Common genetic variants in the chromogranin A promoter alter autonomic activity and blood pressure. Academic Article uri icon

Overview

MeSH

  • Adaptation, Physiological
  • Genotype
  • Haplotypes
  • Humans
  • Linkage Disequilibrium
  • Promoter Regions, Genetic

MeSH Major

  • Autonomic Nervous System
  • Blood Pressure
  • Chromogranin A
  • Polymorphism, Single Nucleotide

abstract

  • Chromogranin A (CHGA) is stored and released from the same secretory vesicles that contain catecholamines in chromaffin cells and noradrenergic neurons. We had previously identified common genetic variants at the CHGA locus in several human populations. Here we focus on whether inter-individual variants in the promoter region are of physiological significance. A common haplotype, CGATA (Hap-B), blunted the blood pressure response to cold stress and the effect exhibited molecular heterosis with the greatest blood pressure change found in Hap-A/Hap-B heterozygotes. Homozygosity for three minor alleles with peak effects within the haplotype predicted lower stress-induced blood pressure changes. The G-462A variant predicted resting blood pressure in the population with higher pressures occurring in heterozygotes (heterosis). Using cells transfected with CHGA promoter-luciferase reporter constructs, the Hap-B haplotype had decreased luciferase expression compared to the TTGTC (Hap-A) haplotype under both basal conditions and after activation by pre-ganglionic stimuli. The G-462A variant altered a COUP-TF transcriptional control motif. The two alleles in transfected promoters differed in basal activity and in the responses to COUP-II-TF transactivation and to retinoic acid. In vitro findings of molecular heterosis were also noted with the transfected CHGA promoter wherein the diploid combination of the two G-462A alleles gave rise to higher luciferase expression than either allele in isolation. Our results suggest that common genetic variants in the CHGA promoter may regulate heritable changes in blood pressure.

publication date

  • July 2008

has subject area

  • Adaptation, Physiological
  • Autonomic Nervous System
  • Blood Pressure
  • Chromogranin A
  • Genotype
  • Haplotypes
  • Humans
  • Linkage Disequilibrium
  • Polymorphism, Single Nucleotide
  • Promoter Regions, Genetic

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2576285

Digital Object Identifier (DOI)

  • 10.1038/ki.2008.113

PubMed ID

  • 18432188

Additional Document Info

start page

  • 115

end page

  • 125

volume

  • 74

number

  • 1