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1 Psychiatry, University of California, San Diego, San Diego, California, United States; Polymorphism Research Laboratory, University of California, San Diego, San Diego, California, United States
2 Medicine, University of California, San Diego, San Diego, California, United States
3 Medical Sciences, Clinical Chemistry, University Hospital, Uppsala, Sweden
4 Medicine, University of California, San Diego, San Diego, California, United States; VA San Diego Healthcare System, San Diego, California, United States
5 Psychiatry, University of California, San Diego, San Diego, California, United States; Polymorphism Research Laboratory, University of California, San Diego, San Diego, California, United States; Center for Human Genetics and Genomics, University of California, San Diego, San Diego, California, United States
6 Medicine, University of California, San Diego, San Diego, California, United States; Pharmacology, University of California, San Diego, San Diego, California, United States; Center for Human Genetics and Genomics, University of California, San Diego, San Diego, California, United States
* To whom correspondence should be addressed. E-mail: doconnor{at}ucsd.edu.
Family studies have suggested a genetic contribution to variation in blood pressure, but the genes responsible have thus far eluded identification. The use of intermediate phenotypes associated with hypertension, such as chromogranin plasma concentrations, may assist the discovery of hypertension-predisposing loci. We measured the concentrations of four CHGA and CHGB peptides in 742 individuals from 235 nuclear families. The CHGA- and CHGB-derived peptides displayed significant heritability and revealed significant genetic correlations, most strikingly observed between CHGA361-372 (catestatin) and CHGB439-451. A 5cM microsatellite genome scan revealed significant and suggestive evidence for linkage on several chromosomes for three of the peptides. Subsequent bivariate linkage analysis for peptides CHGA361-372 and CHGB439-451, which showed evidence for convergent linkage peaks on chromosomes 2, 7, and 13, resulted in increased evidence for linkage to these regions, suggesting pleiotropic effects of these three loci on multiple chromogranin traits. Since CHGA itself is on chromosome 14q32, and CHGB on chromosome 20pter-p12, the pleiotropic regions on chromosomes 2, 7, and 13 must represent trans-acting QTLs coordinately affecting CHGA/CHGB biosynthesis and/or exocytotic secretion, likely by regulating efferent sympathetic outflow, a conclusion consistent with in vitro studies presented here of the dual control of both exocytosis and transcription of these peptides by secretory stimuli in chromaffin cells. The results suggest a new approach to heritable autonomic control of circulation and the genetic basis of cardiovascular diseases such as systemic hypertension.
This article has been cited by other articles:
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  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]
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 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]
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F. Rao, J. Wessel, G. Wen, L. Zhang, B. K. Rana, B. P. Kennedy, T. A. Greenwood, R. M. Salem, Y. Chen, S. Khandrika, et al. Renal Albumin Excretion: Twin Studies Identify Influences of Heredity, Environment, and Adrenergic Pathway Polymorphism Hypertension, May 1, 2007; 49(5): 1015 - 1031. [Abstract] [Full Text] [PDF]
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