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(Circulation. 2007;115:2271-2281.)
© 2007 American Heart Association, Inc.

Genetics

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; 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.

Correspondence to Daniel T. O’Connor, MD, or Sushil K. Mahata, PhD, Department of Medicine and Center for Human Genetics and Genomics (0838), UCSD School of Medicine and VASDHS, 9500 Gilman Drive, La Jolla, CA 92093–0838. E-mail doconnor{at}ucsd.edu or smahata@ucsd.edu

Received March 31, 2006; accepted November 13, 2006.

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.

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