197hypertension it was reasoned that genetic variation at the CHGA locus might con-
tribute to hypertension and hypertensive renal disease. Systematic polymorphism
discovery at the CHGA locus was conducted in several ethnic groups at the
University of California, San Diego (UCSD) (Wen et al. 2004 ), in an Indian popula-
tion at the Indian Institute of Technology Madras (IITM) (Allu et al. 2014 ; Sahu
et al. 2012 ), and in a Japanese population at the University of Tsukuba (Choi et al.
2015 ). Functional genetic variations at the human CHGA locus, in both the proxi-
mal promoter (Chen et al. 2008a) and 3′-UTR (Chen et al. 2008b) showed associa-
tions with essential hypertension and hypertensive end-organ damage (Salem et al.
2008 ), and non-synonymous variations within the CST and PST regions displayed
changes in potencies of these peptide hormones in regulation of catecholamine
secretion (Mahata et al. 2004 ; Sahu et al. 2012 ; Wen et al. 2004 ) and glucose uptake
(Allu et al. 2014 ; O’Connor et al. 2005 ), respectively. The above SNP-associated
findings may lead to novel approaches to the pathophysiology, diagnosis, and treat-
ments of the autonomic and metabolic dysfunctions.
2 SNPs in the Gene Regulatory Regions
2.1 Discovery of SNPs in the Regulatory Region of CHGA
The reference sequence (RefSeq) for human CHGA gene was obtained from the
UCSC Genome Browser. To probe for the SNPs at CHGA locus that might alter
its function, resequencing of CHGA was conducted at the University of California
at San Diego (UCSD) in all eight exons and adjacent intronic regions from 180
ethnically diverse (88 Asian American, 114 African American, 56 Hispanic
American and 102 European American) human subjects (2n = 360 chromosomes)
(Wen et al. 2004 ). Resequencing detected 53 SNPs and 2 single-base insertion/
deletions in 5725 bp footprint. Eight of the common SNPs (minor allele fre-
quency ≥ 5%) were found in the promoter region (G-1106A, rs9658628; A-1018T,
rs9658629; T-1014C, rs9658630; T-988G, rs9658631; G-462A, rs9658634;
T-415C, rs9658635; C-89A, rs7159323; C-57T, rs9658638) (Figs. 1 and 2 ). The
use of PHASE software for reconstructing haplotypes (variants that are inherited
together) revealed 8 haplotypes in CHGA proximal promoter: haplotype 1
(GATTGTCC), haplotype 2 (AATTGTCC), haplotype 3 (GACGATAC), haplo-
type 4 (GATTGCCC), haplotype 5 (GTTTGCCT), haplotype 6 (GACGATCC),
haplotype 7 (GATTGCCT), and haplotype 8 (GTTTGCCC) (Table 1 ). Four pro-
moter SNPs in tight LD with each other (T-1014, T-988, G-462, and C-89) were
common in the general population. Haplotype networks were constructed through
use of Arlequin to illustrate relationships among the promoter haplotypes (Fig. 3a).
Four linked SNPs appeared to divide CHGA promoter haplotypes into two
Chromogranin A SNPs and Disease Association