Quantitative trait loci for obesity- and diabetes-related traits and their dietary responses to high-fat feeding in LGXSM recombinant inbred mouse strains
Quantitative trait loci for obesity- and diabetes-related traits and their dietary responses to high-fat feeding in LGXSM recombinant inbred mouse strains
复制标题
DOI：
10.2337/diabetes.53.12.3328
复制
发表时间：
2004-12-01
期刊：
影响因子：
7.7
通讯作者：
Semenkovich, CF
中科院分区：
文献类型：
--
作者：
Cheverud, JM;Ehrich, TH;Semenkovich, CF
对于理解导致肥胖症和2型糖尿病增加的长期趋势，对高脂肪饮食反应的基因变异很重要。在包括LGXSM重组近交系(RI)在内的小鼠模型系统中，可以有效地检测肥胖和糖尿病相关性状的数量性状基因座(QTL)及其对高脂饮食的反应。从16个RI品系中测量了一系列与肥胖和糖尿病相关的特征，每个品系每性别8只动物，分别饲喂高脂或低脂饮食。使用嵌套式方差分析，测量了分布在小鼠基因组中的506个微卫星标记的标记关联性。在对多重比较进行校正后，通过限制误检率来确定对性状本身和/或性状饮食反应有显著影响的位置。标记基因间的非共线关联在QTL位置上很常见，因此显着结果仅限于在多个QTL模型中仍显着的座位。我们在39个地点发现了91个QTL。这些位置中的许多(n=31)也表现出对饮食反应的遗传效应，通常是因为这些基因座对高脂肪饮食产生了明显更大的影响。脂肪储备重量、瘦素水平和尸检时的体重往往映射到相同的位置，并负责大多数饮食反应QTL。基础血糖水平和对葡萄糖挑战的反应在不同于影响肥胖的位置被映射在一起。这些QTL位置形成了一个小组，用于进一步研究和精细定位影响肥胖和糖尿病相关特征及其对高脂肪喂养的反应的基因座。
Genetic variation in response to high-fat diets is important in understanding the recent secular trends that have led to increases in obesity and type 2 diabetes. The examination of quantitative trait loci (QTLs) for both obesity- and diabetes-related traits and their responses to a high-fat diet can be effectively addressed in mouse model systems, including LGXSM recombinant inbred (RI) mouse strains. A wide range of obesity- and diabetes-related traits were measured in animals from 16 RI strains with 8 animals of each sex fed a high- or low-fat diet from each strain. Marker associations were measured at 506 microsatellite markers spread throughout the mouse genome using a nested ANOVA. Locations with significant effects on the traits themselves and/or trait dietary responses were identified after correction for multiple comparisons by limiting the false detection rate. Nonsyntenic associations of marker genotypes were common at QTL locations so that the significant results were limited to loci still significant in multiple QTL models. We discovered 91 QTLs at 39 locations. Many of these locations (n = 31) also showed genetic effects on dietary response, typically because the loci produced significantly larger effects on the high-fat diet. Fat depot weights, leptin levels, and body weight at necropsy tended to map to the same locations and were responsible for a majority of the dietary response QTLs. Basal glucose levels and the response to glucose challenge mapped together in locations distinct from those affecting obesity. These QTL locations form a panel for further research and fine mapping of loci affecting obesity- and diabetes-related traits and their responses to high-fat feeding.