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triglycerides, and high- density lipoproteins) functions. The above SNP-associated
findings may thus lead to novel approaches to the pathophysiology, diagnosis, and
treatments of the autonomic and metabolic dysfunctions.
1 Introduction
The secretory proprotein Chromogranin A (CgA) is co-stored and co-released with
catecholamines from dense core vesicles in the adrenal medulla and the post-
ganglionic sympathetic axons (Bartolomucci et al. 2011 ; Winkler and Fischer-
Colbrie 1992 ). CgA gene (CHGA) is located on human chromosome 14q32, with
eight exons (encoding 439 amino acids) separated by 7 introns (Mouland et al.
1994 ). Although initially detected in chromaffin granules, this protein was subse-
quently detected ubiquitously in secretory vesicles of endocrine, neuroendocrine,
and neuronal cells (Bartolomucci et al. 2011 ; Winkler and Fischer-Colbrie 1992 ).
The circulatory concentrations of CgA show a ~7 to ~22-fold (Tramonti et al. 2001 ;
Ziegler et al. 1990 ) increase in patients with renal failure and a ~2-fold increase in
essential hypertensive subjects (O’Connor et al. 2008 ). Both stimulated and basal
CgA concentrations in the circulation are influenced by exocytotic catecholamine
secretion. CgA plays an important role in formation of catecholamine storage vesi-
cles and storage of catecholamines in chromaffin cells (Kim et al. 2001 ; Mahapatra
et al. 2005 ; Pasqua et al. 2016 ). The extracellular function of CgA includes the
generation of bioactive peptides, such as the insulin-regulatory hormone pancreast-
atin (Bandyopadhyay et al. 2015 ; Gayen et al. 2009 ; Sanchez-Margalet et al. 2010 ;
Tatemoto et al. 1986 ), the vasodilating and cardioprotective vasostatin (Aardal et al.
1993 ; Tota et al. 2008 ), the anti-adrenergic (Mahata et al. 1997 , 2003 , 2010 ), anti-
hypertensive (Mahapatra et al. 2005 ), anti-obesity (Bandyopadhyay et al. 2012 ),
pro-angiogenic (Theurl et al. 2010 ) and cardioprotective catestatin (CST) (Angelone
et al. 2008 ; Mahata et al. 2010 ), and the pro-adrenergic serpinin (Tota et al. 2012 ).
Single nucleotide polymorphisms (SNPs) refer to changes of a single DNA base,
which accounts for ~90% of human sequence variations (Collins et al. 1998 ). The
majority of SNPs are functionally neutral. SNPs in gene regulatory regions such as
promoters, enhancers, silencers, and introns affect gene expression level in an allele
specific manner (Ponomarenko et al. 2002 ). SNPs in gene coding regions (cSNPs)
may lead to changes in the function of the encoded protein (Bell et al. 1993 ; Ingram
and Stretton 1959 ).
CgA has been implicated in the pathogenesis of human essential (genetic) hyper-
tension as hypertensive subjects display heritable increase in plasma CgA (O’Connor
1985 ; Takiyyuddin et al. 1995 ). Plasma CST in monozygotic and dizygotic twins
from two continents (North America and Australia) displayed significant heritabil-
ity (O’Connor et al. 2008 ). Because of the heritable nature of CgA, CST, and
N.R. Mahapatra et al.