Hypertension Suppression, Not a Cumulative Thrust of Quantitative Trait Loci, Predisposes Blood Pressure Homeostasis to Normotension

BACKGROUND: Genetics of high blood pressure (BP) has revealed causes of hypertension. The cause of normotension, however, is poorly understood. Inbred Lewis rats sustain normotension despite a genetic push in altering BP. It was unknown whether this rigid resistance to BP changes is because of an insufficient hypertensive impact from limited alleles of quantitative trait loci (QTLs) or because of an existence of a master control superseding the combined strength of hypertensive QTL alleles. METHODS AND RESULTS: Currently, BP-elevating QTL alleles from hypertensive Dahl salt-sensitive rats (DSS) replaced those of Lewis on chromosomes 7, 8, 10, and 17 on the Lewis background. These hypertensive QTL alleles were then merged to systematically achieve multiple combinations. Results showed that there was no quantitative correlation between BP variations and the number of hypertensive QTL alleles, and that BP was only slightly elevated from a combined force of normotensive alleles from 7 QTLs. Thus, a genetic factor aside from the known QTLs seemed to be at play in preserving normotension and act as a hypertension suppressor. A follow-up study using consecutive backcrosses from Dahl salt-sensitive rats and Lewis identified a chromosome segment where a hypertension suppressor might reside. CONCLUSIONS: Our results provide the first evidence that normotension is not enacted via a numeric advantage of BP-lowering QTL alleles, and instead can be achieved by a particular genetic component actively suppressing hypertensive QTL alleles. The identification of this hypertension suppressor could result in formulating unique diagnostic and therapeutic targets, and above all, preventive measures against essential hypertension.