Combined genealogical, mapping, and expression approaches to identify spontaneously hypertensive rat hypertension candidate genes
Combined genealogical, mapping, and expression approaches to identify spontaneously hypertensive rat hypertension candidate genes
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DOI：
10.1161/01.hyp.0000156498.78896.37
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发表时间：
2005-04-01
期刊：
影响因子：
8.3
通讯作者：
Doris, PA
中科院分区：
文献类型：
--
作者：
Hinojos, CA;Boerwinkle, E;Doris, PA
基因中的等位基因表达已被认为是产生表型的可遗传性状。我们使用全基因组微阵列技术（Affymetrix）检测了大鼠肾脏中的基因表达。测定了4个大鼠品系、3个高血压自发性高血压大鼠（SHR）亚品系（SHR- a3、SHR- b2和SHR- c）和1个正常血压品系（Wistar-Kyoto [WKY]）的基因表达。在4周、8周、12周和18周龄的4个时间点对所有品系的多只动物进行表达测定，包括SHR期高血压前期（4周）、血压快速升高期（8周和12周）和持续高血压期（18周）。回归分析显示，在前3个时间点，所有菌株之间的关系密切，之后SHR-A3成为明显的异常值。SHR-B2和SHR-C在任何时候都表现出非常密切的基因表达关系，但在18周龄时与其他菌株相比差异也有所增加。我们确定了表达一致不同的基因，将所有SHR亚株在每个时间点与WKY进行比较。将得到的基因列表与报道的SHR血压数量性状位点进行比较，以确定一些在SHR亚株和WKY之间持续表达差异的基因，这些基因在多个时间点上持续表达差异，并且位于SHR血压决定区域。谱系关系和SHR亚株间的杂交表明SHR中负责遗传性高血压的基因在SHR亚株中是共享的。目前的方法通过等位基因对基因表达的影响确定了一些可能影响SHR血压的基因。
Allelic expression in genes has become recognized as a heritable trait by which phenotypes are generated. We have examined gene expression in the rat kidney using genome-wide microarray technology (Affymetrix). Gene expression was determined across 4 rat strains, 3 hypertensive spontaneously hypertensive rat (SHR) substrains (SHR-A3, SHR-B2, and SHR-C), and a normotensive strain (Wistar-Kyoto [WKY]). Expression measurements were made in multiple animals from all strains at 4 time points (4 weeks, 8 weeks, 12 weeks, and 18 weeks of age), covering the prehypertensive period in SHR ( 4 weeks), and the period of rapidly rising blood pressure (8 and 12 weeks) and of sustained hypertension (18 weeks). Regression analysis revealed a close relationship across all strains during the first 3 time points, after which SHR-A3 became a substantial outlier. SHR-B2 and SHR-C demonstrated a very close relationship in gene expression at all times but also showed increased differences compared with the other strains at 18 weeks of age. We identified genes that were consistently different in expression, comparing all SHR substrains at each time point with WKY. The resulting list of genes was compared with blood pressure quantitative trait loci reported for SHR to refine a number of genes consistently differentially expressed between SHR substrains and WKY, persistently differentially expressed across multiple time points, and located in SHR blood pressure-determinative regions of the genome. Genealogical relationships and SHR substrain intercrosses suggest that genes responsible for heritable hypertension in SHR are shared across SHR substrains. The present approach identifies a number of genes that may influence blood pressure in SHR by virtue of allelic effects on gene expression.