Molecular genetics of salt-sensitivity and hypertension

For the past decade, hypertension research has shifted strongly in the direction of molecular genetics. The success stories are the monogenic hypertensive syndromes. Classic linkage analyses have located the responsible genes for glucocorticoid-remediable aldosteronism, Liddle syndrome, and apparent mineralocorticoid excess. Furthermore, a recent gain-of-function mutation has recently been described in the gene for the mineralocorticoid receptor. These genes have been cloned and their functions elucidated. Other monogenic syndromes are currently being intensively studied. However, in the area of primary hypertension, the successes have relied on the candidate gene approach. Allelic variants in the genes for angiotensinogen, alpha-adducin, the beta2-adrenergic receptor, the G-protein beta3-subunit, and the T594M mutation in the beta-subunit of the epithelial sodium channel have been identified; however, the importance of these allelic variants to primary hypertension as a whole is not yet clear. Recently, an association approach was employed to implicate the mineralocorticoid receptor gene in salt-sensitivity. Linkage approaches have been attempted and the beta-subunit of the epithelial sodium channel has been linked to hypertension and to blood pressure as a quantitative trait locus. New approaches are necessary to elucidate salt-sensitive hypertension. The analysis of multiple genes simultaneously in terms of a metabolic control analysis may provide a more promising approach.