| Summary: | 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.
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