Fine-mapping diabetes-related traits, including insulin resistance, in heterogeneous stock rats.
Fine-mapping diabetes-related traits, including insulin resistance, in heterogeneous stock rats.
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DOI：
10.1152/physiolgenomics.00040.2012
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发表时间：
2012-11
影响因子：
4.6
通讯作者：
Leah C. Solberg Woods;K. Holl;D. Oreper;Yuying Xie;Shirng-Wern Tsaih;W. Valdar
中科院分区：
文献类型：
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作者：
Leah C. Solberg Woods;K. Holl;D. Oreper;Yuying Xie;Shirng-Wern Tsaih;W. Valdar
2型糖尿病（T2D）是一种由胰岛素抵抗和β细胞衰竭引起的相对胰岛素缺乏症。我们以前使用异质性股票（HS）大鼠精细地图的葡萄糖耐量的基因座。我们在这里表明，葡萄糖不耐症的创始人株HS殖民地是由不同的机制介导的：胰岛素抵抗WKY和ACI的胰岛素分泌缺陷，我们表现出高度的变异性的措施，胰岛素抵抗和胰岛素分泌HS大鼠。因此，我们的目标是使用HS大鼠在大鼠1号染色体上的一个区域内精细定位几种糖尿病相关性状。我们测量了782只雄性HS大鼠在葡萄糖耐量试验后的血糖和血浆胰岛素水平。使用97 SSLP标记，我们基因分型68 Mb的区域在大鼠1号染色体上先前牵连的葡萄糖和胰岛素调节。我们使用连锁不平衡映射的混合模型回归推断下降，以确定一个区域，从198.85至205.9，包含一个或多个数量性状基因座（QTL）的空腹胰岛素和胰岛素抵抗的措施，定量胰岛素敏感性检查指数。该区域还包括针对空腹血糖和胰岛素_AUC（曲线下面积）鉴定的基因座。对于体重鉴定了单独的<3Mb的QTL。使用一种新的惩罚回归方法，然后我们估计每个位点下的替代单倍型配对的影响。这些研究强调了HS大鼠用于精细定位T2D潜在病因所涉及的遗传基因座的实用性。
Type 2 diabetes (T2D) is a disease of relative insulin deficiency resulting from both insulin resistance and beta cell failure. We have previously used heterogeneous stock (HS) rats to fine-map a locus for glucose tolerance. We show here that glucose intolerance in the founder strains of the HS colony is mediated by different mechanisms: insulin resistance in WKY and an insulin secretion defect in ACI, and we demonstrate a high degree of variability for measures of insulin resistance and insulin secretion in HS rats. As such, our goal was to use HS rats to fine-map several diabetes-related traits within a region on rat chromosome 1. We measured blood glucose and plasma insulin levels after a glucose tolerance test in 782 male HS rats. Using 97 SSLP markers, we genotyped a 68 Mb region on rat chromosome 1 previously implicated in glucose and insulin regulation. We used linkage disequilibrium mapping by mixed model regression with inferred descent to identify a region from 198.85 to 205.9 that contains one or more quantitative trait loci (QTL) for fasting insulin and a measure of insulin resistance, the quantitative insulin sensitivity check index. This region also encompasses loci identified for fasting glucose and Insulin_AUC (area under the curve). A separate <3 Mb QTL was identified for body weight. Using a novel penalized regression method we then estimated effects of alternative haplotype pairings under each locus. These studies highlight the utility of HS rats for fine-mapping genetic loci involved in the underlying causes of T2D.