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

Olsson, Lina M. LU ; Johansson, Åsa C. LU ; Gullstrand, Birgitta LU ; Jönsen, Andreas LU ; Saevarsdottir, Saedis; Rönnblom, Lars; Leonard, Dag; Wetterö, Jonas; Sjöwall, Christopher and Svenungsson, Elisabet, et al. (2017) In Annals of the Rheumatic Diseases 76(9). p.1607-1613
Abstract

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). Methods: We 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... (More)

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). Methods: We 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. Results: We 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. Conclusions: These 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.

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publication status
published
subject
keywords
autoimmunity, NADPH oxidase complex, NCF1, reactive oxygen species, SLE
in
Annals of the Rheumatic Diseases
volume
76
issue
9
pages
7 pages
publisher
British Medical Association
external identifiers
  • scopus:85024929994
  • wos:000407833100033
ISSN
0003-4967
DOI
10.1136/annrheumdis-2017-211287
language
English
LU publication?
yes
id
d4d93f2c-ccd3-4e46-a04e-3ee44793ab5c
date added to LUP
2017-08-30 09:38:00
date last changed
2017-09-18 11:43:29
@article{d4d93f2c-ccd3-4e46-a04e-3ee44793ab5c,
  abstract     = {<p>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). Methods: We 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. Results: We 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<sup>-20</sup>. 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<sup>-6</sup>. Conclusions: These 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.</p>},
  author       = {Olsson, Lina M. and Johansson, Åsa C. and Gullstrand, Birgitta and Jönsen, Andreas and Saevarsdottir, Saedis and Rönnblom, Lars and Leonard, Dag and Wetterö, Jonas and Sjöwall, Christopher and Svenungsson, Elisabet and Gunnarsson, Iva and Bengtsson, Anders A. and Holmdahl, Rikard},
  issn         = {0003-4967},
  keyword      = {autoimmunity,NADPH oxidase complex,NCF1,reactive oxygen species,SLE},
  language     = {eng},
  month        = {09},
  number       = {9},
  pages        = {1607--1613},
  publisher    = {British Medical Association},
  series       = {Annals of the Rheumatic Diseases},
  title        = {A single nucleotide polymorphism in the NCF1 gene leading to reduced oxidative burst is associated with systemic lupus erythematosus},
  url          = {http://dx.doi.org/10.1136/annrheumdis-2017-211287},
  volume       = {76},
  year         = {2017},
}