This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 115/17/2271    most recent CIRCULATIONAHA.106.628859v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rao, F. Articles by O’Connor, D. T. Search for Related Content PubMed PubMed Citation Articles by Rao, F. Articles by O’Connor, D. T. Related Collections Clinical genetics Hypertension - basic studies Clinical Studies

(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.

---

 

CLINICAL PERSPECTIVE

This article has been cited by other articles:

				N. R. Mahapatra Catestatin is a novel endogenous peptide that regulates cardiac function and blood pressure Cardiovasc Res, June 25, 2008; (2008) cvn155v2. [Abstract] [Full Text] [PDF]

				P.-a. B. Shih and D. T. O'Connor Hereditary Determinants of Human Hypertension: Strategies in the Setting of Genetic Complexity Hypertension, June 1, 2008; 51(6): 1456 - 1464. [Full Text] [PDF]

				R. M. Salem, P. E. Cadman, Y. Chen, F. Rao, G. Wen, B. A. Hamilton, B. K. Rana, D. W. Smith, M. Stridsberg, H. J. Ward, et al. Chromogranin A Polymorphisms Are Associated With Hypertensive Renal Disease J. Am. Soc. Nephrol., March 1, 2008; 19(3): 600 - 614. [Abstract] [Full Text] [PDF]

				N. Biswas, S. M. Vaingankar, M. Mahata, M. Das, J. R. Gayen, L. Taupenot, J. W. Torpey, D. T. O'Connor, and S. K. Mahata Proteolytic Cleavage of Human Chromogranin A Containing Naturally Occurring Catestatin Variants: Differential Processing at Catestatin Region by Plasmin Endocrinology, February 1, 2008; 149(2): 749 - 757. [Abstract] [Full Text] [PDF]

				D. S. Goldstein Genotype and Vascular Phenotype Linked by Catecholamine Systems Circulation, January 29, 2008; 117(4): 458 - 461. [Full Text] [PDF]