Published online before print April 16, 2007, doi: 10.1161/CIRCULATIONAHA.106.648345
(Circulation. 2007;115:2282-2291.)
© 2007 American Heart Association, Inc.
Genetics |
Heredity of Endothelin Secretion
Human Twin Studies Reveal the Influence of Polymorphism at the Chromogranin A Locus, a Novel Determinant of Endothelial Function
From the Departments of Medicine (E.O.L., M.M., S.K., F.R., G.W., Y.C., L.T., D.W.S., S.K.M., M.G.Z., D.T.O), Psychiatry (N.J.S.), and Pharmacology (R.A.B., D.T.O.), Polymorphism Research Laboratory (D.W.S., N.J.S.), and Center for Human Genetics and Genomics (N.J.S., D.T.O.), University of California at San Diego, San Diego; the VA San Diego Healthcare System (S.K.M., D.T.O.), San Diego, Calif; and the Department of Preventive Medicine (M.C.), University of Southern California, Los Angeles.
Correspondence to Daniel T. O’Connor, MD, or Nicholas J. Schork, PhD, Department of Medicine and Center for Human Genetics and Genomics, UCSD, 9500 Gilman Dr, La Jolla, CA 92093–0838. E-mail doconnor{at}ucsd.edu or nschork@ucsd.edu
Received June 27, 2006; accepted January 19, 2007.
Background— Endothelial dysfunction predisposes to vascular injury in association with hypertension. Endothelin (ET-1) is a potent vasoactive peptide that is synthesized and released by the vascular endothelium and is a marker of endothelial function. Chromogranin A (CHGA) regulates the storage and release of catecholamines and may have direct actions on the microvasculature. CHGA, a candidate gene for intermediate phenotypes that contribute to hypertension, shows a pattern of single nucleotide polymorphism variations that alter the expression and function of this gene both in vivo and in vitro.
Methods and Results— In a study of twins (n=238 pairs), plasma ET-1 was 58±5% (P<0.0001) heritable. Plasma ET-1 was both correlated and associated with chromogranin fragment levels, and the 2 were influenced by shared genetic determination (pleiotropy [
G]; for the CHGA precursor, G=0.318±0.105; P=0.0032). We therefore hypothesized that variation in the CHGA gene may influence ET-1 secretion. Carriers of the CHGA promoter –988G, –462A, and –89A minor alleles showed significantly higher mean plasma ET-1 than their major allele homozygote counterparts (P=0.02, P=0.006, P=0.03, respectively). Analysis of a linkage disequilibrium block that spans these 3 single nucleotide polymorphisms showed a significant association between the GATACA haplotype and plasma ET-1 (P=0.0075). In cultured human umbilical vein endothelial cells, CHGA caused dose-dependent secretion of ET-1 over a brief (<1 hour) time course at relatively low concentrations of CHGA (10 to 100 nmol/L) with a threshold concentration (10 nmol/L) in the range found circulating in humans in vivo.
Conclusions— These results suggest that common, heritable variation in expression of the human CHGA gene influences endothelial ET-1 secretion in vivo, explained by a CHGA stimulus/ET-1 secretion coupling in endothelial cells in vitro. The findings document a previously unsuspected interaction between the sympathochromaffin system and the endothelium and suggest novel genetic and cell biological approaches to the prediction, diagnosis, and mechanism of endothelial dysfunction in human disease.
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