Chen Mei-Hua, Chagari Bilhan, Abramson Ashley M, Shi Lisa J, He Jiang, Shi Weibin
Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, VA 22903, USA.
Biochemistry & Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA.
Int J Mol Sci. 2025 Apr 29;26(9):4241. doi: 10.3390/ijms26094241.
Overweight and obese individuals show lower mortality rates or better prognoses than those of normal weight in a variety of diseases, a phenomenon called the "obesity paradox". An inverse association of adiposity with atherosclerosis has been observed in both humans and mice. To dissect phenotypic and genetic connections between the traits, 154 female and 145 male F2 mice were generated from an intercross between BALB/cJ and LP/J apolipoprotein E-deficient mice and fed a Western diet for 12 weeks. Atherosclerotic lesion size in the aortic root, body weight, plasma lipids, and glucose were measured, and genotyping was performed on miniMUGA SNP arrays. Quantitative trait locus (QTL) analyses on all F2 mice with sex as a covariate revealed four significant QTLs on chromosomes (Chr) 3, 6, 13, and 15 for atherosclerosis and three significant QTLs on Chr2, 7, and 15 for body weight. Chr15 QTL for atherosclerosis overlapped with one for body weight near 36 Mb. After adjusting for variation in body weight, Chr15 atherosclerosis QTL was downgraded from significant to suggestive linkage. Body weight was inversely correlated with atherosclerotic lesion sizes and accounted for more variance than a single other risk factor for atherosclerosis among F2 mice. Analysis of public data collected from two backcross cohorts revealed strong correlations between body weight and fat mass in adult mice (r ≥ 0.93; ≤ 1.6 × 10). Thus, the obesity paradox in atherosclerosis is partially attributable to shared genetic components that have an opposite effect on adiposity and atherosclerosis.
在多种疾病中，超重和肥胖个体的死亡率低于正常体重个体，或预后更好，这一现象被称为“肥胖悖论”。在人类和小鼠中均观察到肥胖与动脉粥样硬化之间存在负相关。为了剖析这些性状之间的表型和遗传联系，通过将BALB/cJ和LP/J载脂蛋白E缺陷小鼠进行杂交，产生了154只雌性和145只雄性F2小鼠，并给予西式饮食12周。测量了主动脉根部的动脉粥样硬化病变大小、体重、血脂和血糖，并在miniMUGA SNP阵列上进行基因分型。以性别作为协变量，对所有F2小鼠进行数量性状基因座（QTL）分析，结果显示，在染色体（Chr）3、6、13和15上有4个与动脉粥样硬化相关的显著QTL，在Chr2、7和15上有3个与体重相关的显著QTL。位于Chr15上的动脉粥样硬化QTL与位于36 Mb附近的体重QTL重叠。在调整体重差异后，Chr15动脉粥样硬化QTL从显著连锁降为提示性连锁。在F2小鼠中，体重与动脉粥样硬化病变大小呈负相关，且比动脉粥样硬化的单一其他危险因素解释了更多的变异。对从两个回交群体收集的公共数据进行分析发现，成年小鼠的体重与脂肪量之间存在强相关性（r≥0.93；≤1.6×10）。因此，动脉粥样硬化中的肥胖悖论部分归因于对肥胖和动脉粥样硬化具有相反作用的共同遗传成分。
