Genetic analysis of the stress-responsive adrenocortical axis.
Genetic analysis of the stress-responsive adrenocortical axis.
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DOI：
10.1152/physiolgenomics.00052.2006
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发表时间：
2006-11
影响因子：
4.6
通讯作者：
L. C. Solberg;A. Baum;N. Ahmadiyeh;K. Shimomura;Renhua Li;F. Turek;J. Takahashi;G. Churchill;E. Redei
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文献类型：
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作者：
L. C. Solberg;A. Baum;N. Ahmadiyeh;K. Shimomura;Renhua Li;F. Turek;J. Takahashi;G. Churchill;E. Redei
导致应激反应下丘脑-垂体-肾上腺轴(HPA)功能个体差异的潜在遗传成分尚不清楚。为了确定调节肾上腺皮质功能的三个方面的遗传位点，我们对Wistar京都(WKY)×Fischer 344(F344)杂交F2世代进行了数量性状基因座(QTL)分析，这两个近交系大鼠在几个HPA轴测量上存在差异。已知肾上腺皮质功能的三个组成部分由不同的机制调节，这些机制通过下丘脑上、下丘脑、垂体和肾上腺内的影响来调节：基础血浆皮质酮(CORT)水平、对10分钟束缚应激的血浆皮质酮反应和肾上腺重量。基因组扫描确定了基本CORT表型的复杂遗传结构，包括性别和母系影响。两两交互作用也被确定为这一特征。我们确定了三个显著的和两个暗示的与应激相关的QTL，以及这一性状的两对相互作用的基因座。发现了四个对肾上腺重量有极显著意义的基因座和两个有提示意义的基因座，没有发现相互作用的基因座。与基础皮质醇相比，压力皮质醇或肾上腺重量没有性别或血统相关的QTL被发现，尽管这些表型存在很大的性别差异。我们在一个明显的候选基因中发现了三个核苷酸变化，该基因定位于应激皮质醇最显著的QTL，皮质醇结合球蛋白(CBG)，其中一个已知改变CBG结合。这一分析证实，HPA轴调控的三个独立性状受多个但主要不重叠的QTL控制。
The underlying genetic components contributing to individual variability in functions of the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis are poorly understood. To determine genetic loci mediating three aspects of the adrenocortical function, we conducted a quantitative trait locus (QTL) analysis in the segregating F2 generation of a Wistar Kyoto (WKY) x Fischer 344 (F344) cross, two inbred rat strains that differ in several HPA axis measures. The following three components of adrenocortical function are known to be regulated by different mechanisms that are mediated via suprahypothalamic, hypothalamic, pituitary, and intra-adrenal influences: basal plasma corticosterone (Cort) levels, plasma Cort response to a 10-min restraint stress, and adrenal weight. Genome scans identified a complex genetic architecture for the basal Cort phenotype, including sex and maternal lineage effects. Pairwise interactions were also identified for this trait. We identified three significant and two suggestive QTLs for stress Cort, along with two pairs of interacting loci for this trait. Four highly significant and two suggestive loci were identified for adrenal weight, with no interacting loci. In contrast to basal Cort, no sex- or lineage-dependent QTL were identified for stress Cort or adrenal weight, despite the large sex differences in these phenotypes. We identified three nucleotide alterations in an obvious candidate gene mapped to the most significant QTL for stress Cort, Cort-binding globulin (CBG), one of which is known to alter CBG binding. This analysis confirms that three separate traits regulated by the HPA axis are controlled by multiple, but mainly nonoverlapping, QTLs.