Catecholamine release-inhibitory peptide catestatin (chromogranin A352-372): Naturally occurring amino acid variant Gly364Ser causes profound changes in human autonomic activity and alters risk for hypertension
2007 (English)In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 115, no 17, 2271-2281 p.Article in journal (Refereed) Published
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 ≈47%) and downward deflections (by ≈44%), increased cardiac parasympathetic index (by ≈2.4-fold), and decreased cardiac sympathetic index (by ≈26%). Renal norepinephrine excretion was diminished by ≈26% and epinephrine excretion by ≈34% in Gly/Ser heterozygotes. The coalescent dated emergence of the variant to ≈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 ≈5 to 6 mm Hg, and the polymorphism accounted for ≈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.
Place, publisher, year, edition, pages
2007. Vol. 115, no 17, 2271-2281 p.
Acetylcholine, Blood pressure, Catecholamines, Genetics, Heart rate, Hypertension, Nervous system, sympathetic
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-15957DOI: 10.1161/CIRCULATIONAHA.106.628859ISI: 000246122600005PubMedID: 17438154OAI: oai:DiVA.org:uu-15957DiVA: diva2:43728