GENETIC-VARIATION IN P450C11AS IN CHILEAN PATIENTS WITH LOW RENIN HYPERTENSION

Low renin hypertension (LRH), which accounts for 10-20% of patients wi th idiopathic ''essential'' hypertension, bears hormonal similarities to mineralocorticoid-induced hypertension, but elevated mineralocortic oid concentrations have not been found. Some patients with LRH have no rmal, rather than suppressed, plasma aldosterone concentrations, so th at the ratio of aldosterone concentration to PRA (Aldo/PRA) is high, s uggesting inappropriately increased aldosterone biosynthesis. We chara cterized the CYP11B2 gene that encodes the aldosterone synthase, P450c 11AS, in hypertensive and control populations in a single clinic in Sa ntiago, Chile. We directly sequenced the entire CYP11B2 gene in 12 pat ients with LRH, 2 high renin hypertensive controls, and 2 normotensive controls. All sequences were identical, except that 8 of 24 LRH allel es encoded arginine rather than lysine at position 173. The Arg(173) a nd Lys(173) variants were expressed in transfected MA-10 cells, and th eir ability to convert deoxycorticosterone to aldosterone was measured ; the apparent Michaelis constant (K-m) for Lys(173) was 2.73 mu mol/L ; the K-m for Arg(173) was 2.53 mu mol/L. The apparent maximal velocit y (V-max) for Lys(173) was 6.5x10(-3) mu g/mL . 24 h; the V-max for Ar g(173) was 7.8x10(-3) mu g/mL . 24 h. The first order rate constant, V -max/K-m was 2.38 for Lys(173) and 3.08 for Arg(173). As these values were not significantly different, we sought to determine whether Arg(1 73) is a polymorphism linked to LRH. We examined position 173 in 52 un selected patients with idiopathic hypertension and 55 normotensive con trols by PCR amplification of CYP11B2 exons 3-5 followed by digestion with Bsu36I, which digests the Arg(173) sequence, but not the Lys(173) sequence. More of the hypertensive alleles (39 of 104, 37.5%) than no rmotensive alleles (25 of 110, 22.5%) carried Arg(173) (chi(2)=5.57; P <0.02). Most of the Arg(173) alleles (31 of 72, 43.1%) were from hype rtensive patients with Aldo/PRA below 30, whereas only 5 of 24 (20.8%) Arg(173) alleles were found in patients with Aldo/PRA greater than 30 (chi(2)=3.79; P=0.05) Thus, the Arg(173) variant of CYP11B2 may be li nked to LRH in Chilean patients.