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NCF1-339 polymorphism is associated with altered formation of neutrophil extracellular traps, high serum interferon activity and antiphospholipid syndrome in systemic lupus erythematosus
  1. Petrus Linge1,
  2. Sabine Arve1,
  3. Lina M Olsson2,
  4. Dag Leonard3,
  5. Christopher Sjöwall4,
  6. Martina Frodlund4,
  7. Iva Gunnarsson5,
  8. Elisabet Svenungsson5,
  9. Helena Tydén1,
  10. Andreas Jönsen1,
  11. Robin Kahn6,7,
  12. Åsa Johansson8,9,
  13. Lars Rönnblom3,
  14. Rikard Holmdahl2,
  15. Anders Bengtsson1
  1. 1 Department of Clinical Sciences Lund, Section of Rheumatology, Lunds University Faculty of Medicine, Lund, Skane, Sweden
  2. 2 Department of Medical Biochemistry and Biophysics, Division of Medical Inflammation Research, Karolinska Institute, Stockholm, Stockholm County, Sweden
  3. 3 Department of Medical Sciences, Science for Life Laboratories, Rheumatology Unit, Uppsala University, Uppsala, Uppland, Sweden
  4. 4 Department of Clinical and Experimental Medicine, Rheumatology/AIR, Linköping University, Linkoping, Ostergotland, Sweden
  5. 5 Department of Medicine Solna, Unit of Rheumatology, Karolinska Institute, Stockholm, Stockholm County, Sweden
  6. 6 Department of Clinical Sciences Lund, Section of Pediatrics, Lund University, Lund, Skane, Sweden
  7. 7 Wallenberg Center for Molecular Medicin, Lund University, Lund, Skane, Sweden
  8. 8 Division for Hematology and Transfusion Medicine, Department of laboratory medicine, Lund University, Lund, Skane, Sweden
  9. 9 Regional Laboratories Region Skane, Department of Clinical Immunology and Transfusion Medicine, Skanes universitetssjukhus Lund Labmedicin Skane, Lund, Skane, Sweden
  1. Correspondence to Dr Petrus Linge, Department of Clinical Sciences Lund, Section of Rheumatology, Lund University, Faculty of Medicine, Lund, Skåne, Sweden; petrus.linge{at}


​Objectives A single nucleotide polymorphism in the NCF1 gene (NCF1-339, rs201802880), encoding NADPH oxidase type II subunit NCF1/p47phox, reducing production of reactive oxygen species (ROS) is strongly associated with the development of systemic lupus erythematosus (SLE). This study aimed at characterising NCF1-339 effects on neutrophil extracellular trap (NET) formation, type I interferon activity and antibody profile in patients with SLE.

​Methods Neutrophil NET-release pathways (n=31), serum interferon (n=141) and finally antibody profiles (n=305) were investigated in SLE subjects from Lund, genotyped for NCF1-339. Then, 1087 SLE subjects from the rheumatology departments of four Swedish SLE centres, genotyped for NCF1-339, were clinically characterised to validate these findings.

​Results Compared with patients with normal-ROS NCF1-339 genotypes, neutrophils from patients with SLE with low-ROS NCF1-339 genotypes displayed impaired NET formation (p<0.01) and increased dependence on mitochondrial ROS (p<0.05). Low-ROS patients also had increased frequency of high serum interferon activity (80% vs 21.4%, p<0.05) and positivity for anti-β2 glycoprotein I (p<0.01) and anticardiolipin antibodies (p<0.05) but were not associated with other antibodies. We confirmed an over-representation of having any antiphospholipid antibody, OR 1.40 (95% CI 1.01 to 1.95), anti-β2 glycoprotein I, OR 1.82 (95% CI 1.02 to 3.24) and the antiphospholipid syndrome (APS), OR 1.74 (95% CI 1.19 to 2.55) in all four cohorts (n=1087).

​Conclusions The NCF1-339 SNP mediated decreased NADPH oxidase function, is associated with high interferon activity and impaired formation of NETs in SLE, allowing dependence on mitochondrial ROS. Unexpectedly, we revealed a striking connection between the ROS deficient NCF1-339 genotypes and the presence of phospholipid antibodies and APS.

  • systemic lupus erythematosus
  • antiphospholipid syndrome
  • antiphospholipid antibodies
  • gene polymorphism
  • autoimmunity

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  • SA and PL are joint first authors.

  • Handling editor Josef S Smolen

  • Contributors All listed authors meet the criteria for authorship and have contributed to data generation and manuscript review. SA performed the experimental procedures. CPL, SA, RH and AB contributed to study design, data analysis, manuscript drafting and revision. Final version was approved by all authors.

  • Funding AB and RH are supported by grants from FOREUM and ES, CS, AB and RH by the King Gustav V’ s 80th Birthday Foundation and the Swedish Rheumatism Association. ES, AB and RH are supported by the Swedish Research Council. AB is supported by Anna-Greta Crafoord Foundation and Greta and Johan Kock’ s Foundation, Lund University Hospital and the Medical Faculty of Lund University. RH is supported by the KA Wallenberg foundation and the Swedish Science Strategic foundation. ES is supported by Swedish Heart-Lung foundation, Swedish Society of Medicine: the Ingegerd Johansson Donation, SLS-713911 and ALF funding from Stockholm County council. CS is supported by the King Gustaf V and Queen Victoria’s Freemasons Foundation, and the County Council of Östergötland.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval The study protocol for the genetic analysis was approved by the regional ethics boards in Lund, Linköping, Uppsala and Stockholm and functional analyses by the ethical review board in Lund.

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

  • Data availability statement Data are available on reasonable request. Data may be obtained from a third party and are not publicly available. All data relevant to the study are included in the article or uploaded as online supplementary information.