Human tyrosine hydroxylase natural allelic variation: influence on autonomic function and hypertension. Academic Article uri icon

Overview

MeSH

  • Blood Pressure
  • Humans
  • Microsatellite Repeats
  • Promoter Regions, Genetic
  • Transcription, Genetic

MeSH Major

  • Alleles
  • Autonomic Nervous System
  • Genetic Variation
  • Hypertension
  • Tyrosine 3-Monooxygenase

abstract

  • The catecholamine biosynthetic pathway consists of several enzymatic steps in series, beginning with the amino acids phenylalanine and tyrosine, and eventuating in the catecholamines norepinephrine (noradrenaline) and epinephrine (adrenaline). Since the enzyme tyrosine hydroxylase (TH; tyrosine 3-mono-oxygenase; EC 1.14.16.2; chromosome 11p15.5) is generally considered to be rate-limiting in this pathway, probed as to whether common genetic variation at the TH gene occurred, and whether such variants contributed to inter-individual alterations in autonomic function, either biochemical or physiological. We began with sequencing a tetranucleotide (TCAT) repeat in the first intron, and found that the two most common versions, (TCAT)(6) and (TCAT)(10i), predicted heritable autonomic traits in twin pairs. We then conducted systematic polymorphism discovery across the ~8 kbp locus, and discovered numerous variants, principally non-coding. The proximal promoter block contained four common variants, and its haplotypes and SNPs (especially C-824T, rs10770141) predicted catecholamine secretion, environmental stress-induced BP increments, and hypertension. Finally, we found that two of the common promoter variants, C-824T (rs10770141) and A-581G (rs10770140), were functional in that they differentially affected transcriptional activity of the isolated promoter, disrupted recognition motifs for specific transcription factor binding, altered the promoter responses to the co-transfected (exogenous) factors, and bound the endogenous factors in the chromatin fraction of the nucleus. We concluded that common variation in the proximal TH promoter is functional, giving rise to changes in autonomic function and consequently cardiovascular risk.

publication date

  • November 2010

has subject area

  • Alleles
  • Autonomic Nervous System
  • Blood Pressure
  • Genetic Variation
  • Humans
  • Hypertension
  • Microsatellite Repeats
  • Promoter Regions, Genetic
  • Transcription, Genetic
  • Tyrosine 3-Monooxygenase

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3008933

Digital Object Identifier (DOI)

  • 10.1007/s10571-010-9535-7

PubMed ID

  • 20571875

Additional Document Info

start page

  • 1391

end page

  • 1394

volume

  • 30

number

  • 8