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- Title
Identification of Novel Causal Blood Biomarkers Linking Metabolically Favorable Adiposity With Type 2 Diabetes Risk.
- Authors
Pigeyre, Marie; Sjaarda, Jennifer; Shihong Mao; Chong, Michael; Hess, Sibylle; Yusuf, Salim; Gerstein, Hertzel; Paré, Guillaume; Mao, Shihong
- Abstract
<bold>Objective: </bold>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.<bold>Research Design and Methods: </bold>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).<bold>Results: </bold>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).<bold>Conclusions: </bold>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.
- Publication
Diabetes Care, 2019, Vol 42, Issue 9, p1800
- ISSN
0149-5992
- Publication type
journal article
- DOI
10.2337/dc18-2444