Molecular genetics of human hypertension

For the past decade, hypertension research has shifted strongly in the dire ction of molecular genetics. The success stories are the monogenic hyperten sive syndromes. Classic linkage analyses has located the responsible genes for glucocorticoid-remediable aldosteronism, Liddle syndrome, and apparent mineralocorticoid excess. The genes have been cloned and their function elu cidated. 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 angiotensin ogen, alpha-adducin, beta(2)-adrenergic receptor, the G-protein beta(3)-sub unit and the T594M mutation in the beta-subunit of the epithelial sodium ch annel have been identified; however, the importance of these allelic varian ts to primary hypertension as a whole, is not yet clear. A variant in the a ngiotensin-converting enzyme gene could not, initially, be convincingly ass ociated with hypertension, but more recent analyses suggest an influence of the deletion allele on blood pressure in men, but apparently not in women. In all likelihood we are dealing with many genes with small effects. Affec ted sibling pair linkage analyses will probably not be successful in identi fying the loci of these genes. To find new genes, novel approaches will be necessary, including searching for quantitative trait loci linked to blood pressure in normotensive persons, haplotype sharing methodology in trios an d family units, the use of better study designs, and the investigation of i solated populations. Finally, rethinking the phenotype 'hypertension' and i ts intermediates must also receive priority. J Hypertens 1998, 16:1871-1878 (C) 1998 Lippincott Williams & Wilkins.