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

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 approximate to 47%) and downward deflections ( by approximate to 44%), increased cardiac parasympathetic index ( by approximate to 2.4-fold), and decreased cardiac sympathetic index ( by approximate to 26%). Renal norepinephrine excretion was diminished by approximate to 26% and epinephrine excretion by approximate to 34% in Gly/Ser heterozygotes. The coalescent dated emergence of the variant to approximate 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 approximate to 5 to 6 mm Hg, and the polymorphism accounted for approximate to 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.