Section of Cardiovascular Medicine, Department of Medicine, and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, United States of America.
PLoS One. 2012;7(7):e42214. doi: 10.1371/journal.pone.0042214. Epub 2012 Jul 30.
The detection of multiple sex-specific blood pressure (BP) quantitative trait loci (QTLs) in independent total genome analyses of F2 (Dahl S x R)-intercross male and female rat cohorts confirms clinical observations of sex-specific disease cause and response to treatment among hypertensive patients, and mandate the identification of sex-specific hypertension genes/mechanisms. We developed and studied two congenic strains, S.R5A and S.R5B introgressing Dahl R-chromosome 5 segments into Dahl S chromosome 5 region spanning putative BP-f1 and BP-f2 QTLs. Radiotelemetric non-stressed 24-hour BP analysis at four weeks post-high salt diet (8% NaCl) challenge, identified only S.R5B congenic rats with lower SBP (-26.5 mmHg, P = 0.002), DBP (-23.7 mmHg, P = 0.004) and MAP (-25.1 mmHg, P = 0.002) compared with Dahl S female controls at four months of age confirming BP-f1 but not BP-f2 QTL on rat chromosome 5. The S.R5B congenic segment did not affect pulse pressure and relative heart weight indicating that the gene underlying BP-f1 does not influence arterial stiffness and cardiac hypertrophy. The results of our congenic analysis narrowed BP-f1 to chromosome 5 coordinates 134.9-141.5 Mbp setting up the basis for further fine mapping of BP-f1 and eventual identification of the specific gene variant accounting for BP-f1 effect on blood pressure.
在对 F2（达尔 S x R）杂交雄性和雌性大鼠队列的全基因组独立分析中检测到多个性别特异性血压（BP）数量性状位点（QTL），证实了临床观察到的高血压患者中性别特异性疾病病因和治疗反应，并需要确定性别特异性高血压基因/机制。我们开发并研究了两个近交系，S.R5A 和 S.R5B，将达尔 R 染色体 5 片段导入达尔 S 染色体 5 区域，跨越假定的 BP-f1 和 BP-f2 QTL。在高盐饮食（8%NaCl）挑战后 4 周进行的无线电遥测非应激 24 小时 BP 分析，仅发现 S.R5B 近交系大鼠的 SBP（-26.5mmHg，P=0.002）、DBP（-23.7mmHg，P=0.004）和 MAP（-25.1mmHg，P=0.002）低于 4 个月大的达尔 S 雌性对照，证实了大鼠 5 号染色体上的 BP-f1，但不是 BP-f2 QTL。S.R5B 近交系片段不影响脉搏压和相对心脏重量，表明 BP-f1 下的基因不影响动脉僵硬和心脏肥大。我们的近交系分析结果将 BP-f1 缩小到染色体 5 的坐标 134.9-141.5Mbp，为进一步精细定位 BP-f1 和最终确定导致 BP-f1 对血压影响的特定基因变异奠定了基础。
