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Restraint to Induce Stress in Mice and Rats
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Adrenergic polymorphism and the human stress response.

Fangwen Rao1, Lian Zhang, Jennifer Wessel

  • 1Department of Medicine, University of California at San Diego, La Jolla, California 92093-0838, USA. frao@ucsd.edu

Annals of the New York Academy of Sciences
|January 6, 2009
PubMed
Summary

Genetic variations in human Tyrosine hydroxylase (TH) influence catecholamine secretion and autonomic activity. Specific TH promoter variations are linked to blood pressure regulation and hypertension risk.

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Area of Science:

  • Genetics
  • Cardiovascular Physiology
  • Biochemistry

Background:

  • Tyrosine hydroxylase (TH) is the key enzyme in catecholamine biosynthesis.
  • Common genetic variations in TH may influence autonomic activity and cardiovascular disease risk.
  • Understanding TH genetic contributions is crucial for catecholamine metabolism and blood pressure regulation.

Purpose of the Study:

  • To investigate the impact of genetic variation in the human TH gene on autonomic activity and blood pressure.
  • To identify specific TH variants associated with catecholamine secretion and hypertension.
  • To explore the pleiotropic effects of TH genetic variants on physiological traits.

Main Methods:

  • Systematic polymorphism discovery and sequencing across the TH locus in diverse individuals.
  • Evaluation of sympathetic traits, catecholamine production, and stress responses in twin pairs.
  • Genotyping for association studies in extreme blood pressure percentiles and hypertension cases.
  • Functional analysis using TH promoter haplotype/reporter plasmids in chromaffin cells.

Main Results:

  • Forty-nine single nucleotide polymorphisms (SNPs) and one tetranucleotide repeat were identified in TH.
  • Common phenotypic variation was not explained by coding region polymorphisms.
  • Significant heritability of catecholamine secretion and stress-induced blood pressure changes was observed.
  • TH promoter variants, particularly haplotype #2 (TGGG), showed pleiotropic associations with norepinephrine excretion and blood pressure during stress.
  • The C-824T variant in the TH promoter was significantly associated with blood pressure determination in hypertension.

Conclusions:

  • Human catecholamine secretory traits are heritable and genetically linked to autonomic activity and blood pressure.
  • Genetic variation in TH, especially in the promoter region, influences catecholamine metabolism and blood pressure regulation.
  • Novel pathophysiological links between TH, catecholamine metabolism, and hypertension are suggested.
  • These findings may inform new diagnostic and therapeutic strategies for systemic hypertension.