Published Online
on April 16, 2007

A more recent version of this article appeared on May 1, 2007

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Submitted on March 31, 2006
Accepted on November 13, 2006

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

Fangwen Rao MD, Gen Wen MD, PhD, Jiaur R. Gayen PhD, Madhusudan Das PhD, Sucheta M. Vaingankar PhD, Brinda K. Rana PhD, Manjula Mahata PhD, Brian P. Kennedy PhD, Rany M. Salem MPH, Mats Stridsberg PhD, Kenneth Abel PhD, Douglas W. Smith PhD, Eleazar Eskin PhD, Nicholas J. Schork PhD, Bruce A. Hamilton PhD, Michael G. Ziegler MD, Sushil K. Mahata PhD, and Daniel T. O’Connor MD^*

From the Departments of Medicine (F.R., G.W., J.R.G., M.D., S.M.V., M.M., B.P.K., R.M.S., K.A., B.A.H., M.G.Z., S.K.M., D.T.O.), Psychiatry (B.K.R., N.J.S.), Computer Science (E.E.), Pharmacology (D.T.O.), and Biology (D.W.S.), Polymorphism Research Laboratory (B.K.R., N.J.S.), and Center for Human Genetics and Genomics (N.J.S., D.T.O.), University of California at San Diego; the VA San Diego Healthcare System (S.K.M., D.T.O.), San Diego, Calif; and the Department of Medical Sciences (M.S.), University of Uppsala, Uppsala, Sweden.

^* To whom correspondence should be addressed. E-mail: doconnor{at}ucsd.edu.

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.

Key words: acetylcholine • blood pressure • catecholamines • genetics • heart rate • hypertension • nervous system, sympathetic

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