CELA2A mutations predispose to early-onset atherosclerosis and metabolic syndrome and affect plasma insulin and platelet activation
| Autor: | Richard G. Kibbey, John Hwa, Michael H. Nathanson, Arya Mani, James S. Broughton, Ephraim N. Weiss, Adebowale J. Adeniran, Mateus T. Guerra, Richard P. Lifton, Miklós Sahin-Tóth, Fred S. Gorelick, Tarun Tyagi, Mitra Mani, Shrikant Mane, Bani Azari, Jeffrey R. Bender, Nelson Ugwu, Gerald Kayingo, Emily Smith, Mohsen Fathzadeh, Renata Belfort-DeAguiar, Sunny Chung, Rebecca L. Cardone, András Szabó, Fatemehsadat Esteghamat |
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| Rok vydání: | 2019 |
| Předmět: |
Adult
Male medicine.medical_specialty medicine.medical_treatment Biology Linkage Disequilibrium Article Islets of Langerhans 03 medical and health sciences 0302 clinical medicine Internal medicine Genetics medicine Humans Insulin Genetic Predisposition to Disease Platelet activation Age of Onset Pancreatic elastase Exome sequencing 030304 developmental biology Metabolic Syndrome chemistry.chemical_classification 0303 health sciences Pancreatic Elastase Serine Endopeptidases Elastase Middle Aged Atherosclerosis Platelet Activation medicine.disease Phenotype Pedigree Endocrinology Enzyme chemistry Case-Control Studies Mutation Female Insulin Resistance Metabolic syndrome 030217 neurology & neurosurgery |
| Zdroj: | Nature genetics |
| ISSN: | 1546-1718 1061-4036 |
| Popis: | 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. Editorial summary: Exome sequencing identifies loss-of-function CELA2A mutations in families with early-onset atherosclerosis and metabolic syndrome. Functional studies show that CELA2A is a circulating enzyme that reduces platelet activation, triggers insulin secretion and degradation, and increases insulin sensitivity. |
| Databáze: | OpenAIRE |
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