Catecholamine release-inhibitory peptide catestatin (chromogranin A(352-372)): naturally occurring amino acid variant Gly364Ser causes profound changes in human autonomic activity and alters risk for hypertension

Circulation. 2007 May 1;115(17):2271-81. doi: 10.1161/CIRCULATIONAHA.106.628859. Epub 2007 Apr 16.


Background: Chromogranin A, coreleased with catecholamines by exocytosis, is cleaved to the catecholamine release-inhibitory fragment catestatin. We identified a natural nonsynonymous variant of catestatin, Gly364Ser, that alters human autonomic function and blood pressure.

Methods and results: Gly364Ser heterozygotes and controls underwent physiological and biochemical phenotyping, including catecholamine production, chromogranin A precursor, and its catestatin product. Case-control studies replicated effects of the gene on blood pressure in the population. Gly364Ser displayed diminished inhibition of catecholamine secretion from cultured neurons. Gly/Ser heterozygotes displayed increased baroreceptor slope during upward deflections (by approximately 47%) and downward deflections (by approximately 44%), increased cardiac parasympathetic index (by approximately 2.4-fold), and decreased cardiac sympathetic index (by approximately 26%). Renal norepinephrine excretion was diminished by approximately 26% and epinephrine excretion by approximately 34% in Gly/Ser heterozygotes. The coalescent dated emergence of the variant to approximately 70,000 years ago. Gly364Ser was in linkage disequilibrium with 1 major Chromogranin A promoter haplotype, although promoter haplotypes did not predict autonomic phenotypes. The 364Ser variant was associated with lower diastolic blood pressure in 2 independent/confirmatory groups of patients with hypertension; genotype groups differed by approximately 5 to 6 mm Hg, and the polymorphism accounted for approximately 1.8% of population diastolic blood pressure variance, although a significant gene-by-sex interaction existed, with an enhanced effect in men.

Conclusions: The catestatin Gly364Ser variant causes profound changes in human autonomic activity, both parasympathetic and sympathetic, and seems to reduce risk of developing hypertension, especially in men. A model for catestatin action in the baroreceptor center of the nucleus of the tractus solitarius accounts for these actions.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Autonomic Nervous System / physiology*
  • Blood Pressure / genetics
  • Catecholamines / metabolism*
  • Chromogranin A / blood
  • Chromogranin A / genetics*
  • Female
  • Genetic Predisposition to Disease / epidemiology
  • Genetic Variation
  • Genomics
  • Haplotypes
  • Heart Rate / genetics
  • Heterozygote
  • Homozygote
  • Humans
  • Hypertension / epidemiology*
  • Hypertension / genetics*
  • Hypertension / physiopathology
  • Linkage Disequilibrium
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Peptide Fragments / blood
  • Peptide Fragments / genetics*
  • Phenotype
  • Phylogeny
  • Polymorphism, Single Nucleotide
  • Receptors, Nicotinic / metabolism
  • Risk Factors
  • Sex Distribution


  • Catecholamines
  • Chromogranin A
  • Peptide Fragments
  • Receptors, Nicotinic
  • chromogranin A (344-364)