Quantitative trait mapping in Diversity Outbred mice identifies novel genomic regions associated with the hepatic glutathione redox system.
Quantitative trait mapping in Diversity Outbred mice identifies novel genomic regions associated with the hepatic glutathione redox system.
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DOI：
10.1016/j.redox.2021.102093
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发表时间：
2021-10
期刊：
影响因子：
11.4
通讯作者：
Pazdro R
中科院分区：
文献类型：
--
作者：
Gould RL;Craig SW;McClatchy S;Churchill GA;Pazdro R
三肽谷胱甘肽（GSH）有助于抗氧化保护和异生物质代谢，其还原和氧化形式（GSH/GSSG）的比例指示细胞氧化还原环境并维持细胞信号传导的关键方面。长期以来，GSH水平和GSH/GSSG的破坏与各种慢性疾病有关，许多研究已经检查了负责GSH合成和代谢的基因中的变异等位基因是否与疾病风险增加有关。然而，过去的研究仅限于已建立的，典型的GSH基因，虽然新的证据表明，新的位点和基因影响特定组织中的GSH氧化还原系统。本研究标志着迄今为止最全面的努力，直接确定与GSH氧化还原系统相关的遗传位点。我们采用了多样性远交（DO）小鼠种群，人类遗传学模型，并测量了GSH和肝脏中的必需氧化还原辅因子NADPH，肝脏是体内GSH水平最高的器官。在正常生理条件下，我们观察到肝脏GSH和NADPH水平及其氧化还原平衡的实质性变化，并发现了一个新的，重要的数量性状位点（QTL）的小鼠16号染色体上的GSH/GSSG的生物信息学分析显示，Socs 1是最有可能的候选基因。我们还发现了与肝脏NADP+水平和NADP+/NADPH相关的新QTL，以及每个性状背后的独特候选基因。总的来说，这些发现改变了我们对GSH氧化还原系统的理解，揭示了控制它的遗传位点，并提出了新的候选基因，以在未来的机制努力中进行研究。小鼠16号染色体上的一个新位点与肝GSH/GSSG相关。生物信息学分析表明，Socs 1是肝GSH/GSSG的基础基因。离散QTL与肝脏NADP +水平和NADP+/NADPH相关。在远交系小鼠中，GSH、GSSG和GSH/GSSG的肝脏水平从5倍变化到16倍。
The tripeptide glutathione (GSH) is instrumental to antioxidant protection and xenobiotic metabolism, and the ratio of its reduced and oxidized forms (GSH/GSSG) indicates the cellular redox environment and maintains key aspects of cellular signaling. Disruptions in GSH levels and GSH/GSSG have long been tied to various chronic diseases, and many studies have examined whether variant alleles in genes responsible for GSH synthesis and metabolism are associated with increased disease risk. However, past studies have been limited to established, canonical GSH genes, though emerging evidence suggests that novel loci and genes influence the GSH redox system in specific tissues. The present study marks the most comprehensive effort to date to directly identify genetic loci associated with the GSH redox system. We employed the Diversity Outbred (DO) mouse population, a model of human genetics, and measured GSH and the essential redox cofactor NADPH in liver, the organ with the highest levels of GSH in the body. Under normal physiological conditions, we observed substantial variation in hepatic GSH and NADPH levels and their redox balances, and discovered a novel, significant quantitative trait locus (QTL) on murine chromosome 16 underlying GSH/GSSG; bioinformatics analyses revealed Socs1 to be the most likely candidate gene. We also discovered novel QTL associated with hepatic NADP+ levels and NADP+/NADPH, as well as unique candidate genes behind each trait. Overall, these findings transform our understanding of the GSH redox system, revealing genetic loci that govern it and proposing new candidate genes to investigate in future mechanistic endeavors. A novel locus on murine chromosome 16 was associated with hepatic GSH/GSSG. Bioinformatics analyses suggested Socs1 as the gene underlying hepatic GSH/GSSG. Discrete QTL were associated with hepatic NADP + levels and NADP+/NADPH. Hepatic levels of GSH, GSSG, and GSH/GSSG varied from 5- to 16-fold in outbred mice.
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