Chromogranins from Cell Biology to Physiology and Biomedicine

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Association of PST Gly297Ser Variant with Biochemical Parameters

Because the Gly297Ser variant occurred in fairly large section of the Indian popula-
tion (~13% subjects in the IITM study) it was possible to carry out association of
various biochemical parameters with Gly297Gly and Gly297Ser genotype groups.
The Gly297Ser subjects displayed markedly elevated plasma glucose (by ~17 mg/
dl) and cholesterol (by ~12  mg/dl) compared to the Gly 297 Gly individuals. The
higher glucose level in the carriers of PST 297Ser allele was consistent with the
greater inhibition of insulin-stimulated glucose uptake and increased expression of
gluconeogenic genes (viz. glucose-6-phosphatase and phosphoenolpyruvate car-
boxykinase- 1) by the PST variant peptide as compared to WT-PST.
Interestingly, while the variants of PST in the C-terminal half of the molecule at
287 (Glu287Arg) and at 297 (Gly297Ser) enhance anti-insulin effects and elevate
plasma glucose by inhibition of glucose uptake and stimulation of gluconeogenic
effects, experimental deletion of N-terminal three amino acids Pro-Glu-Gly of
human WT-PST (CgA273–276) demonstrated opposite effects by reducing plasma glu-
cose level and hepatic gluconeogenesis in rodent obese model (Bandyopadhyay
et  al. 2015 ). Therefore, finding the variants of N-terminal end of PST in human
population may lead to discovery of a trait which would confer protection against
insulin resistance as shown in mouse obese model with the N-terminal deletion vari-
ant of PST (Bandyopadhyay et al. 2015 ).

G364-CST

Wild-type GG

(Gly/Gly)

Heterozygous

variant GA

(Gly/Ser)

Homozygous

Variant AA

(Ser/Ser)

G297-PST

Wild-type GG

(Gly/Gly)

Heterozygous

variant GA

(Gly/Ser)

Homozygous

Variant AA

(Ser/Ser)

a b

c

GESRSEALAVDGAGKPGAEEAQDPEGKGEQEHSQQKEEEEEMAVVPQGLFR SSMKLSFRARAYGFRGPGPQLRR

1 76 250 301 324 337 352 372 402 439

R253W

A256G E287K

G297S

G364S

G367V

P370L

R374Q

VS1 PST WE14 CST SPN

Fig. 4 (a) Electropherogram showing changes of G (major allele) to A (minor allele) in the PST
domain at 9358 bp. (b) Electropherogram showing changes of G (major allele) to A (minor allele)
in the CST domain at 9559 bp. (c) Schematic diagram showing nonsynonymous SNPs in the PST
and CST domains of the CHGA gene

Chromogranin A SNPs and Disease Association