Genetic variation within a metabolic motif in the chromogranin A promoter: Pleiotropic influence on cardiometabolic risk traits in twins

Rao, Fangwen, Chiron, Stephane, Wei, Zhiyun, Fung, Maple M., Chen, Yuqing, Wen, Gen, Khandrika, Srikrishna, Ziegler, Michael G., Benyamin, Beben, Montgomery, Grant, Whitfield, John B., Martin, Nicholas G., Waalen, Jill, Hamiltoni, Bruce A., Mahata, Sushil K. and O'Connor, Daniel T. (2012) Genetic variation within a metabolic motif in the chromogranin A promoter: Pleiotropic influence on cardiometabolic risk traits in twins. American Journal of Hypertension, 25 1: 29-40. doi:10.1038/ajh.2011.163


Author Rao, Fangwen
Chiron, Stephane
Wei, Zhiyun
Fung, Maple M.
Chen, Yuqing
Wen, Gen
Khandrika, Srikrishna
Ziegler, Michael G.
Benyamin, Beben
Montgomery, Grant
Whitfield, John B.
Martin, Nicholas G.
Waalen, Jill
Hamiltoni, Bruce A.
Mahata, Sushil K.
O'Connor, Daniel T.
Title Genetic variation within a metabolic motif in the chromogranin A promoter: Pleiotropic influence on cardiometabolic risk traits in twins
Journal name American Journal of Hypertension   Check publisher's open access policy
ISSN 0895-7061
1941-7225
Publication date 2012-01
Sub-type Article (original research)
DOI 10.1038/ajh.2011.163
Volume 25
Issue 1
Start page 29
End page 40
Total pages 12
Place of publication New York, NY, United States
Publisher Nature Publishing Group
Collection year 2013
Language eng
Formatted abstract
Background
The cardiometabolic syndrome comprised of multiple correlated traits, but its origin is incompletely understood. Chromogranin A (CHGA) is required for formation of the catecholamine secretory pathway in sympathochromaffin cells. In twin pair studies, we found that CHGA traits aggregated with body mass index (BMI), as well as its biochemical determinant leptin.

Methods

Here we used the twin method to probe the role of heredity in generating such risk traits, and then investigated the role of risk-trait-associated CHGA promoter genetic variation in transfected chromaffin cells. Trait heritability (h2) and shared genetic determination among traits (pleiotropy, genetic covariance, ρG) were estimated by variance components in twin pairs.

Results

CHGA, BMI, and leptin each displayed substantial h2, and the traits also aggregated with several features of the metabolic syndrome (e.g., insulin resistance, blood pressure (BP), hypertension, catecholamines, and C-reactive protein (CRP)). Twin studies demonstrated genetic covariance (pleiotropy, ρG) for CHGA, BMI, and leptin with other metabolic traits (insulin resistance, BP, and CRP). We therefore investigated the CHGA locus for mechanisms of codetermination with such metabolic traits. A common functional variant in the human CHGA promoter (G-462A, rs9658634, minor allele frequency ~21%) was associated with leptin and CRP secretion, as well as BMI, especially in women; marker-on-trait effects on BMI were replicated across twin populations on two continents. In CHGA promoter/luciferase reporter plasmids transfected into chromaffin cells, G-462A alleles differed markedly in reporter expression. The G-462A variant disrupted predicted transcriptional control by a PPARγ/RXRα motif and costimulation by PPARγ/RXRα and their cognate ligands, differentially activated the two alleles. During chromatin immunoprecipitation, endogenous PPARγ bound the motif.

Conclusions

Multiple features of the metabolic syndrome are thus under joint (pleiotropic) genetic determination, with CHGA as one such contributory locus: a common polymorphism in the promoter (G-462A) of CHGA predicts such heritable metabolic traits as BMI and leptin. CHGA promoter variant G-462A was not only associated with such metabolic traits but also disrupted a PPARγ/RXRα motif and responded differentially to characteristic trans-activators of that motif. The results suggest novel links between the catecholaminergic system and risk for the metabolic syndrome as well as systemic hypertension.
Keyword Adrenal
Blood pressure
BMI
C-reactive protein
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Non HERDC
 
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