Blood pressure and heredity. Is it all in the genes, or not?

We have come to appreciate that maintenance of "normal" blood pressure is based on the complex interaction of genetic factors and environmental variables in the context of a highly complicated and sophisticated maze of regulatory and feedback circuits. Primary hypertension (or, probably more accurately, hypertensions) then reflects a breakdown somewhere in this circuitry not explained by a readily apparent physiopathological mechanism that leads to a readjustment of the target set point. We understand today that the genetic background of this entity is both polygenic and heterogeneous and that it is likely to involve both specific gene-gene (epistatic) and gene-environment (ecogenetic) interactions. Add to this the analytic challenges posed by quantitative (rather than qualitative) traits and incomplete penetrance and the confounding phenomenon of a pronounced sexual dimorphism, and it becomes obvious to the most optimistic that the investigation of the genes contributing to primary hypertension in humans is a daunting task. Thus, the use of animal models of "genetic" hypertension has been a mainstay of hypertension research for more than three decades: The creation of fully inbred strains eliminated the problem of genetic heterogeneity, and the (perceived) ability to control and standardize environmental influences stringently was viewed as an effective means to avoid the noise of multifactorial interactions. Recent advances in molecular genetics and theoretical concepts of quantitative trait analysis have been applied to these model systems with the hope of elucidating at least some of the major genes that form the genetic background in animal hypertension, albeit without any certainty that analogies to human hypertension will follow. Thus, the world of the experimental investigator using animal models of hypertension appeared to be neatly split into unknown genes and conventionally recognized environmental perturbations as the causative principles that lead, alone or in concert, to pathological elevations of blood pressure. Presence of an offending gene mutation (and, in the case of a true ecogenetic interaction, of