Sex-specific QTLs and interacting loci underlie salt-sensitive hypertension and target organ complications in Dahl S/jrHS hypertensive rats

Section of Molecular Medicine, Department of Medicine, and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 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 F 2 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 F 2 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. sex-specific susceptibility; genetics; blood pressure; renal disease; relative heart weight; quantitative trait locus