Pancreastatin (PST), a chromogranin A (CHGA)-derived
potent physiological dysglycemic peptide, regulates glucose/insulin
homeostasis. We have identified a non-synonymous functional PST variant (p.Gly297Ser;
rs9658664) that occurs in a large section of human populations. Association
analysis of this single nucleotide polymorphism with cardiovascular/metabolic
diseases states in Indian populations (n≈4300 subjects) displays elevated
plasma glucose, glycosylated hemoglobin, diastolic blood pressure and
catecholamines in Gly/Ser subjects as compared to wild-type individuals
(Gly/Gly). Consistently, the 297Ser allele confers an increased risk (~1.3-1.6-fold)
for type-2 diabetes/hypertension/coronary artery disease/metabolic syndrome. In
corroboration, the variant peptide (PST-297S) displays gain-of-potency in
several cellular events relevant for cardiometabolic disorders (<i>e.g.</i>, increased expression of
gluconeogenic genes, increased catecholamine secretion, greater inhibition of
insulin-stimulated glucose-uptake) than the wild-type peptide (PST-WT).
Computational docking analysis and molecular dynamics simulations show higher
affinity binding of PST-297S peptide with glucose-regulated protein 78 (GRP78)
and insulin receptor (IR) than PST-WT, providing a mechanistic basis for the
enhanced activity of the variant peptide. <i>In
vitro</i> binding assays validate these <i>in
silico</i> predictions of PST peptides binding to GRP78 and IR. In conclusion,
the PST 297Ser allele influences cardiovascular/metabolic phenotypes and
emerges as a novel risk factor for type-2 diabetes/hypertension/coronary artery
disease in human populations.