
authors.initials: R
authors.lastname: Hesselstrand
authors.forename: B
authors.initials: B
authors.lastname: Diaz
authors.forename: H
authors.initials: H
authors.lastname: Suárez
authors.forename: N
authors.initials: N
authors.lastname: Ortego-Centeno
authors.forename: G
authors.initials: G
authors.lastname: Riemekasten
authors.forename: V
authors.initials: V
authors.lastname: Fonollosa
authors.forename: M C
authors.initials: MC
authors.lastname: Vonk
authors.forename: F H J
authors.initials: FH
authors.lastname: van den Hoogen
authors.forename: J
authors.initials: J
authors.lastname: Sanchez-Román
authors.forename: M A
authors.initials: MA
authors.lastname: Aguirre-Zamorano
authors.forename: R
authors.initials: R
authors.lastname: García-Portales
authors.forename: A
authors.initials: A
authors.lastname: Pros
authors.forename: M T
authors.initials: MT
authors.lastname: Camps
authors.forename: M A
authors.initials: MA
authors.lastname: Gonzalez-Gay
authors.forename: M J H
authors.initials: MJ
authors.lastname: Coenen
authors.forename: P
authors.initials: P
authors.lastname: Airo
authors.forename: L
authors.initials: L
authors.lastname: Beretta
authors.forename: R
authors.initials: R
authors.lastname: Scorza
authors.forename: J
authors.initials: J
authors.lastname: van Laar
authors.forename: M F
authors.initials: MF
authors.lastname: Gonzalez-Escribano
authors.forename: J L
authors.initials: JL
authors.lastname: Nelson
authors.forename: T R D J
authors.initials: TR
authors.lastname: Radstake
authors.forename: J
authors.initials: J
authors.lastname: Martin
mesh_terms: D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D050797:STAT4 Transcription Factor / Q000235:genetics*; D012595:Scleroderma, Systemic / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D044465:White People / Q000208:ethnology / Q000235:genetics*
chemical_list: D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human