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1 Department of Medicine, Boston University School of Medicine, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: nruizo{at}bu.edu.
Essential (polygenic) hypertension is a complex genetic disorder that remains a major risk factor for cardiovascular disease despite clinical advances, reiterating the need to elucidate molecular genetic mechanisms. Elucidation of susceptibility genes remains a challenge, however. Blood pressure regulatory pathways through angiotensin-II (AngII) and endothelin-1 (ET-1) receptor systems comprise 
priori candidate susceptibility pathways. Here we report that the dual ET-1/AngII receptor gene (Dear) is structurally and functionally distinct between Dahl salt-sensitive, hypertensive (S) and salt-resistant, normotensive (R) rats. The Dahl S S44/M74 variant is identical to the previously reported Dear cDNA with equivalent affinities for both ET-1 and AngII, in contrast to Dahl R S44P/M74T variant which exhibits absent AngII binding but effective ET-1 binding. The S44P substitution localizes to the AngII-binding domain predicted by the molecular recognition theory providing compelling support of this theory. The Dear gene maps to rat chromosome-2 and cosegregates with blood pressure (BP) in female F2 [RxS]-intercross rats with highly significant linkage (LOD 3.61) accounting for 14 % of BP variance, but not in male F2 [RxS]-intercross rats. Altogether, the data suggest the hypothesis that modification of the critical balance between AngII and ET-1 systems through variant Dear contributes to hypertension-susceptibility in female F2 [RxS]-intercross rats. Further investigations are necessary to corroborate genetic linkage thru congenic rat studies, to investigate putative gene interactions and to show causality by transgenesis and/or intervention. More importantly, the data reiterate the importance of gender-specific factors in hypertension susceptibility.
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