Johnson Michelle D, He Liqun, Herman Daniel, Wakimoto Hiroko, Wallace Caroline A, Zidek Vaclav, Mlejnek Petr, Musilova Alena, Simakova Miroslava, Vorlicek Jaroslav, Kren Vladimir, Viklicky Ondrej, Qi Nathan R, Wang Jiaming, Seidman Christine E, Seidman Jonathan, Kurtz Theodore W, Aitman Timothy J, Pravenec Michal
Institute of Physiology, Czech Academy of Sciences, Vídenská 1083, 142 20 Prague 4, Czech Republic.
Hypertension. 2009 Sep;54(3):639-45. doi: 10.1161/HYPERTENSIONAHA.108.126664. Epub 2009 Jul 20.
Hypertension in humans and experimental models has a strong hereditary basis, but identification of causative genes remains challenging. Quantitative trait loci (QTLs) for hypertension and salt sensitivity have been reported on rat chromosome 18. We set out to genetically isolate and prioritize genes within the salt-sensitivity and hypertension QTLs on the spontaneously hypertensive rat (SHR) chromosome 18 by developing and characterizing a series of congenic strains derived from the SHR and normotensive Brown Norway rat strains. The SHR.BN-D18Rat113/D18Rat82 congenic strain exhibits significantly lower blood pressure and is salt resistant compared with the SHR. Transplantation of kidneys from SHR.BN-D18Rat113/D18Rat82 donors into SHR recipients is sufficient to attenuate increased blood pressure but not salt sensitivity. Derivation of congenic sublines allowed for the separation of salt sensitivity from hypertension QTL regions. Renal expression studies with microarray and Solexa-based sequencing in parental and congenic strains identified 4 differentially expressed genes within the hypertension QTL region, one of which is an unannotated transcript encoding a previously undescribed, small, nonprotein coding RNA. Sequencing selected biological candidate genes within the minimal congenic interval revealed a nonsynonymous variant in SHR transcription factor 4. The minimal congenic interval is syntenic to a region of human chromosome 18 where significant linkage to hypertension was observed in family based linkage studies. These congenic lines provide reagents for identifying causative genes that underlie the chromosome 18 SHR QTLs for hypertension and salt sensitivity. Candidate genes identified in these studies merit further investigation as potentially causative hypertension genes in SHR and human hypertension.
人类和实验模型中的高血压具有很强的遗传基础，但确定致病基因仍然具有挑战性。大鼠18号染色体上已报道了高血压和盐敏感性的数量性状基因座（QTL）。我们通过开发和鉴定一系列源自自发性高血压大鼠（SHR）和正常血压的褐家鼠品系的近交系，从基因上分离并确定SHR 18号染色体上盐敏感性和高血压QTL内的基因优先级。与SHR相比，SHR.BN-D18Rat113/D18Rat82近交系表现出显著更低的血压且具有耐盐性。将SHR.BN-D18Rat113/D18Rat82供体的肾脏移植到SHR受体中足以减轻血压升高，但不能减轻盐敏感性。近交亚系的衍生使得盐敏感性与高血压QTL区域得以分离。通过对亲本和近交系进行微阵列和基于Solexa的测序进行肾脏表达研究，在高血压QTL区域内鉴定出4个差异表达基因，其中一个是未注释的转录本，编码一种先前未描述的小的非蛋白质编码RNA。对最小近交区间内选定的生物学候选基因进行测序，发现SHR转录因子4中存在一个非同义变体。最小近交区间与人类18号染色体的一个区域同线，在基于家系的连锁研究中观察到该区域与高血压有显著连锁。这些近交系为鉴定导致SHR 18号染色体上高血压和盐敏感性QTL的致病基因提供了试剂。在这些研究中鉴定出的候选基因作为SHR和人类高血压中潜在的致病高血压基因值得进一步研究。
