Genetic factors associated with volume-sensitive hypertension.

Defining the genetic basis of essential hypertension is most informative when the blood pressure regulation is correlated with physiologic mechanisms, e.g., responses of the renin-angiotensin aldosterone system (RAAS) in hypertensive subjects. The aldosterone response to angiotensin II (Ang II) on a low salt diet is influenced by gender, plasma renin activity, and most significantly, familial resemblance, but only in males and in post-menopausal females. There is familial aggregation of low-renin hypertension, no association with candidate genes of the RAAS, but, a highly significant association with polymorphisms in the alpha-adducin gene. Finally, angiotensinogen (AGT) genotype effects renal and adrenal responses to Ang II in patients with hypertension. These results strongly suggest that in contrast to population-based studies that use hypertension as the phenotype, classifying patients by the variability in physiologic, mechanistic traits enhances the probability of identifying the genetic factors influencing a rise in blood pressure.