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Identification of Novel Causal Blood Biomarkers Linking Metabolically Favorable Adiposity With Type 2 Diabetes Risk.

Authors
  • Pigeyre, Marie1, 2, 3
  • Sjaarda, Jennifer1, 2, 3
  • Mao, Shihong1, 2, 3
  • Chong, Michael1, 2, 3
  • Hess, Sibylle4
  • Yusuf, Salim1, 5
  • Gerstein, Hertzel1, 5
  • Paré, Guillaume6, 2, 3, 5
  • 1 Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada. , (Canada)
  • 2 Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada. , (Canada)
  • 3 Department of Pathology and Molecular Medicine, Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada. , (Canada)
  • 4 R&D, Translational Medicine and Early Development, Biomarkers and Clinical Bioanalyses, Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany. , (Germany)
  • 5 Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada. , (Canada)
  • 6 Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada [email protected] , (Canada)
Type
Published Article
Journal
Diabetes care
Publication Date
Sep 01, 2019
Volume
42
Issue
9
Pages
1800–1808
Identifiers
DOI: 10.2337/dc18-2444
PMID: 31235487
Source
Medline
Language
English
License
Unknown

Abstract

Observations of a metabolically unhealthy normal weight phenotype suggest that a lack of favorable adiposity contributes to an increased risk of type 2 diabetes. We aimed to identify causal blood biomarkers linking favorable adiposity with type 2 diabetes risk for use in cardiometabolic risk assessments. A weighted polygenic risk score (PRS) underpinning metabolically favorable adiposity was validated in the UK Biobank (n = 341,872) and the Outcome Reduction With Initial Glargine Intervention (ORIGIN Trial) (n = 8,197) and tested for association with 238 blood biomarkers. Associated biomarkers were investigated for causation with type 2 diabetes risk using Mendelian randomization and for its performance in predictive models for incident major adverse cardiovascular events (MACE). Of the 238 biomarkers tested, only insulin-like growth factor-binding protein (IGFBP)-3 concentration was associated with the PRS, where a 1 unit increase in PRS predicted a 0.28-SD decrease in IGFBP-3 blood levels (P < 0.05/238). Higher IGFBP-3 levels causally increased type 2 diabetes risk (odds ratio 1.26 per 1 SD genetically determined IGFBP-3 level [95% CI 1.11-1.43]) and predicted a higher incidence of MACE (hazard ratio 1.13 per 1 SD IGFBP-3 concentration [95% CI 1.07-1.20]). Adding IGFBP-3 concentrations to the standard clinical assessment of metabolic health enhanced the prediction of incident MACE, with a net reclassification improvement of 11.5% in normal weight individuals (P = 0.004). We identified IGFBP-3 as a novel biomarker linking a lack of favorable adiposity with type 2 diabetes risk and a predictive marker for incident cardiovascular events. Using IGFBP-3 blood concentrations may improve the risk assessment of cardiometabolic diseases. © 2019 by the American Diabetes Association.

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