Blood pressure is a quantitative trait that varies along a continuum in the general population and is regulated via multiple mechanisms involving many genetic loci and environmental factors. Family studies and twin studies suggest that about 30% of blood pressure variance is attributable to genetic factors and 50% to environmental factors. Two forms of
hypertension transmitted on an autosomal recessive basis have been identified: one is
glucocorticoid-suppressible hyperaldosteronism (GSH) and the other is Liddle's syndrome (
amiloride-suppressible hyperactivity of the
epithelial sodium channel). The molecular basis for these two forms of severe
hypertension has recently been elucidated. GSH is due to expression of a chimeric gene produced by fusion of the
11 beta-hydroxylase promoter with the region encoding the
enzyme aldosterone-synthase. Expression of this chimeric gene occurs in the zona fasciculata of the adrenal cortex, under the control of
ACTH, and can be suppressed by administration of
glucocorticoids. Liddle's syndrome is due to mutations in the beta or gamma chain of the
epithelial sodium channel in distal renal tubule cells. The hyperactivity of this channel caused by the mutations results in increased
sodium reabsorption, which can be suppressed by administration of
amiloride or
triamterene. Apart from these rare genetic defects, a number of susceptibility genes can increase the risk of
hypertension in a given environment. Their presence is neither necessary nor sufficient to cause
hypertension. The best documented example is the
angiotensinogen gene. Angiotensiongen is the substrate of
renin, and the
renin-
angiotensinogen reaction is the first and limiting step in the pathway that leads to production of
angiotensin II, a
peptide with important effects on blood pressure control and the metabolism of water and
sodium. Several studies have demonstrated a link between the
angiotensinogen gene and familial
hypertension or
hypertension of pregnancy. The M235T variant of
angiotensinogen is more prevalent among hypertensive than among normotensive subjects in several Caucasian and Japanese populations. The M235T variant is also associated with plasma
angiotensinogen elevation, which is potentially responsible for increased production of
angiotensin II. In other terms, relationships exist between the
angiotensinogen genotype, the intermediate phenotype (i.e., plasma
angiotensinogen elevation), and the distal phenomenon (i.e., blood pressure elevation). DNA libraries for the study of
hypertension have been set up, and many informative
genetic markers distributed along the genome have been identified. Using position cloning techniques, these markers could be used in the search for genetic links between arterial
hypertension and a chromosomal locus.