CELA2A mutations predispose to early-onset atherosclerosis and metabolic syndrome and affect plasma insulin and platelet activation

Abstract

Factors that underlie the clustering of metabolic syndrome traits are not fully known. We performed whole exome sequence analysis in kindreds with extreme phenotypes of early-onset atherosclerosis and metabolic syndrome and identified novel loss-of-function mutations in the gene encoding the pancreatic elastase CELA2A. We further show that CELA2A is a circulating enzyme that reduces platelet hyperactivation, triggers both insulin secretion and degradation, and increases insulin sensitivity. CELA2A plasma levels rise postprandially and parallel insulin levels in humans. Loss of these functions by the mutant proteins provides insight into disease mechanisms and suggests that CELA2A could be an attractive therapeutic target.

Trans-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation

“…These observations are consistent with an effect of the T2D-risk alleles on gene and protein expression in the exocrine pancreas, which subsequently influence pancreatic endocrine function. This is in line with a recent study reporting rare mutations in another protein produced by the exocrine pancreas, chymotrypsin-like elastase family member 2A, which were found to influence levels of digestive enzymes and glucagon, a glucose-raising hormone secreted from the alpha cells in the pancreatic islets (39) . Taken together, these complementary findings add to a growing body of evidence linking defects in the exocrine pancreas and T2D pathogenesis (40,41) .…”

Genetic Regulations of Thrombosis

“…However, mutant CELA2A stimulates platelet hyperactivation and aggregation. Connections between CELA2A mutations and early onset CAD were also shown in the same study [16]. Thromboprophylaxis is mandatory in all major surgeries to manage a hypercoagulable state which causes high quantities of coagulation factors with the greatest effect produced by factor VIII.…”

“…Mechanisms of stroke in PFO patients are known to have in-situ thrombus formation as a causal factor [7]. Associations with CELA2A mutations and CAD show a promising future to possible therapeutic interventions [16]. With several therapeutic methods undergoing clinical trials, there is growing enthusiasm for development of far more efficient therapeutics to combat this global burden.…”

Exocrine Pancreatic Function Modulates Plasma Metabolites Through Changes in Gut Microbiota Composition

“…The negative association of the sum of hexoses, which is basically a measure of plasma glucose metabolism, can be explained by a concomitant reduction of insulin-secretion in individuals with reduced exocrine pancreatic function. Additionally, pancreatic elastase has been shown to enter the circulation where it increases insulin secretion and insulin sensitivity ( 26 ); hence, its loss may further deteriorate glucose tolerance. Several acylcarnitine species were inversely associated with exocrine pancreatic function.…”