Sex-specific QTLs and interacting loci underlie salt-sensitive hypertension and target organ complications in Dahl S/jrHS hypertensive rats
Sex-specific QTLs and interacting loci underlie salt-sensitive hypertension and target organ complications in Dahl S/jrHS hypertensive rats
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DOI：
10.1152/physiolgenomics.00285.2005
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发表时间：
2006-09-14
影响因子：
4.6
通讯作者：
Ruiz-Opazo, Nelson
中科院分区：
文献类型：
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作者：
Herrera, Victoria L. M.;Tsikoudakis, Aristides;Ruiz-Opazo, Nelson
多基因(原发性)高血压的性别差异通常归因于性类固醇激素受体系统在绝经前妇女中弱化性常见病机制的作用。然而，新出现的观察表明，性别特有的遗传易感性存在于各种特征中，因此需要进行系统研究。本文报道了高盐(8%氯化钠)大鼠饲料喂养的雄性和雌性F-2[Dahl R/JR(HS)X S/JR(HS)]杂交大鼠盐敏感型高血压易感性QTL的独立全基因组扫描的比较分析。高血压分型有三个数量性状：血压升高伴高血压肾病[肾小球损伤评分(GIS)]和心脏重量[相对心脏重量(RHW)]增加，在高盐攻击后8~12wk；虽然在BP[染色体(CHR)1-144.3 MBP；Chr 1-208.8 Mbp、Gis(Chr 1-208.8 Mbp)和心脏质量(Chr 5-150.3 Mbp)，这三个表型的QTL大多具有性别特异性：雌性QTL对BP(Chr 2-106.7 Mbp、Chr 2-181.7 Mbp、Chr 5-113.9 Mbp、Chr 5-146.7 Mbp、Chr 12-12.8Mbp)、Gis(Chr15-59.6Mbp)和RHW(Chr2-31.5Mbp、Chr5-154.7 Mbp、Chr5-110.9 Mbp)；雄性QTL分别位于BP(Chr 2-196.7 Mbp、Chr 11-48.0Mbp、Chr 20-35.7Mbp)、地理信息(Chr 6-3.3Mbp、Chr 20-40.7Mbp)和RHW(Chr 6-3.3Mbp、Chr 20-40.7Mbp)。此外，仅在雌性F2杂交大鼠中检测到与血压和高血压肾病显著连锁的相互作用基因座。比较分析显示，BP QTL峰与先前报道的大鼠模型和人类高血压易感基因以及先前S大田衍生的F2杂交研究中的BP QTL一致，并提出了性别特异决定因素的品系特异性遗传修饰物。总之，这些数据为人类多基因高血压的性别特异性机制以及干预和预防策略的研究提供了关键的实验基础。
Sex-specific differences in polygenic ( essential) hypertension are commonly attributed to the role of sex steroid hormone-receptor systems attenuating sex-common disease mechanisms in premenopausal women. However, emerging observations indicate sex-specific genetic susceptibility in various traits, thus requiring systematic study. Here we report a comparative analysis of independent total genome scans for salt-sensitive hypertension susceptibility quantitative trait loci (QTLs) in male and female F-2 [Dahl R/jr(HS) X S/jr(HS)] intercross rats exposed to high-salt (8% NaCl) rat diets. Hypertension was phenotyped with three quantitative traits: blood pressure (BP) elevation associated with increased hypertensive renal disease [glomerular injury score (GIS)] and increased cardiac mass [relative heart weight (RHW)] obtained 8 - 12 wk after high-salt challenge; 24-h nonstress, telemetric BP measurements were used. Although sex-common QTLs were detected for BP [chromosome (chr) 1-144.3 Mbp; chr 1-208.8 Mbp], GIS (chr 1-208.8 Mbp), and cardiac mass (chr 5-150.3 Mbp), most QTLs across the three phenotypes studied are gender specific as follows: female QTLs for BP (chr 2-106.7 Mbp, chr 2-181.7 Mbp, chr 5-113.9 Mbp, chr 5-146.7 Mbp, chr 12-12.8 Mbp), GIS (chr 15-59.6 Mbp), and RHW (chr 2-31.5 Mbp, chr 5-154.7 Mbp, chr 5-110.9 Mbp); male QTLs for BP (chr 2-196.7 Mbp, chr 11-48.0 Mbp, chr 20-35.7 Mbp), GIS (chr 6-3.3 Mbp, chr 20-40.7 Mbp), and RHW (chr 6-3.3 Mbp, chr 20-40.7 Mbp). Furthermore, interacting loci with significant linkage were detected only in female F2 intercross rats for BP and hypertensive renal disease. Comparative analyses revealed concordance of BP QTL peaks with previously reported rat model and human hypertension susceptibility genes and with BP QTLs in previous Dahl S-derived F2 intercross studies and also suggest strain-specific genetic modifiers of sex-specific determinants. Altogether, the data provide key experimental bases for sex-specific investigation of mechanisms and intervention and prevention strategies for polygenic hypertension in humans.