Clinical Research
Hypertension
Common Functional Genetic Variants in Catecholamine Storage Vesicle Protein Promoter Motifs Interact to Trigger Systemic Hypertension

https://doi.org/10.1016/j.jacc.2009.11.064Get rights and content
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Objectives

The purpose of this study is to understand whether naturally occurring genetic variation in the promoter of chromogranin B (CHGB), a major constituent of catecholamine storage vesicles, is functional and confers risk for cardiovascular disease.

Background

CHGB plays a necessary (catalytic) role in catecholamine storage vesicle biogenesis. Previously, we found that genetic variation at CHGB influenced autonomic function, with association maximal toward the 5′ region.

Methods

Here we explored transcriptional mechanisms of such effects, characterizing 2 common variants in the proximal promoter, A-296C and A-261T, using transfection/cotransfection, electrophoretic mobility shift assay (EMSA), and chromatin immunoprecipitation (ChIP). We then tested the effects of promoter variation on cardiovascular traits.

Results

The A-296C disrupted a c-FOS motif, exhibiting differential mobility shifting to chromaffin cell nuclear proteins during EMSA, binding of endogenous c-FOS on ChIP, and differential response to exogenous c-FOS. The A-261T disrupted motifs for SRY and YY1, with similar consequences for EMSA, endogenous factor binding, and responses to exogenous factors. The 2-SNP CHGB promoter haplotypes had a profound (p = 3.16E-20) effect on blood pressure (BP) in the European ancestry population, with a rank order of CT<AA<<CA<AT on both systolic blood pressure (SBP) and diastolic blood pressure (DBP), accounting for ≈2.3% to ≈3.4% of SBP/DBP variance; the haplotype effects on BP in vivo paralleled those on promoter activity in cella. Site-by-site interactions at A-296C and A-261T yielded highly nonadditive effects on SBP/DBP. The CHGB haplotype effects on BP were also noted in an independent (African ancestry) sample. In normotensive twins, parallel effects were noted for a pre-hypertensive phenotype, BP response to environmental stress.

Conclusions

The common CHGB promoter variants A-296C and A-261T, and their consequent haplotypes, alter binding of specific transcription factors to influence gene expression in cella as well as BP in vivo. Such variation contributes substantially to risk for human hypertension. Involvement of the sex-specific factor SRY suggests a novel mechanism for development of sexual dimorphism in BP.

Key Words

hypertension
catecholamine
chromaffin
chromogranin
exocytosis

Abbreviations and Acronyms

ANOVA
analysis of variance
BMI
body mass index
BP
blood pressure
CHGB
chromogranin B
ChIP
chromatin immunoprecipitation
DBP
diastolic blood pressure
DNA
dioxyribonucleic acid
EMSA
electrophoretic mobility shift assay
HWE
Hardy-Weinberg equilibrium
LD
linkage disequilibrium
MAF
minor allele frequency
OR
odds ratio
QTL
quantitative trait locus
SBP
systolic blood pressure
SNP
single nucleotide polymorphism
SRY
sex-determining region Y
YY1
Yin-Yang 1

Cited by (0)

This study is supported by the Department of Veterans Affairs, National Institutes of Health (NIH), the NIH/National Heart, Lung, and Blood Institute (HL58120), the NIH/National Center on Minority Health and Health Disparities-sponsored (MD000220) EXPORT/Comprehensive Research Center in Health Disparities Minority Health Center, and the NIH/National Center for Research Resources-sponsored (RR00827) General Clinical Research Center.