Genetic dissection of a blood pressure quantitative trait locus on rat chromosome 1 and gene expression analysis identifies SPON1 as a novel candidate hypertension gene.
Genetic dissection of a blood pressure quantitative trait locus on rat chromosome 1 and gene expression analysis identifies SPON1 as a novel candidate hypertension gene.
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DOI：
10.1161/01.res.0000261961.41889.9c
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发表时间：
2007-04-13
影响因子：
20.1
通讯作者：
Samani NJ
中科院分区：
文献类型：
--
作者：
Clemitson JR;Dixon RJ;Haines S;Bingham AJ;Patel BR;Hall L;Lo M;Sassard J;Charchar FJ;Samani NJ
对血压有主要影响的区域位于大鼠的1号染色体上。我们以前从自发性高血压大鼠(SHR)和Wistar-京都大鼠(WKY)的杂交后代(SHR)和WKY大鼠(WKY)的正反向同源品系(WKY.SHR-Sa和SHR.WKY-Sa)中分离到该区域，并发现在该区域存在两个不同的BP数量性状基因(QTL)：BP1和BP2。Sisa1是SHR.WKY-sa动物的同源亚株，携带4.3Mb的导入片段，含有BP1。在这里，我们报告了通过创建两个相互排斥的同源亚株(Sisa1a和Sisa1b)以及通过表达谱和靶向转录测序询问候选基因来进一步剖析BP1。只有一个亚株(Sisa1a)继续显示出BP差异，但导入片段减少了3MB。对位于Sisa1a区域的20个基因的外显子测序没有发现SHR和WKY之间有任何重大差异。然而，全肾样本的微阵列表达谱和随后的定量RT-PCR发现了单个基因SPON1，该基因在6周龄和24周龄时显示出WKY和SHR基因型之间的显著差异。Western印迹分析证实，SHR肾脏中SPON1基因产物的水平增加。SPON1属于一个具有抗血管生成特性的基因家族。这些发现证明了在高血压大鼠模型和人类中进一步研究这种新的位置候选基因在血压控制中的作用。
A region with a major effect on blood pressure is located on rat chromosome 1. We have previously isolated this region in reciprocal congenic strains (WKY.SHR-Sa and SHR.WKY-Sa) derived from a cross of the spontaneously hypertensive rat (SHR) with the Wistar-Kyoto rat (WKY) and shown that there are two distinct BP quantitative trait loci (QTLs), BP1 and BP2, in this region. Sisa1, a congenic sub-strain from the SHR.WKY-Sa animals carrying an introgressed segment of 4.3Mb, contains BP1. Here, we report further dissection of BP1 by the creation of two new mutually exclusive congenic sub-strains (Sisa1a and Sisa1b) and interrogation of candidate genes by expression profiling and targeted transcript sequencing. Only one of the sub-strains (Sisa1a) continued to demonstrate a BP difference but with a reduced introgressed segment of 3Mb. Exonic sequencing of the twenty genes located in the Sisa1a region did not identify any major differences between SHR and WKY. However, microarray expression profiling of whole kidney samples and subsequent quantitative RT-PCR identified a single gene, Spon1 that exhibited significant differential expression between the WKY and SHR genotypes at both 6 and 24 weeks of age. Western blot analysis confirmed an increased level of the Spon1 gene product in SHR kidneys. Spon1 belongs to a family of genes with anti-angiogenic properties. These findings justify further investigation of this novel positional candidate gene in BP control in hypertensive rat models and humans.