title: A STAT4 risk allele is associated with ischaemic cerebrovascular events and anti-phospholipid antibodies in systemic lupus erythematosus.
abstract: OBJECTIVE
  To investigate whether the risk allele for systemic lupus erythematosus (SLE) in the signal transducer and activator of transcription factor 4 (STAT4) gene, defined by the single nucleotide polymorphism (SNP) rs10181656(G), is associated with vascular events and/or presence of prothrombotic anti-phospholipid antibodies (aPL) in patients with SLE.
  
  
  METHODS
  Two independent groups of unrelated patients with SLE of Swedish ethnicity (n=424 and 154) were genotyped, and occurrence of previous manifestations of ischaemic heart disease (IHD), ischaemic cerebrovascular disease (ICVD) and venous thromboembolic events (VTE) was tabulated. aPL values were measured by ELISA. Matched controls (n=492 and 194) were genotyped.
  
  
  RESULTS
  The STAT4 risk allele was more frequent in patients with SLE with previous arterial events (combined OR (OR(c))=1.5, 95% CI 1.1 to 2.0) compared to patients without such events. The association was mainly attributable to an accumulation of the risk allele among patients with ICVD (OR(c)=2.3, CI 1.6 to 3.3). There was no association with IHD or VTE. The presence of two or more aPLs was associated with the risk allele (OR(c)=1.6, 95% CI 1.2 to 2.0). In multivariable-adjusted logistic regression analyses treatment for hypertension, at least one STAT4 risk allele, older age, IgG anti-cardiolipin antibodies and longer SLE duration remained independently associated with previous ICVD (p<or=0.02 for all).
  
  
  CONCLUSIONS
  Patients with SLE with the STAT4 risk allele had a strikingly increased risk of ICVD, comparable in magnitude to that of hypertension. The results imply that a genetic predisposition is an important and previously unrecognised risk factor for ICVD in SLE, and that aPLs may be one underlying mechanism.
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Solna, SE-17176 Stockholm, Sweden. elisabet.svenungsson@ki.se
authors.forename: Elisabet
authors.initials: E
authors.lastname: Svenungsson
authors.forename: Johanna
authors.initials: J
authors.lastname: Gustafsson
authors.forename: Dag
authors.initials: D
authors.lastname: Leonard
authors.forename: Johanna
authors.initials: J
authors.lastname: Sandling
authors.forename: Iva
authors.initials: I
authors.lastname: Gunnarsson
authors.forename: Gunnel
authors.initials: G
authors.lastname: Nordmark
authors.forename: Andreas
authors.initials: A
authors.lastname: Jönsen
authors.forename: Anders A
authors.initials: AA
authors.lastname: Bengtsson
authors.forename: Gunnar
authors.initials: G
authors.lastname: Sturfelt
authors.forename: Solbritt
authors.initials: S
authors.lastname: Rantapää-Dahlqvist
authors.forename: Kerstin
authors.initials: K
authors.lastname: Elvin
authors.forename: Ulf
authors.initials: U
authors.lastname: Sundin
authors.forename: Sophie
authors.initials: S
authors.lastname: Garnier
authors.forename: Julia F
authors.initials: JF
authors.lastname: Simard
authors.forename: Snaevar
authors.initials: S
authors.lastname: Sigurdsson
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Syvänen
authors.forename: Lars
authors.initials: L
authors.lastname: Rönnblom
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D017152:Antibodies, Antiphospholipid / Q000097:blood*; D002545:Brain Ischemia / Q000209:etiology / Q000235:genetics* / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000150:complications / Q000235:genetics* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D050797:STAT4 Transcription Factor / Q000235:genetics*
chemical_list: D017152:Antibodies, Antiphospholipid; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human