Hyperglycaemia-associated Caspase-3 predicts diabetes and coronary artery disease events

J Intern Med. 2021 Oct;290(4):855-865. doi: 10.1111/joim.13327. Epub 2021 Jul 26.


Background: Apoptosis is central in both diabetes and atherosclerosis, linked to pancreatic beta cell death and plaque progression. Circulating Caspase-3 has also been associated with diabetes and coronary calcium score. Here, we explored if soluble Caspase-3 (sCaspase-3) is associated with cardio-metabolic risk factors and predicts incidence of diabetes and coronary artery disease (CAD).

Methods: Clinical data and plasma from 4637 individuals from the Malmö Diet and Cancer cohort were studied. Plasma sCaspase-3 was measured by a Proximity Extension Assay. National registers were used to identify diabetes and CAD events during follow-up. Type 2 diabetes risk variants and expression quantitative trait loci (eQTL) for sCaspase-3 were retrieved from the DIAGRAM consortium and the Genotype-Tissue Expression project.

Results: HbA1c was the factor with the strongest association with sCaspase-3 (r = 0.18, P = 1.3x10-36 ). During follow-up 666 individuals developed diabetes and 648 individuals suffered from CAD. Increasing sCaspase-3 was associated with a higher risk of developing diabetes (hazard ratio (HR) 1.18 per 1unit; P = 7 × 10-5 ) and CAD (HR 1.2 per 1 unit, P = 1 × 10-4 ) during follow-up. A genetic variant rs60780116, located upstream of CASP3, showed strong association with type 2 diabetes (OR 1.06, 95%CI 1.04-1.07, P = 8.4 × 10-11 ). An eQTL was identified between this variant and gene expression of CASP3, where the allele positively correlated with type 2 diabetes was associated with increased CASP3 expression in blood.

Conclusions: The present study provides evidence for plasma sCaspase-3 as a marker of cardio-metabolic risk factors and as a predictor of future diabetes and CAD in a cohort without cardiovascular disease or diabetes at baseline.

Keywords: apoptosis; atherosclerosis; biomarker; diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caspase 3 / blood*
  • Coronary Artery Disease* / epidemiology
  • Diabetes Mellitus, Type 2* / complications
  • Diabetes Mellitus, Type 2* / epidemiology
  • Humans
  • Hyperglycemia*
  • Risk Factors


  • CASP3 protein, human
  • Caspase 3