Functional Gly297Ser Variant of the Physiological Dysglycemic Peptide Pancreastatin is a Novel Risk Factor for Cardiometabolic Disorders

Abstract

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.