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

Fatemehsadat Esteghamat, James S. Broughton, Emily Smith, Rebecca Cardone, Tarun Tyagi, Mateus Guerra, András Szabó, Nelson Ugwu, Mitra V. Mani, Bani Azari, Gerald Kayingo, Sunny Chung, Mohsen Fathzadeh, Ephraim Weiss, Jeffrey Bender, Shrikant Mane, Richard P. Lifton, Adebowale Adeniran, Michael H. Nathanson, Fred S. GorelickJohn Hwa, Miklós Sahin-Tóth, Renata Belfort-DeAguiar, Richard G. Kibbey, Arya Mani

Research output: Contribution to journalArticle

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1233-1243
Number of pages11
JournalNature Genetics
Volume51
Issue number8
DOIs
StatePublished - Aug 1 2019
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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    Esteghamat, F., Broughton, J. S., Smith, E., Cardone, R., Tyagi, T., Guerra, M., Szabó, A., Ugwu, N., Mani, M. V., Azari, B., Kayingo, G., Chung, S., Fathzadeh, M., Weiss, E., Bender, J., Mane, S., Lifton, R. P., Adeniran, A., Nathanson, M. H., ... Mani, A. (2019). CELA2A mutations predispose to early-onset atherosclerosis and metabolic syndrome and affect plasma insulin and platelet activation. Nature Genetics, 51(8), 1233-1243. https://doi.org/10.1038/s41588-019-0470-3