Association of NOX2 subunits genetic variants with autoimmune diseases

Zhong, Jianghong; Olsson, Lina; Urbonaviciute, Vilma; Yang, Min; Bäckdahl, Liselotte; Holmdahl, Rikard

doi:10.1016/j.freeradbiomed.2018.03.005

Cited by 56 publications

(63 citation statements)

References 114 publications

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“…Studies of functional effects of the polymorphism in question have been demonstrated both in this report as well as in earlier work by our group 3 4. NCF1 (p47 phox ) plays an vital role in the assembly and stability of the extensively studied nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 complex5 and the nucleotide shift from C to T at NCF1-339 alters the amino acid from arginine to histidine at a PX domain of the NCF1 protein 6. This domain has been shown to be of crucial importance in the membrane binding and mutations in the NCF1-339 position reduces reactive oxygen species (ROS) response,4 7 providing a mechanistic explanation for the observed ROS-decreasing effect of the polymorphism.…”

supporting

confidence: 55%

Response to: ‘NCF1-339 polymorphism and systemic lupus erythematosus’ by Joob and Wiwanitkit

Linge

Bengtsson

2019

Ann Rheum Dis

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supporting

confidence: 55%

Response to: ‘NCF1-339 polymorphism and systemic lupus erythematosus’ by Joob and Wiwanitkit

Linge

Bengtsson

2019

Ann Rheum Dis

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“…Any genotype with less than two NCF1-339 C-alleles is predicted to have impaired ROS-production 10 13. Low-ROS genotypes are associated with lower age at SLE onset, a type I IFN signature in patients with rheumatoid arthritis and strongly predisposes to SLE,11 14 consistent with the concept that deficient NOX2 function promotes autoimmunity and SLE 14…”

Section: Introductionmentioning

confidence: 64%

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

et al. 2019

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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.

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“…Myriad enzymes contribute to ROS generation, of which NOX family is dedicated generators of intracellular superoxide and hydrogen that strongly involve in redox signaling under healthy and pathological conditions [20][21][22]. NOX family consists of five isoforms including NOX1, NOX2, NOX3, NOX4 and NOX5, which accelerate ROS production in the vasculature [23][24][25][26][27]. In this scenario, we shift the concept to NOX4 as a critical driver for various renal disorders since NOX4 is most plentiful in kidney [28][29][30].…”

Section: Nox Signalingmentioning

confidence: 99%

Redox signaling in aging kidney and opportunity for therapeutic intervention through natural products

Chen

et al. 2019

Free Radical Biology and Medicine

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Kidney diseases are serious public problems with high morbidity and mortality in the general population and heavily retard renal function with aging regardless of the cause. Although myriad strategies have been assigned to prevent or harness disease progression, unfortunately, thus far, there is a paucity of effective therapies partly due to an insufficient knowledge of underlying pathological mechanisms, indicating deeper studies are urgently needed. Additionally, natural products are increasingly recognized as an alternative source for disease intervention owing to the potent safety and efficacy, which might be exploited for novel drug discovery. In this review, we primarily expatiate the new advances on mediators that might be amenable to targeting aging kidney and kidney diseases, including nicotinamide adenine dinucleotide phosphate oxidase (NOX), transforming growth factor-β (TGF-β), renin-angiotensin system (RAS), nuclear factor-erythroid 2 related factor 2 (Nrf2), peroxisome proliferator-activated γ receptor (PPARγ), advanced glycation endproducts (AGEs) as well as microRNAs and vitagenes. Of note, we conclude by highlighting some natural products which have the potential to facilitate the development of novel treatment for patients with myriad renal diseases.

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Association of NOX2 subunits genetic variants with autoimmune diseases

Cited by 56 publications

References 114 publications

Response to: ‘NCF1-339 polymorphism and systemic lupus erythematosus’ by Joob and Wiwanitkit

Response to: ‘NCF1-339 polymorphism and systemic lupus erythematosus’ by Joob and Wiwanitkit

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

Redox signaling in aging kidney and opportunity for therapeutic intervention through natural products

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