Autonomic Function in Hypertension
Authors: Zhang Kuixing , Rao Fangwen , Rana Brinda K. , Gayen Jiaur R. , Calegari Federico , King Angus , Rosa Patrizia , Huttner Wieland B. , Stridsberg Mats , Mahata Manjula , Vaingankar Sucheta , Mahboubi Vafa , Salem Rany M. , Rodriguez-Flores Juan L. , Fung Maple M. , Smith Douglas W. , Schork Nicholas J. , Ziegler Michael G. , Taupenot Laurent , Mahata Sushil K. , O'Connor Daniel T. 
Published: January 2009

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.