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A single nucleotide polymorphism in the NCF1 gene leading to reduced oxidative burst is associated with systemic lupus erythematosus
  1. Lina M Olsson1,
  2. Åsa C Johansson2,
  3. Birgitta Gullstrand3,
  4. Andreas Jönsen3,
  5. Saedis Saevarsdottir4,
  6. Lars Rönnblom5,
  7. Dag Leonard5,
  8. Jonas Wetterö6,
  9. Christopher Sjöwall6,
  10. Elisabet Svenungsson4,
  11. Iva Gunnarsson4,
  12. Anders A Bengtsson3,
  13. Rikard Holmdahl1
  1. 1 Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
  2. 2 Division for Hematology and Transfusion Medicine and Division for Clinical Immunology and Transfusion Medicine, Department of Laboratory Medicine, Faculty of Medicine, Lund University, Lund, Sweden
  3. 3 Rheumatology, Department of Clinical Sciences Lund, Faculty of Medicine, Lund University, Lund, Sweden
  4. 4 Department of Medicine Solna, Unit of Rheumatology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
  5. 5 Department of Medical Sciences, Science for Life Laboratories, Rheumatology Unit, Uppsala University, Uppsala, Sweden
  6. 6 Department of Clinical and Experimental Medicine, Rheumatology/Division of Neuro and Inflammation Sciences, Linköping University, Linköping, Sweden
  1. Correspondence to Professor Rikard Holmdahl, Division of Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden; rikard.holmdahl{at}


Objectives Ncf1 polymorphisms leading to low production of reactive oxygen species (ROS) are strongly associated with autoimmune diseases in animal models. The human NCF1 gene is very complex with both functional and non-functional gene copies and genotyping requires assays specific for functional NCF1 genes. We aimed at investigating association and function of the missense single nucleotide polymorphism (SNP), rs201802880 (here denoted NCF1-339) in NCF1 with systemic lupus erythematosus (SLE).

Methods We genotyped the NCF1-339 SNP in 973 Swedish patients with SLE and 1301 controls, using nested PCR and pyrosequencing. ROS production and gene expression of type 1 interferon-regulated genes were measured in isolated cells from subjects with different NCF1-339 genotypes.

Results We found an increased frequency of the NCF1-339 T allele in patients with SLE, 11% compared with 4% in controls, OR 3.0, 95% CI 2.4 to 3.9, p=7.0×10−20. The NCF1-339 T allele reduced extracellular ROS production in neutrophils (p=0.004) and led to an increase expression of type 1 interferon-regulated genes. In addition, the NCF1-339 T allele was associated with a younger age at diagnosis of SLE; mean age 30.3 compared with 35.9, p=2.0×1−6.

Conclusions These results clearly demonstrate that a genetically controlled reduced production of ROS increases the risk of developing SLE and confirm the hypothesis that ROS regulate chronic autoimmune inflammatory diseases.

  • NCF1
  • NADPH oxidase complex
  • SLE
  • autoimmunity
  • reactive oxygen species

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  • Contributors LMO and RH designed the research. LMO performed the major part of the experimental work and statistical analyses. ÅCJ performed the Phagoburst assay analysis and BG helped with preparing the patient samples. AJ, SS, LR, DL, JW, CS, ES, IG and AAB contributed patient samples and clinical data. LMO and RH wrote the manuscript. All authors revised and approved the final manuscript.

  • Funding The work was supported by grants from the Knut and Alice Wallenberg Foundation, the Swedish Rheumatism Association, the Swedish Medical Research Council, the Swedish Research Council, the Swedish Foundation for Strategic Research and the following foundations: King Gustaf V’s 80-Year Fund, Alfred Österlund, Greta and Johan Kock, Anna-Greta Crafoord and Swedish Heart-Lung. The work was also supported by the Stockholm County Council and Skåne University Hospital (ALF) and the FOREUM Foundation. The research leading to these results received further funding from the European Union Innovative Medicine Initiative project BeTheCure.

  • Competing interests None declared.

  • Ethics approval The regional ethics review boards in Lund, Linköping, Uppsala and Stockholm.

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