Department of Pharmacology, Physiology and Toxicology, Joan C, Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA.
BMC Genomics. 2010 Dec 19;11:713. doi: 10.1186/1471-2164-11-713.
Type 2 diabetes (T2D) is the most common form of diabetes in humans and is closely associated with dyslipidemia and obesity that magnifies the mortality and morbidity related to T2D. The genetic contribution to human T2D and related metabolic disorders is evident, and mostly follows polygenic inheritance. The TALLYHO/JngJ (TH) mice are a polygenic model for T2D characterized by obesity, hyperinsulinemia, impaired glucose uptake and tolerance, hyperlipidemia, and hyperglycemia.
In order to determine the genetic factors that contribute to these T2D related characteristics in TH mice, we interbred TH mice with C57BL/6J (B6) mice. The parental, F1, and F2 mice were phenotyped at 8, 12, 16, 20, and 24 weeks of age for 4-hour fasting plasma triglyceride, cholesterol, insulin, and glucose levels and body, fat pad and carcass weights. The F2 mice were genotyped genome-wide and used for quantitative trait locus (QTL) mapping. We also applied a genetical genomic approach using a subset of the F2 mice to seek candidate genes underlying the QTLs. Major QTLs were detected on chromosomes (Chrs) 1, 11, 4, and 8 for hypertriglyceridemia, 1 and 3 for hypercholesterolemia, 4 for hyperglycemia, 11 and 1 for body weight, 1 for fat pad weight, and 11 and 14 for carcass weight. Most alleles, except for Chr 3 and 14 QTLs, increased phenotypic values when contributed by the TH strain. Fourteen pairs of interacting loci were detected, none of which overlapped the major QTLs. The QTL interval linked to hypercholesterolemia and hypertriglyceridemia on distal Chr 1 contains Apoa2 gene. Sequencing analysis revealed polymorphisms of Apoa2 in TH mice, suggesting Apoa2 as the candidate gene for the hyperlipidemia QTL. Gene expression analysis added novel information and aided in selection of candidates underlying the QTLs.
We identified several genetic loci that affect the quantitative variations of plasma lipid and glucose levels and obesity traits in a TH × B6 intercross. Polymorphisms in Apoa2 gene are suggested to be responsible for the Chr 1 QTL linked to hypercholesterolemia and hypertriglyceridemia. Further, genetical genomic analysis led to potential candidate genes for the QTLs.
2 型糖尿病（T2D）是人类中最常见的糖尿病形式，与血脂异常和肥胖密切相关，这加剧了与 T2D 相关的死亡率和发病率。人类 T2D 及相关代谢紊乱的遗传贡献是明显的，并且主要遵循多基因遗传。TALLYHO/JngJ（TH）小鼠是一种多基因 T2D 模型，其特征为肥胖、高胰岛素血症、葡萄糖摄取和耐量受损、血脂异常和高血糖。
为了确定导致 TH 小鼠出现这些 T2D 相关特征的遗传因素，我们将 TH 小鼠与 C57BL/6J（B6）小鼠进行杂交。在 8、12、16、20 和 24 周龄时，对亲代、F1 和 F2 小鼠进行 4 小时禁食血浆甘油三酯、胆固醇、胰岛素和葡萄糖水平以及体重、脂肪垫和胴体重量的表型分析。对 F2 小鼠进行全基因组基因型分析，并用于数量性状基因座（QTL）作图。我们还使用 F2 小鼠的一个亚群应用遗传基因组学方法，寻找 QTL 下的候选基因。在高甘油三酯血症方面，主要 QTL 位于第 1、11、4 和 8 号染色体上，在高胆固醇血症方面，主要 QTL 位于第 1 和 3 号染色体上，在高血糖症方面，主要 QTL 位于第 4 号染色体上，在体重方面，主要 QTL 位于第 11 和 1 号染色体上，在脂肪垫重量方面，主要 QTL 位于第 1 号染色体上，在胴体重量方面，主要 QTL 位于第 11 和 14 号染色体上。除了第 3 和 14 号染色体 QTL 外，TH 株的大多数等位基因都增加了表型值。检测到 14 对相互作用的基因座，没有一个与主要 QTL 重叠。位于远端第 1 号染色体上的与高胆固醇血症和高甘油三酯血症相关的 QTL 区间包含 Apoa2 基因。TH 小鼠的 Apoa2 基因序列分析显示存在多态性，提示 Apoa2 是该脂质 QTL 的候选基因。基因表达分析提供了新的信息，并有助于选择 QTL 下的候选基因。
我们在 TH×B6 杂交中鉴定出几个影响血浆脂质和葡萄糖水平及肥胖特征的定量变化的遗传位点。Apoa2 基因的多态性被认为是与第 1 号染色体上与高胆固醇血症和高甘油三酯血症相关的 QTL 相关的候选基因。此外，遗传基因组学分析导致了 QTL 的潜在候选基因。
