Background A single nucleotide polymorphism in NCF1 (NCF1-339, rs201802880), encoding NADPH oxidase complex 2 subunit p47phox, reducing production of reactive oxygen species (ROS) is highly associated with development of systemic lupus erythematosus (SLE). However, the effect of NCF1-339 genotype on SLE regarding pathogenetic processes or comorbidities has not been investigated.
Methods NCF1-339 genotyped SLE subjects from four Swedish university hospitals were investigated regarding neutrophil ROS production (n=31), neutrophil extracellular traps (NETs) (n=31), serum interferon (n=141), autoantibody profiles (n=305) and clinical phenotypes (n=1087).
Results Compared to SLE patients with normal-ROS NCF1-339 genotypes, neutrophils from patients with low-ROS genotypes displayed impaired NET-formation and increased dependence on mitochondrial ROS for canonical NET-release. An increased frequency of low-ROS patients had high serum interferon activity. Patients with low-ROS genotypes had an increased frequency of positivity for antiphospholipid antibodies anti-β2 glycoprotein I and anti-cardiolipin, related to the severe comorbidity antiphospholipid syndrome (APS). No other autoantibodies investigated were associated with NCF1-339 genotype. Clinical characterization revealed a strong association between NCF1-339 low-ROS genotypes and secondary APS.
Conclusions NCF1-339 genotype affects neutrophil functions of ROS production, NET formation and dependence on mitochondrial ROS. SLE subjects with low-ROS NCF1-339 genotypes are associated with high serum interferon, presence of antiphospholipid antibodies and secondary APS.
Acknowledgements This study was primarily funded by FOREUM.
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