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

Details

• Alternative Title:
  Nat Genet
• Personal Author:
  Esteghamat, Fatemehsadat ; Broughton, James S. ; Smith, Emily ; Cardone, Rebecca ; Tyagi, Tarun ; Guerra, Mateus ; Szabó, András ; Ugwu, Nelson ; Mani, Mitra V. ; Azari, Bani ; Kayingo, Gerald ; Chung, Sunny ; Fathzadeh, Mohsen ; Weiss, Ephraim ; Bender, Jeffrey ; Mane, Shrikant ; Lifton, Richard P. ; Adeniran, Adebowale ; Nathanson, Michael H. ; Gorelick, Fred S. ; Hwa, John ; Sahin-Tóth, Miklós ; Belfort-DeAguiar, Renata ; Kibbey, Richard G. ; Mani, Arya
• Description:
  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.
• Subjects:
  Article
• Source:
  Nat Genet. 51(8):1233-1243
• Pubmed ID:
  31358993
• Pubmed Central ID:
  PMC6675645
• Document Type:
  Journal Article
• Funding:
  T32 DK007356/NIDDK NIH HHS/National Institute of Diabetes and Digestive and Kidney Diseases/United States ; R35 HL135767/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United States ; S10 OD018034/ODCDC CDC HHS/Office of the Director/United States ; U54 HG006504/NHGRI NIH HHS/National Human Genome Research Institute/United States ; P30 DK034989/NIDDK NIH HHS/National Institute of Diabetes and Digestive and Kidney Diseases/United States ; R01 DK095753/NIDDK NIH HHS/National Institute of Diabetes and Digestive and Kidney Diseases/United States
• Volume:
  51
• Issue:
  8
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:09d445ce7808f5dd386d3b356dea98cb21f0e972184cc5885494f31c2d6ab1d1
• Download URL:
  https://stacks.cdc.gov/view/cdc/80401/cdc_80401_DS1.pdf
• File Type:
  [PDF - 2.65 MB ]