Department of Medicine, University of California, Los Angeles, California 90095-1679, USA.
Physiol Genomics. 2012 Jan 18;44(1):1-13. doi: 10.1152/physiolgenomics.00003.2011. Epub 2011 Oct 18.
Inbred strains of mice are strikingly different in susceptibility to obesity-driven diabetes. For instance, deficiency in leptin receptor (db/db) leads to hyperphagia and obesity in both C57BL/6 and DBA/2 mice, but only on the DBA/2 background do the mice develop beta-cell loss leading to severe diabetes, while C57BL/6 mice are relatively resistant. To further investigate the genetic factors predisposing to diabetes, we have studied leptin receptor-deficient offspring of an F2 cross between C57BL/6J (db/+) males and DBA/2J females. The results show that the genetics of diabetes susceptibility are enormously complex and a number of quantitative trait loci (QTL) contributing to diabetes-related traits were identified, notably on chromosomes 4, 6, 7, 9, 10, 11, 12, and 19. The Chr. 4 locus is likely due to a disruption of the Zfp69 gene in C57BL/6J mice. To identify candidate genes and to model coexpression networks, we performed global expression array analysis in livers of the F2 mice. Expression QTL (eQTL) were identified and used to prioritize candidate genes at clinical trait QTL. In several cases, clusters of eQTLs colocalized with clinical trait QTLs, suggesting a common genetic basis. We constructed coexpression networks for both 5 and 12 wk old mice and identified several modules significantly associated with clinical traits. One module in 12 wk old mice was associated with several measures of hepatic fat content as well as with other lipid- and diabetes-related traits. These results add to the understanding of the complex genetic interactions contributing to obesity-induced diabetes.
近交系小鼠在肥胖型糖尿病易感性方面差异显著。例如，瘦素受体（db/db）缺失会导致 C57BL/6 和 DBA/2 两种小鼠出现过度摄食和肥胖，但只有在 DBA/2 背景下，小鼠才会发生β细胞丢失，导致严重的糖尿病，而 C57BL/6 小鼠则相对具有抗性。为了进一步研究导致糖尿病的遗传因素，我们研究了 C57BL/6J（db/+）雄性和 DBA/2J 雌性之间 F2 杂交后代的瘦素受体缺失小鼠。结果表明，糖尿病易感性的遗传因素极其复杂，许多与糖尿病相关特征有关的数量性状基因座（QTL）已被确定，特别是在染色体 4、6、7、9、10、11、12 和 19 上。Chr. 4 位点可能是由于 C57BL/6J 小鼠中 Zfp69 基因的破坏。为了鉴定候选基因并构建共表达网络，我们对 F2 小鼠的肝脏进行了全基因组表达谱分析。鉴定了表达 QTL（eQTL），并将其用于优先考虑临床特征 QTL 上的候选基因。在几种情况下，eQTL 簇与临床特征 QTL 共定位，提示存在共同的遗传基础。我们构建了 5 周龄和 12 周龄小鼠的共表达网络，并鉴定了与临床特征显著相关的几个模块。12 周龄小鼠的一个模块与肝脂肪含量的几个测量值以及其他与脂质和糖尿病相关的特征相关。这些结果增加了对肥胖诱导型糖尿病复杂遗传相互作用的理解。
