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Meta-Analysis and Systematic Review of the Association between a Hypoactive NCF1 Variant and Various Autoimmune Diseases.

ABSTRACT: Genetic association studies have discovered the GTF2I-NCF1 intergenic region as a strong susceptibility locus for multiple autoimmune disorders, with the missense mutation NCF1 rs201802880 as the causal polymorphism. In this work, we aimed to perform a comprehensive meta-analysis of the association of the GTF2I-NCF1 locus with various autoimmune diseases and to provide a systemic review on potential mechanisms underlying the effect of the causal NCF1 risk variants. The frequencies of the two most extensively investigated polymorphisms within the locus, GTF2I rs117026326 and NCF1 rs201802880, vary remarkably across the world, with the highest frequencies in East Asian populations. Meta-analysis showed that the GTF2I-NCF1 locus is significantly associated with primary Sjögren's syndrome, systemic lupus erythematosus, systemic sclerosis, and neuromyelitis optica spectrum disorder. The causal NCF1 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 NCF1 with autoimmune disorders demonstrates that ROS is an essential regulator of immune tolerance and autoimmunity mediated disease manifestations.

SUBMITTER: Zhang L

PROVIDER: S-EPMC9404811 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Meta-Analysis and Systematic Review of the Association between a Hypoactive NCF1 Variant and Various Autoimmune Diseases.

Zhang Liang L Wax Jacqueline J Huang Renliang R Petersen Frank F Yu Xinhua X

Antioxidants (Basel, Switzerland) 20220816 8

Genetic association studies have discovered the GTF2I-NCF1 intergenic region as a strong susceptibility locus for multiple autoimmune disorders, with the missense mutation NCF1 rs201802880 as the causal polymorphism. In this work, we aimed to perform a comprehensive meta-analysis of the association of the GTF2I-NCF1 locus with various autoimmune diseases and to provide a systemic review on potential mechanisms underlying the effect of the causal NCF1 risk variants. Th ...[more]

PMID: 36009308

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Project description:Parkinson's disease (PD) is a neurodegenerative disorder that frequently occurs in the older population. Previous epidemiological studies have suggested an association between PD and autoimmune diseases (AIDs). However, some studies have shown conflicting results. This study aimed to summarize existing epidemiological studies on the association between PD with AIDs and to conduct a meta-analysis of combinable results. Four electronic databases (PubMed, Embase, Web of Science Core Collection, and MEDLINE) were searched from each database's inception date until December 12, 2022. All studies that explored the relationship between PD and AIDs were included for quantitative analysis and qualitative review. The pooled relative risk with 95% confidence intervals (CIs) was calculated using a random or fixed effects model. A total of 46 observational studies involving 873,643 patients and 13,402,821 controls were included; ultimately, 38 studies were included in the meta-analysis. The risk of PD combined with AIDs was significantly higher (odds ratio [OR]=1.55, 95% CI: 1.33-1.81), and subgroup analysis found no significant differences in risk by study type, gender, age, and race. Regarding the AID types, the results showed an increased risk of PD combined with bullous pemphigoid (OR=2.67, 95% CI: 2.15-3.31), inflammatory bowel disease (OR=1.30, 95% CI: 1.18-1.45), Crohn's disease (OR=1.30, 95% CI: 1.20-1.42), ulcerative colitis (OR=1.31, 95% CI: 1.14-1.50), Sjögren's syndrome (OR=1.61, 95% CI: 1.24-2.09), and Graves' disease (OR=1.45, 95% CI: 1.24-1.70) than controls. However, there appeared to be no significant association between PD and systemic lupus erythematosus (OR=0.82, 95% CI: 0.66-1.03), multiple sclerosis (OR=2.02, 95% CI: 0.87-4.70), rheumatoid arthritis (OR=0.79, 95% CI: 0.61-1.03), or celiac disease (OR=1.16, 95% CI: 0.79-1.69). This study supports the existence of a strong link between AIDs and PD. When PD and AIDs are identified, clinicians need to be aware of the possibility of coexistence. However, there are some limitations of this study, such as the apparent heterogeneity of some of the results and the fact that most of the included study types were retrospective. Therefore, future larger prospective cohort studies are needed to further explore the interaction between PD and AIDs.Systematic review registrationINPLASY, identifier INPLASY202280088.

Dataset Information

Meta-Analysis and Systematic Review of the Association between a Hypoactive NCF1 Variant and Various Autoimmune Diseases.

Publications

Meta-Analysis and Systematic Review of the Association between a Hypoactive <i>NCF1</i> Variant and Various Autoimmune Diseases.

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