NCF1-339 polymorphism is associated with altered formation of neutrophil extracellular traps, high serum interferon activity and antiphospholipid syndrome in systemic lupus erythematosus

Petrus Linge, Sabine Arve, Lina M. Olsson, Dag Leonard, Christopher Sjöwall, Martina Frodlund, Iva Gunnarsson, Elisabet Svenungsson, Helena Tydén, Andreas Jönsen, Robin Kahn, Åsa Johansson, Lars Rönnblom, Rikard Holmdahl, Anders Bengtsson

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskriftPeer review

12 Citeringar (SciVal)

Sammanfattning

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.

Originalspråkengelska
Sidor (från-till)254-261
Antal sidor8
TidskriftAnnals of the Rheumatic Diseases
Volym79
Utgåva2
Tidigt onlinedatum2019 nov 8
DOI
StatusPublished - 2020 feb

Ämnesklassifikation (UKÄ)

  • Reumatologi och inflammation

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