Meta-Analysis and Systematic Review of the Association between a Hypoactive <i>NCF1</i> Variant and Various Autoimmune Diseases
Genetic association studies have discovered the <i>GTF2I-NCF1</i> intergenic region as a strong susceptibility locus for multiple autoimmune disorders, with the missense mutation <i>NCF1</i> rs201802880 as the causal polymorphism. In this work, we aimed to perform a comprehen...
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| Format: | Article |
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MDPI AG
2022-08-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/11/8/1589 |
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| author | Liang Zhang Jacqueline Wax Renliang Huang Frank Petersen Xinhua Yu |
| author_facet | Liang Zhang Jacqueline Wax Renliang Huang Frank Petersen Xinhua Yu |
| author_sort | Liang Zhang |
| collection | DOAJ |
| description | Genetic association studies have discovered the <i>GTF2I-NCF1</i> intergenic region as a strong susceptibility locus for multiple autoimmune disorders, with the missense mutation <i>NCF1</i> rs201802880 as the causal polymorphism. In this work, we aimed to perform a comprehensive meta-analysis of the association of the <i>GTF2I-NCF1</i> locus with various autoimmune diseases and to provide a systemic review on potential mechanisms underlying the effect of the causal <i>NCF1</i> risk variants. The frequencies of the two most extensively investigated polymorphisms within the locus, <i>GTF2I</i> rs117026326 and <i>NCF1</i> rs201802880, vary remarkably across the world, with the highest frequencies in East Asian populations. Meta-analysis showed that the <i>GTF2I-NCF1</i> locus is significantly associated with primary Sjögren’s syndrome, systemic lupus erythematosus, systemic sclerosis, and neuromyelitis optica spectrum disorder. The causal <i>NCF1</i> rs201802880 polymorphism leads to an amino acid substitution of p.Arg90His in the p47phox subunit of the phagocyte NADPH oxidase. The autoimmune disease risk His90 variant results in a reduced ROS production in phagocytes. Clinical and experimental evidence shows that the hypoactive His90 variant might contribute to the development of autoimmune disorders via multiple mechanisms, including impairing the clearance of apoptotic cells, regulating the mitochondria ROS-associated formation of neutrophil extracellular traps, promoting the activation and differentiation of autoreactive T cells, and enhancing type I IFN responses. In conclusion, the identification of the association of <i>NCF1</i> with autoimmune disorders demonstrates that ROS is an essential regulator of immune tolerance and autoimmunity mediated disease manifestations. |
| first_indexed | 2024-03-09T11:58:18Z |
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| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-09T11:58:18Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-3007155dfe444f76ad0a4920dc84aad82023-11-30T23:06:36ZengMDPI AGAntioxidants2076-39212022-08-01118158910.3390/antiox11081589Meta-Analysis and Systematic Review of the Association between a Hypoactive <i>NCF1</i> Variant and Various Autoimmune DiseasesLiang Zhang0Jacqueline Wax1Renliang Huang2Frank Petersen3Xinhua Yu4Priority Area Chronic Lung Diseases, Research Center Borstel, Member of the German Center for Lung Research (DZL), 23845 Borstel, GermanyPriority Area Chronic Lung Diseases, Research Center Borstel, Member of the German Center for Lung Research (DZL), 23845 Borstel, GermanyHainan Women and Children’s Medical Center, Haikou 571100, ChinaPriority Area Chronic Lung Diseases, Research Center Borstel, Member of the German Center for Lung Research (DZL), 23845 Borstel, GermanyPriority Area Chronic Lung Diseases, Research Center Borstel, Member of the German Center for Lung Research (DZL), 23845 Borstel, GermanyGenetic association studies have discovered the <i>GTF2I-NCF1</i> intergenic region as a strong susceptibility locus for multiple autoimmune disorders, with the missense mutation <i>NCF1</i> rs201802880 as the causal polymorphism. In this work, we aimed to perform a comprehensive meta-analysis of the association of the <i>GTF2I-NCF1</i> locus with various autoimmune diseases and to provide a systemic review on potential mechanisms underlying the effect of the causal <i>NCF1</i> risk variants. The frequencies of the two most extensively investigated polymorphisms within the locus, <i>GTF2I</i> rs117026326 and <i>NCF1</i> rs201802880, vary remarkably across the world, with the highest frequencies in East Asian populations. Meta-analysis showed that the <i>GTF2I-NCF1</i> locus is significantly associated with primary Sjögren’s syndrome, systemic lupus erythematosus, systemic sclerosis, and neuromyelitis optica spectrum disorder. The causal <i>NCF1</i> rs201802880 polymorphism leads to an amino acid substitution of p.Arg90His in the p47phox subunit of the phagocyte NADPH oxidase. The autoimmune disease risk His90 variant results in a reduced ROS production in phagocytes. Clinical and experimental evidence shows that the hypoactive His90 variant might contribute to the development of autoimmune disorders via multiple mechanisms, including impairing the clearance of apoptotic cells, regulating the mitochondria ROS-associated formation of neutrophil extracellular traps, promoting the activation and differentiation of autoreactive T cells, and enhancing type I IFN responses. In conclusion, the identification of the association of <i>NCF1</i> with autoimmune disorders demonstrates that ROS is an essential regulator of immune tolerance and autoimmunity mediated disease manifestations.https://www.mdpi.com/2076-3921/11/8/1589neutrophil cytosolic factor 1reactive oxygen speciesgenetic association |
| spellingShingle | Liang Zhang Jacqueline Wax Renliang Huang Frank Petersen Xinhua Yu Meta-Analysis and Systematic Review of the Association between a Hypoactive <i>NCF1</i> Variant and Various Autoimmune Diseases Antioxidants neutrophil cytosolic factor 1 reactive oxygen species genetic association |
| title | Meta-Analysis and Systematic Review of the Association between a Hypoactive <i>NCF1</i> Variant and Various Autoimmune Diseases |
| title_full | Meta-Analysis and Systematic Review of the Association between a Hypoactive <i>NCF1</i> Variant and Various Autoimmune Diseases |
| title_fullStr | Meta-Analysis and Systematic Review of the Association between a Hypoactive <i>NCF1</i> Variant and Various Autoimmune Diseases |
| title_full_unstemmed | Meta-Analysis and Systematic Review of the Association between a Hypoactive <i>NCF1</i> Variant and Various Autoimmune Diseases |
| title_short | Meta-Analysis and Systematic Review of the Association between a Hypoactive <i>NCF1</i> Variant and Various Autoimmune Diseases |
| title_sort | meta analysis and systematic review of the association between a hypoactive i ncf1 i variant and various autoimmune diseases |
| topic | neutrophil cytosolic factor 1 reactive oxygen species genetic association |
| url | https://www.mdpi.com/2076-3921/11/8/1589 |
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