Neuropeptide Y(1) Receptor NPY1R discovery of naturally occurring human genetic variants governing gene expression in cella as well as pleiotropic effects on autonomic activity and blood pressure in vivo. Academic Article uri icon

Overview

MeSH

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Baroreflex
  • Cold Temperature
  • Escherichia coli
  • Female
  • Haplotypes
  • Humans
  • Hypertension
  • Linkage Disequilibrium
  • Luciferases
  • Male
  • Middle Aged
  • Neuropeptide Y
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic
  • Stress, Physiological
  • Transfection
  • Young Adult
  • beta-Galactosidase

MeSH Major

  • Autonomic Nervous System
  • Blood Pressure
  • Gene Expression Regulation
  • Polymorphism, Genetic
  • Receptors, Neuropeptide Y

abstract

  • We asked whether naturally occurring genetic variation at the human NPY1R locus alters autonomic traits that might predispose individuals to cardiovascular disease. Neuropeptide Y (NPY) interacts with the Y(1) receptor, NPY1R, to control adrenergic activity and blood pressure (BP). We searched for polymorphism at NPY1R by systematic resequencing in ethnically diverse people. There were 376 twins/siblings who were evaluated for heritable autonomic traits: baroreflex function and pressor response to environmental stress. The common NPY1R variant A+1050G in the 3'-untranslated region (3'-UTR) predicted baroreceptor slope (p = 0.014-0.047) and BP change to cold stress (p = 0.0091-0.016), with minor allele homozygotes displaying blunted slope and exaggerated pressor response. In 936 individuals with the most extreme BPs in the population, not only 3'-UTR A+1050G (p = 1.2 x 10(-4)) but also promoter A-585T (p = 0.001) affected both systolic BP and diastolic BP, in interactive fashion (p = 0.007), with combined homozygotes showing the highest diastolic BP (>20 mm Hg). The 3'-UTR variant +1050G decreased expression of a transfected luciferase reporter/NPY1R 3'-UTR plasmid; promoter variant A-585 also decreased expression of an NPY1R promoter/luciferase reporter. Thus, alleles that increased BP in vivo (3'-UTR +1050G, promoter A-585) also decreased NPY1R expression in cella. Computational alignment showed that A+1050G disrupted a microRNA motif. Our results indicate that naturally occurring genetic variation at the NPY1R locus has implications for heritable autonomic control of the circulation, and ultimately, for systemic hypertension. The findings suggest novel pathophysiological links between the NPY1R locus, autonomic activity, and blood pressure, and suggest new strategies to approach the mechanism, diagnosis, and treatment of systemic hypertension.

publication date

  • September 1, 2009

has subject area

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Autonomic Nervous System
  • Baroreflex
  • Blood Pressure
  • Cold Temperature
  • Escherichia coli
  • Female
  • Gene Expression Regulation
  • Haplotypes
  • Humans
  • Hypertension
  • Linkage Disequilibrium
  • Luciferases
  • Male
  • Middle Aged
  • Neuropeptide Y
  • Phenotype
  • Polymorphism, Genetic
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic
  • Receptors, Neuropeptide Y
  • Stress, Physiological
  • Transfection
  • Young Adult
  • beta-Galactosidase

Research

keywords

  • Journal Article
  • Twin Study

Identity

Language

  • eng

PubMed Central ID

  • PMC2792636

Digital Object Identifier (DOI)

  • 10.1016/j.jacc.2009.05.035

PubMed ID

  • 19712806

Additional Document Info

start page

  • 944

end page

  • 954

volume

  • 54

number

  • 10