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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

Linge, Petrus LU ; Arve, Sabine LU ; Olsson, Lina M. ; Leonard, Dag ; Sjöwall, Christopher ; Frodlund, Martina ; Gunnarsson, Iva ; Svenungsson, Elisabet ; Tydén, Helena LU and Jönsen, Andreas LU , et al. (2019) In Annals of the Rheumatic Diseases
Abstract

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... (More)

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.

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publication status
epub
subject
keywords
antiphospholipid antibodies, antiphospholipid syndrome, autoimmunity, gene polymorphism, systemic lupus erythematosus
in
Annals of the Rheumatic Diseases
publisher
British Medical Association
external identifiers
  • scopus:85074908587
  • pmid:31704719
ISSN
0003-4967
DOI
10.1136/annrheumdis-2019-215820
project
The role of neutrophils in autoimmune rheumatic diseases
language
English
LU publication?
yes
id
72a242e0-f38f-44c3-aa89-750a8c6f78ea
date added to LUP
2019-12-03 12:02:26
date last changed
2019-12-04 07:24:43
@article{72a242e0-f38f-44c3-aa89-750a8c6f78ea,
  abstract     = {<p>Objectives: A single nucleotide polymorphism in the NCF1 gene (NCF1-339, rs201802880), encoding NADPH oxidase type II subunit NCF1/p47<sup>phox</sup>, 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&lt;0.01) and increased dependence on mitochondrial ROS (p&lt;0.05). Low-ROS patients also had increased frequency of high serum interferon activity (80% vs 21.4%, p&lt;0.05) and positivity for anti-β2 glycoprotein I (p&lt;0.01) and anticardiolipin antibodies (p&lt;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.</p>},
  author       = {Linge, Petrus and Arve, Sabine and Olsson, Lina M. and Leonard, Dag and Sjöwall, Christopher and Frodlund, Martina and Gunnarsson, Iva and Svenungsson, Elisabet and Tydén, Helena and Jönsen, Andreas and Kahn, Robin and Johansson, Åsa and Rönnblom, Lars and Holmdahl, Rikard and Bengtsson, Anders},
  issn         = {0003-4967},
  language     = {eng},
  month        = {11},
  publisher    = {British Medical Association},
  series       = {Annals of the Rheumatic Diseases},
  title        = {NCF1-339 polymorphism is associated with altered formation of neutrophil extracellular traps, high serum interferon activity and antiphospholipid syndrome in systemic lupus erythematosus},
  url          = {http://dx.doi.org/10.1136/annrheumdis-2019-215820},
  doi          = {10.1136/annrheumdis-2019-215820},
  year         = {2019},
}