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Original Articles

Autonomic Function in Hypertension

Role of Genetic Variation at the Catecholamine Storage Vesicle Protein Chromogranin B

Kuixing Zhang, MD, PhD; Fangwen Rao, MD; Brinda K. Rana, PhD; Jiaur R. Gayen, PhD; Federico Calegari, PhD; Angus King, PhD; Patrizia Rosa, PhD; Wieland B. Huttner, MD; Mats Stridsberg, PhD; Manjula Mahata, PhD; Sucheta Vaingankar, PhD; Vafa Mahboubi, PhD; Rany M. Salem, MPH; Juan L. Rodriguez-Flores, MS; Maple M. Fung, MD; Douglas W. Smith, PhD; Nicholas J. Schork, PhD; Michael G. Ziegler, MD; Laurent Taupenot, PhD; Sushil K. Mahata, PhD and Daniel T. O'Connor, MD

From the Departments of Medicine, Pharmacology, and the Center for Human Genetics and Genomics (K.Z., F.R., B.K.R., J.R.G., M.M., S.V., V.M., R.M.S., J.L.R.-F., M.M.F., D.W.S., N.J.S., M.G.Z., L.T., S.K.M., D.T.O.), University of California and the VA San Diego Healthcare System, San Diego, Calif; Max Planck Institute of Molecular Cell Biology and Genetics (F.C., A.K., W.B.H.), Dresden, Germany; Department of Medical Sciences (M.S.), Uppsala University, Uppsala, Sweden; and Department of Medical Pharmacology (P.R.), CNR Institute of Neuroscience, Cellular and Molecular Pharmacology, University of Milan, Italy.

Correspondence to Sushil K. Mahata, PhD or Daniel T. O'Connor, MD, Department of Medicine and CHGG, UCSD School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0838. E-mail: smahata{at}ucsd.edu or doconnor@ucsd.edu

Received April 15, 2008; accepted November 20, 2008.

Background— Hypertension is a complex trait, with deranged autonomic control of circulation. Chromogranin B (CHGB) is the most abundant core protein in human catecholamine secretory vesicles, playing an important role in their biogenesis. Does common interindividual variation at the CHGB locus contribute to phenotypic variation in CHGB and catecholamine secretion, autonomic stability of circulation, or blood pressure (BP) in the population?

Methods and Results— To probe interindividual variability in CHGB, we systematically studied polymorphism across the locus by resequencing CHGB (6 kbp footprint spanning the promoter, 5 exons, exon/intron borders, untranslated regions) in 160 subjects (2n=320 chromosomes) of diverse biogeographic ancestries. We identified 53 single-nucleotide polymorphisms, of which 22 were common. We then studied 1182 subjects drawn from the most extreme BP values in the population (highest and lowest 5th percentiles), typing 4 common polymorphisms spanning the 14 kbp locus. Sliding-window haplotype analysis indicated BP associations peaking in the 5'/promoter region, most prominent in men, and a peak effect in the proximal promoter at variant A-261T (A>T), accounting for 8/6 mmHg BP in males. The promoter allele (A-261) that was a predictor of higher diastolic BP and systolic BP was also associated with lower circulating/plasma CHGB concentration (CHGB_{439 to 451} epitope) in twin pairs. In twins, the same CHGB variants that were predictors of lower basal CHGB secretion were also associated with exaggerated catecholamine secretion and BP response to environmental (cold) stress; likewise, women displayed increased plasma CHGB_{439 to 451} but decreased catecholamine secretion as well as BP response to environmental stress. The effect of A-261T on CHGB expression was confirmed in chromaffin cells by site-directed mutagenesis on transfected CHGB promoter/luciferase reporter activity, and the allelic effects of A-261T on gene expression were directionally coordinate in cella and in vivo. To confirm these clinical associations experimentally, we undertook targeted homozygous (–/–) ablation of the mouse CHGB gene; knockout mice displayed substantially increased BP, by 20/18 mmHg, confirming the mechanistic basis of our findings in humans.

Conclusion— Common genetic variation at the CHGB locus, especially in the proximal promoter, influences CHGB expression and later catecholamine secretion and the early heritable responses to environmental stress, eventuating in changes in resting/basal BP in the population. Both the early (gene expression) and late (population BP) consequences of CHGB variation are sex dependent. These results point to new molecular strategies for probing autonomic control of circulation and, ultimately, the susceptibility to and pathogenesis of cardiovascular disease states such as hypertension.

Key Words: genetics • hypertension • gene expression • catecholamine • epidemiology • nervous system • autonomic

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