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  • High genetic risk score is associated with early disease onset, damage accrual and decreased survival in systemic lupus erythematosus

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Systemic lupus erythematosus
High genetic risk score is associated with early disease onset, damage accrual and decreased survival in systemic lupus erythematosus
  1. Sarah Reid1,
  2. Andrei Alexsson1,
  3. Martina Frodlund2,
  4. David Morris3,
  5. Johanna K Sandling1,
  6. Karin Bolin1,
  7. Elisabet Svenungsson4,
  8. Andreas Jönsen5,
  9. Christine Bengtsson6,
  10. Iva Gunnarsson4,
  11. Vera Illescas Rodriguez4,
  12. Anders Bengtsson5,
  13. Sabine Arve5,
  14. Solbritt Rantapää-Dahlqvist6,
  15. Maija-Leena Eloranta1,
  16. Ann-Christine Syvänen7,
  17. Christopher Sjöwall2,
  18. Timothy James Vyse3,
  19. Lars Rönnblom1,
  20. Dag Leonard1
  1. 1 Rheumatology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
  2. 2 Rheumatology/Division of Neuro and Inflammation Sciences, Department of Clinical and Experimental Medicine, Linköping University, Linkoping, Sweden
  3. 3 Department of Medical and Molecular Genetics, King’s College London, London, UK
  4. 4 Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
  5. 5 Rheumatology, Department of Clinical Sciences, Lund University, Lund, Sweden
  6. 6 Department of Public Health and Clinical Medicine/Rheumatology, Umeå University, Umeå, Sweden
  7. 7 Molecular Medicine and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
  1. Correspondence to Professor Lars Rönnblom, Rheumatology and Science for Life Laboratory, Department of Medical Sciences, Uppsala University, 752 36 Uppsala, Sweden; lars.ronnblom{at}medsci.uu.se

Abstract

Objectives To investigate associations between a high genetic disease risk and disease severity in patients with systemic lupus erythematosus (SLE).

Methods Patients with SLE (n=1001, discovery cohort and n=5524, replication cohort) and healthy controls (n=2802 and n=9859) were genotyped using a 200K Immunochip single nucleotide polymorphism array. A genetic risk score (GRS) was assigned to each individual based on 57 SLE risk loci.

Results SLE was more prevalent in the high, compared with the low, GRS-quartile (OR 12.32 (9.53 to 15.71), p=7.9×10–86 and OR 7.48 (6.73 to 8.32), p=2.2×10–304 for the discovery and the replication cohorts, respectively). In the discovery cohort, patients in the high GRS-quartile had a 6-year earlier mean disease onset (HR 1.47 (1.22 to 1.75), p=4.3×10–5), displayed higher prevalence of damage accrual (OR 1.47 (1.06 to 2.04), p=2.0×10–2), renal disorder (OR 2.22 (1.50 to 3.27), p=5.9×10–5), anti-dsDNA (OR 1.83 (1.19 to 2.81), p=6.1×10–3), end-stage renal disease (ESRD) (OR 5.58 (1.50 to 20.79), p=1.0×10–2), proliferative nephritis (OR 2.42 (1.30 to 4.49), p=5.1×10–3), anti-cardiolipin-IgG (OR 1.89 (1.13 to 3.18), p=1.6×10–2), anti-β2-glycoprotein-I-IgG (OR 2.29 (1.29 to 4.06), p=4.8×10–3) and positive lupus anticoagulant test (OR 2.12 (1.16 to 3.89), p=1.5×10–2) compared with patients in the low GRS-quartile. Survival analysis showed earlier onset of the first organ damage (HR 1.51 (1.04 to 2.25), p=3.7×10–2), first cardiovascular event (HR 1.65 (1.03 to 2.64), p=2.6×10–2), nephritis (HR 2.53 (1.72 to 3.71), p=9.6×10–7), ESRD (HR 6.78 (1.78 to 26.86), p=6.5×10–3) and decreased overall survival (HR 1.83 (1.02 to 3.30), p=4.3×10–2) in high to low quartile comparison.

Conclusions A high GRS is associated with increased risk of organ damage, renal dysfunction and all-cause mortality. Our results indicate that genetic profiling may be useful for predicting outcomes in patients with SLE.

  • antiphospholipid syndrome
  • cardiovascular disease
  • gene polymorphism
  • lupus nephritis
  • systemic lupus erythematosus
https://creativecommons.org/licenses/by/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

https://doi.org/10.1136/annrheumdis-2019-216227

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    Footnotes

    • Handling editor Josef S Smolen

    • Presented at Results included have been presented at the 13th International Congress on SLE (Reid et al., Lupus Sci Med 2019;6:A154-5.) and at the ACR/ARHP Meeting (Reid et al., Arthritis Rheum 2017; 69 (suppl 10).

    • Contributors SR, DL and LR designed the study. SR, MF, JKS, KB, ES, AJ, CB, IG, VIR, AB, SA, SR-D, M-LE, A-CS, CS, LR and DL collected the data. DLM and TJV collected and compiled the replication cohort data. SR, AA and DL performed the statistical analysis. SR, DL and LR analysed the data. SR, DL and LR wrote the manuscript. All authors revised the manuscript critically for important intellectual content and approved the final version of the manuscript.

    • Funding This project was funded by the Swedish Research Council for Medicine and Health, Knut and Alice Wallenberg Foundation, Swedish Society of Medicine and Ingegerd Johansson donation, Swedish Rheumatism Foundation, King Gustaf V’s 80-year 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 and Gustaf Prim Foundation. Several funders, recognised in Langefeld et al including the SLEGEN consortium, supported and funded the replication cohort data.

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Ethics approval The study protocol was approved by the Regional Ethical Review Board, Uppsala (DNR 2016/155) and the local ethics committees. All participants gave their informed consent.

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

    • Data availability statement Data are available on reasonable request.