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The clearance receptor for natriuretic peptides (NPRC), a candidate gene for essential hypertension, is highly expressed in adipose 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.Using polymerase chain reaction (PCR) and direct automated sequencing, a biallelic (A/C) polymorphism was detected at position −55 in a conserved promoter element named P1. The novel C(−55) variant makes the promoter sequence identical to the mouse gene and introduces a second HgaI 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) levels were determined in 84 patients with essential hypertension. In the presence of obesity (body mass index (BMI) ≥ 30 kg/m2) the homozygous CC hypertensives (n = 21) had significantly lower plasma ANP (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 pressure (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 difference in ANP levels were also present when overweight patients (BMI ≥ 27 kg/m2) were considered.A common ‘ancestral’ C(−55) variant of the NPRC P1 promoter is associated with lower ANP levels and higher SBP and MBP in obese hypertensives. The C(−55) variant, in the presence of increased adiposity, might reduce plasma ANP through increased NPRC-mediated ANP clearance, contributing to higher blood pressure.