INDEPENDENT, MARKED ASSOCIATIONS OF ALLELES OF THE INSULIN-RECEPTOR AND DIPEPTIDYL CARBOXYPEPTIDASE-I GENES WITH ESSENTIAL-HYPERTENSION

1. There is evidence to suggest that essential hypertension is a polyg enic disorder and that it arises from yet-to-be-identified predisposin g variants of certain genes that influence blood pressure. The cloning of various hormone, enzyme, adrenoceptor and hormone receptor genes w hose products are involved in blood pressure control and the identific ation of polymorphisms of these has permitted us to test their genetic association with hypertension. 2. Cross-sectional analyses of a numbe r of candidate gene markers were performed in hypertensive and normote nsive subjects who were selected on the basis of both parents being ei ther hypertensive or normotensive, respectively, and the difference in total alleles on all chromosomes for each polymorphism between the hy pertensive and normotensive groups was tested by chi2 analysis with on e degree of freedom. 3. A marked association was observed between hype rtension and insertion alleles of polymorphisms of the insulin recepto r gene (INSR) (P<0.0040) and the dipeptidyl carboxypeptidase-1 (angiot ensin I-converting enzyme; kininase II) gene (DCP1) (P<0.0018). No ass ociation with hypertension was evident, however, for polymorphisms of the growth hormone, low-density lipoprotein receptor, renal kallikrein , alpha2- and beta1-adrenoreceptor, atrial natriuretic factor and insu lin genes. 4. All but one of the hypertensive subjects had at least on e of the hypertension-associated alleles, and although subjects homozy gous for both were three times more frequent in the hypertensive group , examination of the nine possible genotypes suggested that the INSR a nd DCP1 alleles are independent markers for hypertension. 5. The prese nt results suggest that genetic variant(s) in close linkage disequilib rium with polymorphisms at INSR and DCP1 may be involved in part in th e aetiology of essential hypertension.