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

J Hypertens. 1999 Sep;17(9):1301-5. doi: 10.1097/00004872-199917090-00010.

Abstract

Objective and design: 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.

Methods and results: 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 Hgal 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) > or = 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 > or = 27 kg/m2) were considered.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Alleles
  • Animals
  • Atrial Natriuretic Factor / blood*
  • Blood Pressure / genetics*
  • Body Mass Index
  • Female
  • Gene Frequency
  • Genetic Testing
  • Genotype
  • Guanylate Cyclase / genetics*
  • Humans
  • Hypertension / blood
  • Hypertension / genetics*
  • Male
  • Mice
  • Middle Aged
  • Molecular Sequence Data
  • Obesity / genetics*
  • Obesity / physiopathology*
  • Polymerase Chain Reaction
  • Polymorphism, Genetic / genetics
  • Promoter Regions, Genetic / genetics
  • Receptors, Atrial Natriuretic Factor / genetics*
  • Regulatory Sequences, Nucleic Acid / genetics
  • Sequence Homology, Nucleic Acid

Substances

  • Atrial Natriuretic Factor
  • Guanylate Cyclase
  • Receptors, Atrial Natriuretic Factor
  • atrial natriuretic factor receptor C