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HLA-DRB1*04/*13 alleles are associated with vascular disease and antiphospholipid antibodies in systemic lupus erythematosus
  1. Emeli Lundström1,
  2. Johanna T Gustafsson1,
  3. Andreas Jönsen2,
  4. Dag Leonard3,
  5. Agneta Zickert1,
  6. Kerstin Elvin4,
  7. Gunnar Sturfelt2,
  8. Gunnel Nordmark3,
  9. Anders A Bengtsson2,
  10. Ulf Sundin4,
  11. Henrik Källberg5,
  12. Johanna K Sandling6,
  13. Ann-Christine Syvänen6,
  14. Lars Klareskog1,
  15. Iva Gunnarsson1,
  16. Lars Rönnblom3,
  17. Leonid Padyukov1,
  18. Elisabet Svenungsson1
  1. 1Department of Medicine, Rheumatology Unit, Karolinska Institutet/Karolinska University Hospital, Stockholm, Sweden
  2. 2Department of Clinical Sciences, Section of Rheumatology, Lund University, Skåne University Hospital, Lund, Sweden
  3. 3Department of Medical Sciences, Section of Rheumatology, Uppsala University, Uppsala, Sweden
  4. 4Department of Clinical Immunology and Transfusion Medicine, Unit of Clinical Immunology, Karolinska Institutet/Karolinska University Hospital, Stockholm, Sweden
  5. 5Unit of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
  6. 6Department of Medical Sciences, Molecular Medicine, Uppsala University, Uppsala, Sweden
  1. Correspondence to Dr Elisabet Svenungsson, Rheumatology Unit, Department of Medicine, Karolinska University Hospital, 17176 Stockholm, Sweden; elisabet.svenungsson{at}


Background and objectives Vascular disease is common in systemic lupus erythematosus (SLE) and patients with antiphospholipid antibodies (aPL) are at high risk to develop arterial and venous thrombosis. Since HLA class II genotypes have been linked to the presence of pro-thrombotic aPL, we investigated the relationship between HLA-DRB1 alleles, aPL and vascular events in SLE patients.

Methods 665 SLE patients of Caucasian origin and 1403 controls were included. Previous manifestations of ischaemic heart disease, ischaemic cerebrovascular disease (ICVD) and venous thromboembolism (together referred to as any vascular events (AVE)) were tabulated. aPL were measured with ELISA. Two-digit HLA-DRB1 typing was performed by sequence-specific primer-PCR.

Results HLA-DRB1*04 was more frequent among SLE patients with ICVD compared to unaffected patients. This association remained after adjustment for known traditional cardiovascular risk factors. HLA-DRB1*13 was associated with AVE. All measured specificities of aPL—cardiolipin IgG and IgM, β2-glycoprotein-1 IgG, prothrombin (PT) IgG and a positive lupus anticoagulant test were associated with HLA-DRB1*04—while HLA-DRB1*13 was associated with IgG antibodies (β2-glycoprotein-1, cardiolipin and PT). In patients with the combined risk alleles, HLA-DRB1*04/*13, there was a significant additive interaction for the outcomes AVE and ICVD.

Conclusions The HLA-DRB1*04 and HLA-DRB1*13 alleles are associated with vascular events and an aPL positive immune-phenotype in SLE. Results demonstrate that a subset of SLE patients is genetically disposed to vascular vulnerability.

  • Systemic Lupus Erythematosus
  • Antiphospholipid Antibodies
  • Cardiovascular Disease
  • Autoantibodies

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