204
ESRD cases, than ~15% of control subjects, implicating association of TC haplo-
type with ESRD (Salem et al. 2008 ). The above findings indicate that common vari-
ants in CHGA are associated with an increased risk for hypertensive ESRD in
blacks. Since CgA induces secretion of endothelin-1 from glomerular endothelial
cells and TGF-β1 from mesangial cells cocultured with glomerular endothelial
cells, it was believed that CgA acted through the glomerular endothelium to regulate
renal function.
4 SNPs in Gene Coding Regions
4.1 Functional Genetic Polymorphisms in the Pancreastatin
(PST) Domain
4.1.1 Discovery of PST SNPs
The initial discovery of SNPs on PST domain was made at UCSD after resequenc-
ing 180 individuals from ethnic groups as described above (Wen et al. 2004 ). A
UCSD study revealed three naturally occurring non-synonymous (amino acid
replacement) variants in the PST region: Arg253Trp (rs9658662) (two heterozy-
gotes; minor allele frequency, 0.6%), Ala256Gly (rs9658663) (two heterozygotes
and one homozygote; minor allele frequency, 1.1%), and Gly297Ser (rs9658664)
(two heterozygotes; minor allele frequency, 0.6%) (Wen et al. 2004 ). A subse-
quent study on PST SNP discovery at the Indian Institute of Technology Madras
(IITM) resequenced CHGA in an Indian cohort of 410 individuals (= 820 chromo-
somes), which revealed three non-synonymous SNPs: Arg253Trp (minor allele
frequency, 0.24%), Glu287Arg (minor allele frequency, 0.12%), and Gly297Ser
(minor allele frequency, 6.7%, ~10-fold higher than the UCSD population) (Allu
et al. 2014 ) (Fig. 4a, c). While Ala256Gly was not detected in the Indian cohort,
the study discovered the novel Glu287Arg variant. Likewise, Gly297Ser variant
was not detected in a Japanese cohort of 343 individuals (143 men and 200
women) (Choi et al. 2015 ).
4.1.2 Functional Consequences of PST SNPs
Effects of PST Variants on Glucose Homeostasis
Both UCSD and IITM studies showed greater inhibition of insulin-stimulated glu-
cose uptake by Gly297Ser variant followed by Glu287Arg variant compared to
WT-PST (O’Connor et al. 2005 ). The IITM study also revealed increased expres-
sion of gluconeogenic genes by PST variant as compared to WT-PST with compa-
rable potencies by Glu287Arg and Gly297Ser variants (Allu et al. 2014 ).
N.R. Mahapatra et al.