• J. Intern. Med. · Oct 2021

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

    • Jiangming Sun, Pratibha Singh, Johan Österlund, Marju Orho-Melander, Olle Melander, Gunnar Engström, and Andreas Edsfeldt.
    • From the, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden.
    • J. Intern. Med. 2021 Oct 1; 290 (4): 855-865.

    BackgroundApoptosis 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).MethodsClinical 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.ResultsHbA1c 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.ConclusionsThe 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.© 2021 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.

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