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

Sun, Jiangming LU orcid ; Singh, Pratibha LU ; Österlund, Johan LU ; Orho-Melander, Marju LU ; Melander, Olle LU orcid ; Engström, Gunnar LU and Edsfeldt, Andreas LU orcid (2021) In Journal of Internal Medicine 290(4). p.855-865
Abstract

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... (More)

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.

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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Internal Medicine
volume
290
issue
4
pages
855 - 865
publisher
Wiley-Blackwell
external identifiers
  • pmid:34309093
  • scopus:85111160388
ISSN
1365-2796
DOI
10.1111/joim.13327
project
MOVING FROM BIOMARKERS TO MECHANISM ORIENTED PREVENTION OF CARDIOMETABOLIC DISEASE
language
English
LU publication?
yes
additional info
© 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.
id
cd808b22-0e2e-4371-a0b5-5dba72f05370
date added to LUP
2021-11-11 21:18:11
date last changed
2025-04-07 00:50:28
@article{cd808b22-0e2e-4371-a0b5-5dba72f05370,
  abstract     = {{<p>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).</p><p>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.</p><p>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.</p><p>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.</p>}},
  author       = {{Sun, Jiangming and Singh, Pratibha and Österlund, Johan and Orho-Melander, Marju and Melander, Olle and Engström, Gunnar and Edsfeldt, Andreas}},
  issn         = {{1365-2796}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{855--865}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Journal of Internal Medicine}},
  title        = {{Hyperglycaemia-associated Caspase-3 predicts diabetes and coronary artery disease events}},
  url          = {{http://dx.doi.org/10.1111/joim.13327}},
  doi          = {{10.1111/joim.13327}},
  volume       = {{290}},
  year         = {{2021}},
}