Zhang Liang, Wax Jacqueline, Huang Renliang, Petersen Frank, Yu Xinhua
Priority Area Chronic Lung Diseases, Research Center Borstel, Member of the German Center for Lung Research (DZL), 23845 Borstel, Germany.
Hainan Women and Children's Medical Center, Haikou 571100, China.
Antioxidants (Basel). 2022 Aug 16;11(8):1589. doi: 10.3390/antiox11081589.
Genetic association studies have discovered the intergenic region as a strong susceptibility locus for multiple autoimmune disorders, with the missense mutation rs201802880 as the causal polymorphism. In this work, we aimed to perform a comprehensive meta-analysis of the association of the locus with various autoimmune diseases and to provide a systemic review on potential mechanisms underlying the effect of the causal risk variants. The frequencies of the two most extensively investigated polymorphisms within the locus, rs117026326 and rs201802880, vary remarkably across the world, with the highest frequencies in East Asian populations. Meta-analysis showed that the locus is significantly associated with primary Sjögren's syndrome, systemic lupus erythematosus, systemic sclerosis, and neuromyelitis optica spectrum disorder. The causal 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 with autoimmune disorders demonstrates that ROS is an essential regulator of immune tolerance and autoimmunity mediated disease manifestations.
基因关联研究发现基因间区域是多种自身免疫性疾病的一个强烈易感位点，错义突变rs201802880为因果多态性。在本研究中，我们旨在对该位点与各种自身免疫性疾病的关联进行全面的荟萃分析，并对因果风险变异效应的潜在机制进行系统综述。该位点内两个研究最广泛的多态性rs117026326和rs201802880的频率在世界各地差异显著，在东亚人群中频率最高。荟萃分析表明，该位点与原发性干燥综合征、系统性红斑狼疮、系统性硬化症和视神经脊髓炎谱系障碍显著相关。因果性的rs201802880多态性导致吞噬细胞NADPH氧化酶p47phox亚基中发生p.Arg90His氨基酸取代。自身免疫性疾病风险His90变异导致吞噬细胞中活性氧生成减少。临床和实验证据表明，活性低下的His90变异可能通过多种机制促成自身免疫性疾病的发展，包括损害凋亡细胞的清除、调节线粒体活性氧相关的中性粒细胞胞外陷阱形成、促进自身反应性T细胞的活化和分化以及增强I型干扰素反应。总之，该位点与自身免疫性疾病关联的鉴定表明，活性氧是免疫耐受和自身免疫介导的疾病表现的重要调节因子。
