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1 Medicine, Boston University School of Medicine, Boston, Massachusetts, United States
* To whom correspondence should be addressed. E-mail: nruizo{at}bu.edu.
Gender-specific differences in polygenic (essential) hypertension are commonly attributed to the role of sex steroid hormone-receptor systems attenuating gender-common disease mechanisms in pre-menopausal women. However, emerging observations indicate gender-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 F2[Dahl R/jrHS x S/jrHS]-intercross rats exposed to high salt (8% NaCl) rat diets. Hypertension is phenotyped using three quantitative traits: BP elevation associated with increased hypertensive renal disease (glomerular injury scores) and increased cardiac mass (relative heart weight) obtained 8-12 weeks after high salt challenge. 24-hour non-stress, telemetric blood pressure measurements were used. While gender-common QTLs are detected for BP (chr1:144.3Mbp; chr1:208.8Mbp), glomerular injury score (chr1:208.8Mbp), and cardiac mass (chr5:150.3Mbp), most QTLs across the three phenotypes studied are gender-specific as follows: female QTLs for BP (chr2:106.7Mbp, chr2:181.7Mbp, chr5:113.9Mbp, chr5:146.7Mbp, chr12:12.8 Mbp), for GIS (chr15:59.6Mbp), and RHW (chr2:31.5Mbp, chr5:154-7Mbp, chr5:110.9Mbp); male QTLs for BP (chr2:196.7Mbp, chr11:48.0Mbp, chr20:35.7Mbp), for GIS (chr6:3.3Mbp, chr20:40.7Mbp) and RHW (chr6:3.3Mbp, chr20:40.7Mbp). Furthermore, interacting-loci with significant linkage are detected only in female F2-intercross rats for blood pressure and hypertensive renal disease. Comparative analyses reveal 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 gender-specific determinants. Altogether, the data provide key experimental bases for gender-specific investigation of mechanisms, and intervention and prevention strategies for polygenic hypertension in humans.
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