A novel promoter variant of the natriuretic peptide clearance receptor gene is associated with lower atrial natriuretic peptide and higher blood pressure in obese hypertensives

Objective and design The clearance receptor for natriuretic peptides (NPRC) , a candidate gene for essential hypertension, is highly expressed in adipo se tissue, where is nutritionally regulated. The objectives of the present study were to sequence the human 5'-flanking regulatory region of NPRC, to identify allelic variants and their frequencies, and to study the genotype/ phenotype correlation in hypertensive patients. Methods and results Using polymerase chain reaction (PCR) and direct automa ted sequencing, a biallelic (A/C) polymorphism was detected at position -55 in a conserved promoter element named P1. The novel C(-55) variant makes t he promoter sequence identical to the mouse gene and introduces a second Hg al site in the amplified DNA, allowing the genotyping of a large number of subjects. In a random sample of 232 white Caucasians the C(-55) allele was more commonly found (81.7% of all alleles) with 155 CC (66.8%), 69 AC (29.7 %) and only eight AA (3.5%) genotypes. Atrial natriuretic peptide (ANP) lev els were determined in 84 patients with essential hypertension. In the pres ence of obesity (body mass index (BMI) greater than or equal to 30 kg/m(2)) the homozygous CC hypertensives (n = 21) had significantly tower plasma AN P (33.6 +/- 11.1 pg/ml) compared with the AC patients (n = 11; 46.8 +/- 15. 9 pg/ml; P = 0.01), whereas systolic blood pressure (SBP) and mean blood pr essure (MBP) had the opposite association (SBP 163.9 +/- 18.7 versus 150.9 +/- 12.9 and MBP 123.3 +/- 12 versus 114.5 +/- 5.9 mmHg; P< 0.05). The diff erence in ANP levels were also present when overweight patients (BMI greate r than or equal to 27 kg/m(2)) were considered. Conclusion A common 'ancestral' C(-55) variant of the NPRC P1 promoter is a ssociated with lower ANP levels and higher SEP and MBP in obese hypertensiv es. The C(-55) variant, in the presence of increased adiposity, might reduc e plasma ANP through increased NPRC-mediated ANP clearance, contributing to higher blood pressure. J Hypertens 1999, 17:1301-1305 (C) Lippincott Willi ams & Wilkins.