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

• Published in: Annals of the rheumatic diseases Vol. 79; no. 2; pp. 254 - 261
• Main Authors: Linge, Petrus, Arve, Sabine, Olsson, Lina M, Leonard, Dag, Sjöwall, Christopher, Frodlund, Martina, Gunnarsson, Iva, Svenungsson, Elisabet, Tydén, Helena, Jönsen, Andreas, Kahn, Robin, Johansson, Åsa, Rönnblom, Lars, Holmdahl, Rikard, Bengtsson, Anders
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd and European League Against Rheumatism 01.02.2020; Elsevier Limited
• Subjects: Adult; Antibodies, Anticardiolipin - blood; Antibodies, Antiphospholipid - blood; Antiphospholipid antibodies; Antiphospholipid syndrome; Antiphospholipid Syndrome - genetics; Antiphospholipid Syndrome - immunology; Arthritis; Autoimmune diseases; autoimmunity; Cardiolipin; Clinical Medicine; Deoxyribonucleic acid; Disease; DNA; Extracellular Traps - genetics; Female; Gene polymorphism; Genes; Genotype; Genotype & phenotype; Glycoprotein I; Humans; Immunoglobulins; Interferon; Interferon Type I - blood; Klinisk medicin; Leukocytes (neutrophilic); Lupus; Lupus Erythematosus, Systemic - blood; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Male; Medical and Health Sciences; Medical laboratories; Medicin och hälsovetenskap; Mitochondria; NAD(P)H oxidase; NADPH Oxidase 2 - genetics; NADPH Oxidases - genetics; Neutrophils; Pathogenesis; Patients; Phospholipids; Polymorphism, Single Nucleotide; Reactive Oxygen Species; Rheumatology; Single-nucleotide polymorphism; Studies; Sweden; Systemic lupus erythematosus; Sweden; antiphospholipid syndrome; gene polymorphism; systemic lupus erythematosus; autoimmunity; antiphospholipid antibodies
• ISSN: 0003-4967; 1468-2060; 1468-2060
• DOI: 10.1136/annrheumdis-2019-215820

​ObjectivesA 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.​MethodsNeutrophil 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.​ResultsCompared 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).​ConclusionsThe 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.