Genetic linkage of oxidative stress with cardiometabolic traits in an intercross derived from hyperlipidemic mouse strains
Genetic linkage of oxidative stress with cardiometabolic traits in an intercross derived from hyperlipidemic mouse strains
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DOI：
10.1016/j.atherosclerosis.2019.11.034
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发表时间：
2020-01-01
期刊：
影响因子：
5.3
通讯作者：
Shi, Weibin
中科院分区：
文献类型：
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作者：
Fuller, Daniela T.;Grainger, Andrew T.;Shi, Weibin
背景和目标：在观察性研究中，氧化应激与心脏代谢特征相关，但潜在的因果关系仍不清楚。载脂蛋白E缺陷（Apoe（-/-））小鼠在西方饮食中出现显著的高脂血症和高血糖症。在这里，我们进行了连锁分析，以调查心脏代谢性状和oxidative stress.Methods之间的遗传联系：266雌性F2小鼠C57 BL/6（B6）和BALB/c（BALB）Apoe（-/-）小鼠之间的互交产生的，并喂养12周的西方饮食。检测血浆高密度脂蛋白（HDL）、低密度脂蛋白（LDL）、甘油三酯（TG）、血糖（GL）、丙二醛（MDA）水平及主动脉根部和左颈动脉粥样硬化程度。结果：1号染色体（Chr）78.3cM处有一个显著性位点，该位点位于第1号染色体（Chr）78.3cM处（LOD值：3.85），命名为Mda 1，以及在Chr 1上60.3cM附近的两个提示位点（LOD得分：2.32，由于在单独的杂交中复制而命名为Mda 2）和Chr 4上的19.6cM（LOD得分：2.34）被鉴定为MDA水平。MDA 1与LDL、甘油三酯、葡萄糖和体重的位点完全一致，并与主动脉根部动脉粥样硬化的位点重叠。血浆LDL、甘油三酯和葡萄糖分别解释了F2小鼠MDA水平变化的25.5%、19.2%和24.2%。校正甘油三酯或LDL后，Chr 1和Chr 4上的MDA QTL消失。经葡萄糖校正后，第1染色体上的QTL消失，第4染色体上的QTL保留，第12和第13染色体上的QTL增加。在Chr 12的QTL，命名为Mda 3，有一个显着的LOD得分为8.034和峰值62.22 cM。结论：我们证明了心脏代谢特征在氧化应激和确定高脂血症和高血糖症的氧化应激的主要驱动因素的因果关系。
Background and aims: Oxidative stress is associated with cardiometabolic traits in observational studies, yet the underlying causal relationship remains unclear. Apolipoprotein E-deficient (Apoe(-/-)) mice develop significant hyperlipidemia and hyperglycemia on a Western diet. Here we conducted linkage analysis to investigate genetic connections between cardiometabolic traits and oxidative stress.Methods: 266 female F2 mice were generated from an intercross between C57BL/6 (B6) and BALB/c (BALB) Apoe(-/-) mice and fed 12 weeks of Western diet. Plasma levels of HDL, LDL cholesterol, triglycerides, glucose and malondialdehyde (MDA) and atherosclerosis in aortic root and left carotid artery were measured. 127 microsatellite markers across the genome were genotyped.Results: One significant locus at 78.3 cM on chromosome (Chr) 1 (LOD score: 3.85), named Mda1, and two suggestive loci near 60.3 cM on Chr1 (LOD score: 2.32, named Mda2 due to replication in a separate cross) and 19.6 cM on Chr4 (LOD score: 2.34) were identified for MDA levels. Mda1 coincided precisely with loci for LDL, triglyceride, glucose, and body weight and overlapped with a locus for atherosclerosis in the aortic root. Plasma LDL, triglyceride, and glucose explained 25.5, 19.2, and 24.2% of the variation in MDA levels of F2 mice, respectively. After correction for triglyceride or LDL, QTLs for MDA on Chr1 and Chr4 disappeared. QTLs on Chr1 disappeared, remained on Chr4, and additional QTLs on Chr12 and Chr13 were detected after correction for glucose. The QTL on Chr12, named Mda3, had a significant LOD score of 8.034 and peaked 62.22 at cM.Conclusions: We demonstrated a causative role for cardiometabolic traits in oxidative stress and identified hyperlipidemia and hyperglycemia as a major driver of oxidative stress.