A single nucleotide polymorphism in the NCF1 gene leading to reduced oxidative burst is associated with systemic lupus erythematosus

• Published in: Annals of the rheumatic diseases Vol. 76; no. 9; pp. 1607 - 1613
• Main Authors: Olsson, Lina M, Johansson, Åsa C, Gullstrand, Birgitta, Jönsen, Andreas, Saevarsdottir, Saedis, Rönnblom, Lars, Leonard, Dag, Wetterö, Jonas, Sjöwall, Christopher, Svenungsson, Elisabet, Gunnarsson, Iva, Bengtsson, Anders A, Holmdahl, Rikard
• Format: Journal Article
• Language: English
• Published: England Elsevier Limited 01.09.2017
• Subjects: Adult; Alleles; Animal models; Autoimmune diseases; autoimmunity; Case-Control Studies; Clinical Medicine; Disease; Female; Gene Expression; Gene Expression Regulation; Gene polymorphism; Genetic Predisposition to Disease; Genomes; Genotype & phenotype; Genotyping; Humans; Inflammatory diseases; Interferon; Klinisk medicin; Leukocytes (neutrophilic); Lupus; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - metabolism; Lymphocytes; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Mutation; NADPH oxidase complex; NADPH Oxidases - genetics; NCF1; Neutrophils; Neutrophils - immunology; Polymerase chain reaction; Polymorphism, Single Nucleotide; Reactive oxygen species; Reactive Oxygen Species - metabolism; Respiratory Burst - genetics; Rheumatoid arthritis; Rheumatology; Single-nucleotide polymorphism; SLE; Studies; Sweden; Systemic lupus erythematosus; White People - genetics; Sweden; NADPH oxidase complex; NCF1; autoimmunity; SLE; reactive oxygen species
• ISSN: 0003-4967; 1468-2060; 1468-2060
• DOI: 10.1136/annrheumdis-2017-211287

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).MethodsWe 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.ResultsWe 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.ConclusionsThese 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.