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Novel gene variants associated with cardiovascular disease in systemic lupus erythematosus and rheumatoid arthritis
  1. Dag Leonard1,
  2. Elisabet Svenungsson2,
  3. Johanna Dahlqvist3,
  4. Andrei Alexsson1,
  5. Lisbeth Ärlestig4,
  6. Kimberly E Taylor5,
  7. Johanna K Sandling1,
  8. Christine Bengtsson4,
  9. Martina Frodlund6,
  10. Andreas Jönsen7,
  11. Susanna Eketjäll8,
  12. Kerstin Jensen-Urstad9,
  13. Iva Gunnarsson2,
  14. Christopher Sjöwall6,
  15. Anders A Bengtsson7,
  16. Maija-Leena Eloranta1,
  17. Ann-Christine Syvänen10,
  18. Solbritt Rantapää-Dahlqvist4,
  19. Lindsey A Criswell5,
  20. Lars Rönnblom1
  1. 1 Department of Medical Sciences, Science for Life Laboratory, Rheumatology, Uppsala University, Uppsala, Sweden
  2. 2 Department of Medicine, Rheumatology Unit, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
  3. 3 Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
  4. 4 Department of Public Health and Clinical Medicine/Rheumatology, Umeå University, Umeå, Sweden
  5. 5 University of California, San Francisco, Rosalind Russell/Ephraim P. Engleman Rheumatology Research Center, San Francisco, California, USA
  6. 6 Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
  7. 7 Department of Rheumatology, Skåne University Hospital, Lund, Sweden
  8. 8 Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Integrated Cardio Metabolic Centre, Karolinska Institutet, Stockholm, Sweden
  9. 9 Department of Clinical Physiology, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden
  10. 10 Department of Medical Sciences, Science for Life Laboratory, Molecular Medicine, Uppsala University, Uppsala, Sweden
  1. Correspondence to Dr Dag Leonard, Department of Medical Sciences, Rheumatology, Uppsala University, Uppsala S-75185, Sweden; dag.leonard{at}


Objectives Patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) have increased risk of cardiovascular disease (CVD). We investigated whether single nucleotide polymorphisms (SNPs) at autoimmunity risk loci were associated with CVD in SLE and RA.

Methods Patients with SLE (n=1045) were genotyped using the 200K Immunochip SNP array (Illumina). The allele frequency was compared between patients with and without different manifestations of CVD. Results were replicated in a second SLE cohort (n=1043) and in an RA cohort (n=824). We analysed publicly available genetic data from general population, performed electrophoretic mobility shift assays and measured cytokine levels and occurrence of antiphospholipid antibodies (aPLs).

Results We identified two new putative risk loci associated with increased risk for CVD in two SLE populations, which remained after adjustment for traditional CVD risk factors. An IL19 risk allele, rs17581834(T) was associated with stroke/myocardial infarction (MI) in SLE (OR 2.3 (1.5 to 3.4), P=8.5×10−5) and RA (OR 2.8 (1.4 to 5.6), P=3.8×10−3), meta-analysis (OR 2.5 (2.0 to 2.9), P=3.5×10−7), but not in population controls. The IL19 risk allele affected protein binding, and SLE patients with the risk allele had increased levels of plasma-IL10 (P=0.004) and aPL (P=0.01). An SRP54-AS1 risk allele, rs799454(G) was associated with stroke/transient ischaemic attack in SLE (OR 1.7 (1.3 to 2.2), P=2.5×10−5) but not in RA. The SRP54-AS1 risk allele is an expression quantitative trait locus for four genes.

Conclusions The IL19 risk allele was associated with stroke/MI in SLE and RA, but not in the general population, indicating that shared immune pathways may be involved in the CVD pathogenesis in inflammatory rheumatic diseases.

  • rheumatoid arthritis

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  • Handling editor Josef S Smolen

  • Contributors DL, LR, JKS and AA designed the study. JD, SE, M-LE and DL performed the experiments. KJ-U performed the carotid ultrasound examinations. DL, ES, CB, KET, MF, IG, CS, AAB, SR-D, LAC and LR collected the data. AA, KET, LÄ and DL performed the statistical analysis. DL, AA, KET, JKS, LR, ES, JD, A-CS, LAC, SR-D and M-LE analysed the data. DL, JKS, JD and LR wrote the manuscript. All authors approved the final version of the manuscript.

  • Funding This project was funded by the Swedish Research Council for Medicine and Health (D0283001, A0258801, E0226301 and E0395401), Knut and Alice Wallenberg Foundation (2011.0073), AstraZeneca-Science for Life Laboratory Research Collaborationgrant (DISSECT), Swedish Society of Medicine and Ingegerd Johansson donation, Swedish Rheumatism Foundation, King Gustaf V’s 80-year Foundation, Torsten Söderberg Foundation, Uppsala County Council and Uppsala University Hospital (ALF), Stockholm County Council (ALF), Uppsala University, Swedish Heart-Lung foundation, Selander Foundation, Agnes and Mac Rudberg Foundation, Gustaf Prim Foundation and COMBINE. Work related to the UCSF cohort was supported by NIH grants UL1-TR-00004, P60-AR-053308 and R01-AR-44804.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval The regional ethics committee in Uppsala, Sweden and the local ethics committees.

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

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