Abstract
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.
Highlights
Polygenic hypertension is a leading risk factor for heart disease, stroke and renal failure [1]
Results obtained in the present study confirmed the existence of a single chromosome 5 blood pressure (BP) QTL, BP-f1, but not BP-f2, implying that the original confidence interval data was indicating that the position for BP-f1 was not well defined instead
Inspection of the few genome scans for BP QTLs performed on rat female subjects [9,11,12,13] reveal that the chromosome 5 region spanning BP-f1 has been linked to blood pressure in a linkage study performed in Wild rats (Rattus norvegicus) using the SHR rat as contrasting hypertensive strain [11] and in a (Dahl S x Brown Norway)- female intercross cohort [12]
Summary
Polygenic (essential) hypertension is a leading risk factor for heart disease, stroke and renal failure [1]. Hypertension is further compounded by phenotype variation due to its relatively late onset, variable disease course and target organ complications, sex-specific differences and emerging impact of gestational environmental factors. This multi-faceted complexity has made elucidation of hypertension susceptibility genes challenging. Given differential responses to therapy and end-organ disease outcomes, it becomes apparent that hypertension genes are likely hypertension subtype-specific, and modified by diet and developmental programming, which are not accounted for in reported multicenter genetic cohort analyses [5,6,7]. The present study was undertaking to 1) confirm the presence of one or two BP QTLs in this region, and 2) delimit more precisely the chromosomal region (s) harboring this BP QTL
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