Autonomic Function in Hypertension

Abstract

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 (Ϸ6 kbp footprint spanning the promoter, 5 exons, exon/intron borders, untranslated regions) in 160 subjects (2nϭ320 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 Ϸ14 kbp locus. Sliding-window haplotype analysis indicated BP associations peaking in the 5Ј/promoter region, most prominent in men, and a peak effect in the proximal promoter at variant A-261T (AϾT), accounting for Ϸ8/Ϸ6 mm Hg 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 (Ϫ/Ϫ) ablation of the mouse CHGB gene; knockout mice displayed substantially increased BP, by Ϸ20/Ϸ18 mm Hg, 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.

Chromogranin B: intra‐ and extra‐cellular mechanisms to regulate catecholamine storage and release, in catecholaminergic cells and organisms

“…CHGB knockout mice were generated from mouse embryonic stem cells by homologous recombination, as previously described ( 18,22 ). The effect of CHGB knockout on dense-core secretory granule abundance was examined by transmission electron microscopy (EM).…”

“…Therefore CHGB gives rise to early, pathogenic “intermediate phenotypes” ( 17 ) for exploration of sympathoadrenal activity in human essential hypertension. Indeed, we reported that two common CHGB promoter SNPs, A-296C (rs236140) and A-261T (rs236141), are strongly associated with hypertension in the population ( 18,19 ), while in CHGB knockout ( CHGB[ −/−]) mice, we observed substantial elevations in both SBP and DBP ( 18 ). In this report, we have studied how CHGB quantitative variation (both over- and under-expression) affects not only secretory granulogenesis, but also catecholamine uptake, storage, and exocytotic release.…”

Chromogranin B Gene Ablation Reduces the Catecholamine Cargo and Decelerates Exocytosis in Chromaffin Secretory Vesicles

“…Several functions have been proposed for CgB, including the following: granule biogenesis and sorting (Natori and Huttner, 1996;Huh et al, 2003), Ca 2ϩ sequestration and release (Yoo and Jeon, 2000), and a source of bioactive peptides (Strub et al, 1995;Winkler et al, 1998;Taupenot et al, 2003). Chromogranin B has recently grown in importance after the unexpected finding associating it with some classes of human diseases, such as schizophrenia (Landén et al, 1999;Marksteiner et al, 2000), Alzheimer's disease (Marksteiner et al, 2000), and hypertension (Zhang et al, 2009), as well as for its possible involvement in diabetes, which has been observed in mice (Obermüller et al, submitted).…”

Gender-Specific Associations betweenCHGBGenetic Variants and Schizophrenia in a Korean Population

“…Including the previously reported phospho-variant rs910122,31 different genetic effects of CHGB variants on the risk of schizophrenia were also observed depending on sex in this study (Table 2). Furthermore, considering that CHGB rs236141 with a nominal association with schizophrenia ( p =0.05 and OR=0.63 in male subjects) has been found to be a gender-specific marker for blood pressure disease, 39 our findings suggest that CHGB could be a gender-specific marker for schizophrenia development.…”