2. Academic Validation
  3. CELA2A mutations predispose to early-onset atherosclerosis and metabolic syndrome and affect plasma insulin and platelet activation

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

  • Nat Genet. 2019 Aug;51(8):1233-1243. doi: 10.1038/s41588-019-0470-3.
Fatemehsadat Esteghamat 1,  James S Broughton 1,  Emily Smith 1,  Rebecca Cardone 1,  Tarun Tyagi 1,  Mateus Guerra 1,  András Szabó 2,  Nelson Ugwu 1,  Mitra V Mani 1,  Bani Azari 1,  Gerald Kayingo 1,  Sunny Chung 1,  Mohsen Fathzadeh 1,  Ephraim Weiss 3,  Jeffrey Bender 1,  Shrikant Mane 4,  Richard P Lifton 5,  Adebowale Adeniran 6,  Michael H Nathanson 1,  Fred S Gorelick 1,  John Hwa 1,  Miklós Sahin-Tóth 2,  Renata Belfort-DeAguiar 1,  Richard G Kibbey 1,  Arya Mani 7 8
Affiliations

Affiliations

  • 1 Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
  • 2 Center for Exocrine Disorders, Department of Molecular and Cell Biology, Boston University Henry M. Goldman School of Dental Medicine, Boston, MA, USA.
  • 3 Department of Medicine, NYU Medical Center, New York, NY, USA.
  • 4 Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
  • 5 Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA.
  • 6 Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
  • 7 Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA. [email protected].
  • 8 Department of Genetics, Yale School of Medicine, New Haven, CT, USA. [email protected].
PMID: 31358993 DOI: 10.1038/s41588-019-0470-3
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 chymotrypsin-like Elastase family member 2A (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.

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