Abstract

Low renin hypertension (LRH), which accounts for 10-20% of patients with idiopathic 'essential' hypertension, bears hormonal similarities to mineralocorticoid-induced hypertension, but elevated mineralocorticoid concentrations have not been found. Some patients with LRH have normal, rather than suppressed, plasma aldosterone concentrations, so that the ratio of aldosterone concentration to PRA (Aldo/PRA) is high, suggesting inappropriately increased aldosterone biosynthesis. We characterized the CYP11B2 gene that encodes the aldosterone synthase, P450c11AS, in hypertensive and control populations in a single clinic in Santiago, Chile. We directly sequenced the entire CYP11B2 gene in 12 patients with LRH, 2 high renin hypertensive controls, and 2 normotensive controls. All sequences were identical, except that 8 of 24 LRH alleles encoded arginine rather than lysine at position 173. The Arg 173 and Lys 173 variants were expressed in transfected MA-10 cells, and their ability to convert deoxycorticosterone to aldosterone was measured; the apparent Michaelis constant (K(m)) for Lys 173 was 2.73 ?mol/L; the K(m) for Arg 173 was 2.53 ?mol/L. The apparent maximal velocity (V(max)) for Lys 173 was 6.5 x 10 -3 ?g/mL · 24 h; the V(max) for Arg 173 was 7.8 x 10 -3 ?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 173 is a polymorphism linked to LRH. We examined position 173 in 52 unselected patients with idiopathic hypertension and 55 normotensive controls 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 normotensive alleles (25 of 110, 22.5%) carried Arg 173 (? 2 = 5.57; P < 0.02). Most of the Arg 173 alleles (31 of 72, 43.1%) were from hypertensive 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 (? 2 = 3.79; P = 0.05) Thus, the Arg 173 variant of CYP11B2 may be linked to LRH in Chilean patients.