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Extended report
A STAT4 risk allele is associated with ischaemic cerebrovascular events and anti-phospholipid antibodies in systemic lupus erythematosus
  1. Elisabet Svenungsson1,
  2. Johanna Gustafsson1,
  3. Dag Leonard2,
  4. Johanna Sandling3,
  5. Iva Gunnarsson1,
  6. Gunnel Nordmark2,
  7. Andreas Jönsen4,
  8. Anders A Bengtsson4,
  9. Gunnar Sturfelt4,
  10. Solbritt Rantapää-Dahlqvist5,
  11. Kerstin Elvin6,
  12. Ulf Sundin6,
  13. Sophie Garnier3,
  14. Julia F Simard7,
  15. Snaevar Sigurdsson3,
  16. Leonid Padyukov1,
  17. Ann-Christine Syvänen3,
  18. Lars Rönnblom2
  1. 1Department of Medicine, Rheumatology Unit, Karolinska Institutet/Karolinska University Hospital, Stockholm, Sweden
  2. 2Department of Medical Sciences, Section of Rheumatology, Uppsala University, Uppsala, Sweden
  3. 3Department of Medical Sciences, Molecular Medicine, Uppsala University, Uppsala, Sweden
  4. 4Department of Rheumatology, Lund University Hospital, Lund, Sweden
  5. 5Department of Rheumatology, Umeå University Hospital, Umeå, Sweden
  6. 6Department of Clinical Immunology and Transfusion Medicine, Unit of Clinical Immunology, Karolinska University Hospital and Karolinska Institutet/Karolinska University Hospital, Stockholm, Sweden
  7. 7Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden
  1. Correspondence to Elisabet Svenungsson, Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Solna, SE-17176 Stockholm, Sweden; elisabet.svenungsson{at}


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 (ORc)=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 (ORc=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 (ORc=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≤0.02 for all).

Conclusion 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.

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  • JG, DL and JS contributed equally to this work.

  • Funding Funding was received from the Alliance for Lupus Research, the Swedish Research Council, the Swedish Rheumatism Foundation, the Uppsala University Hospital Research and Development Fund, Ulla and Roland Gustafssons Foundation, the Swedish Heart-Lung Foundation, The King Gustaf V 80th Birthday Fund, The Swedish Society of Medicine, The Åke Wiberg Foundation, Alex and Eva Wallstöms Foundation, Karolinska Institutet Foundations, the Knut and Alice Wallenberg Foundation, ALF funding from Stockholm County Council and COMBINE.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Local ethics committees at Karolinska University Hospital, Uppsala University Hospital and Lund University hospital.

  • Provenance and peer review Not commissioned; externally peer reviewed.