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Ischemic vascular disease and antiphospholipid antibodies are associated with HLA-DRB1 *04/*13 alleles in systemic lupus erythematosus
  1. Elisabet Svenungsson1,
  2. Emeli Lundström1,
  3. Johanna Gustafsson1,
  4. Andreas Jönsen2,
  5. Dag Leonard3,
  6. Agneta Zickert1,
  7. Kerstin Elvin4,
  8. Gunnar Sturfelt2,
  9. Gunnel Nordmark3,
  10. Anders Bengtsson2,
  11. Lars Klareskog1,
  12. Iva Gunnarsson1,
  13. Lars Rönnblom2,
  14. Leonid Padyukov1
  1. 1Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
  2. 2Department of Rheumatology, Lund University Hospital, Lund, Sweden
  3. 3Department of Medical Sciences, Section of Rheumatology, Uppsala University, Uppsala, Sweden
  4. 4Unit of Clinical Immunology, Department of Clinical Immunology and Transfusion Medicine, Karolinska Institutet, Stockholm, Sweden

Abstract

Background Cardiovascular disease (CVD) is common in systemic lupus erythematosus (SLE) and SLE patients with antiphospholipid antibodies (anti-PL) are at particularly high risk. HLA-DRB1 genotypes are associated with SLE per se and have also been linked to pro-thrombotic anti-PL. The authors investigated a possible relationship between HLA-DRB1 genes, anti-PL and CVD in patients with SLE.

Methods A total of 665 unrelated SLE patients of Caucasian origin from three clinics and 1403 controls were included. Previous manifestations of objectively verified ischemic heart disease (IHD, angina and/or myocardial infarction), ischemic cerebrovascular disease (ICVD, stroke and/or transitory ischemic attacks) and any arterial event (IHD and/or ICVD and/or ischemic peripheral arterial disease) were retrieved through patient interviews and medical records. Anti-PL in sera of patients were measured with ELISA. Two-digit HLA-DRB1 typing was performed in patient and control individuals by sequence-specific primer-PCR. Meta-analyses, presented below, of the combined results were calculated with RevMan 5.

Results The authors identified 67 patients with IHD, 78 with ICVD and 139 with any previous arterial event. HLA-DRB1*04 was not enriched in SLE per se, but was more frequent among SLE patients with ICVD (OR:1.88, 95% CI:1.16 to 3.05). HLA-DRB1*04 was furthermore associated with all measured specificities of anti-PL: anticardiolipin(CL) IgG (OR: 1.99, 95% CI:1.35 to 2.93), and IgM (OR: 1.76, 95% CI:1.20 to 2.58), anti-β2glycoprotein-1(β2GP-1) IgG (OR: 2.66, 95% CI:1.81 to 3.91), antiprothrombin IgG (OR: 1.69, 95% CI:1.04 to 2.76) and with a positive lupus anticoagulant test (OR:2.57, 95% CI:1.53 to 4.32). Additionally HLA-DRB1*13 was associated with anti-β2GP-1 IgG (OR: 1.69, 95%CI:1.13 to 2.52) and antiprothrombin IgG (OR: 1.66, 95% CI:1.01 to 2.75) antibodies. Carriers of the combined genotype HLA-DRB1*04/*13 were at especially high risk for any arterial event (OR: 4.02, 95% CI1.74 to 9.30) and were frequently diagnosed with positive tests for anti-CL IgG (OR: 3.52, 95% CI 1.68 to 8.71) as well as for anti-β2GP-1 IgG (OR: 3.18, 95% CI1.36 to 7.42). The previously reported associations between SLE and HLA-DRB1*03 and HLA-DRB1*15 were confirmed (OR>2), but neither of these HLA-alleles were associated with CVD in our study.

Conclusion Our results demonstrate that a subgroup of SLE patients, carriers of HLA-DRB1*04, have enhanced risk of ICVD. Prothrombotic anti-PL, associated with HLA-DRB1*04 and to a less extent with HLA-DRB1*13, possibly constitute an underlying mechanism. A potential interaction between DRB1*04 and DRB1*13 is suggested by the fact that the combined genotype (*04/*13) conferred a high risk of several anti-PL and of any arterial event. This study illustrates the importance to investigate subgroups of clinically well-defined patients when evaluating genetic contributions to autoimmune diseases.

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