Genetic variation in P450c11AS in Chilean patients with low renin hypertension
Date
1996
Journal Title
Journal ISSN
Volume Title
Publisher
ENDOCRINE SOC
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 mu mol/L; the K-m for Arg(173) was 2.53 mu mol/L. The apparent maximal velocity (V-max) for Lys(173) was 6.5x10(-3) mu g/mL . 24 h; the V-max for Arg(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(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) (chi(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 (chi(2)=3.79; P=0.05) Thus, the Arg(173) variant of CYP11B2 may be linked to LRH in Chilean patients.
Description
Keywords
ALDOSTERONE SYNTHASE, MOLECULAR-CLONING, ADRENAL-CORTEX, EXPRESSION, CDNA, CYTOCHROME-P-450, CYP11B2, MUTATIONS, VARIANTS, STROKE