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Association of plasma proteomics with incident coronary heart disease in individuals with and without type 2 diabetes: results from the population-based KORA study - PubMed

  • ️Mon Jan 01 2024

Association of plasma proteomics with incident coronary heart disease in individuals with and without type 2 diabetes: results from the population-based KORA study

Hong Luo et al. Cardiovasc Diabetol. 2024.

Abstract

Background: Coronary heart disease (CHD) is a major global health concern, especially among individuals with type 2 diabetes (T2D). Given the crucial role of proteins in various biological processes, this study aimed to elucidate the aetiological role and predictive performance of protein biomarkers on incident CHD in individuals with and without T2D.

Methods: The discovery cohort included 1492 participants from the Cooperative Health Research in the Region of Augsburg (KORA) S4 study with 147 incident CHD cases (45 vs. 102 cases in the group with T2D and without T2D, respectively) during 15.6 years of follow-up. The validation cohort included 888 participants from the KORA-Age1 study with 70 incident CHD cases (19 vs. 51 cases in the group with T2D and without T2D, respectively) during 6.9 years of follow-up. We measured 233 plasma proteins related to cardiovascular disease and inflammation using proximity extension assay technology. Associations of proteins with incident CHD were assessed using Cox regression and Mendelian randomization (MR) analysis. Predictive models were developed using priority-Lasso and were evaluated on top of Framingham risk score variables using the C-index, category-free net reclassification index (cfNRI), and relative integrated discrimination improvement (IDI).

Results: We identified two proteins associated with incident CHD in individuals with and 29 in those without baseline T2D, respectively. Six of these proteins are novel candidates for incident CHD. MR suggested a potential causal role for hepatocyte growth factor in CHD development. The developed four-protein-enriched model for individuals with baseline T2D (ΔC-index: 0.017; cfNRI: 0.253; IDI: 0.051) and the 12-protein-enriched model for individuals without baseline T2D (ΔC-index: 0.054; cfNRI: 0.462; IDI: 0.024) consistently improved CHD prediction in the discovery cohort, while in the validation cohort, significant improvements were only observed for selected performance measures (with T2D: cfNRI: 0.633; without T2D: ΔC-index: 0.038; cfNRI: 0.465).

Conclusions: This study identified novel protein biomarkers associated with incident CHD in individuals with and without T2D and reaffirmed previously reported protein candidates. These findings enhance our understanding of CHD pathophysiology and provide potential targets for prevention and treatment.

Keywords: Cohort study; Coronary heart disease; Mendelian randomization; Proteomics; Type 2 diabetes.

© 2024. The Author(s).

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1

Analysis strategy. CHD: coronary heart disease; C-index: concordance index; FDR: false discovery rate; IDI: integrated discrimination improvement; IV: instrumental variable; NRI: net reclassification index; SNP: single nucleotide polymorphism; T2D: type 2 diabetes

Fig. 2
Fig. 2

Association of 233 proteins with incident coronary heart disease in individuals (a) with type 2 diabetes (T2D), and (b) without T2D at baseline. Hazard ratios have been calculated per 1 SD increase in normalized protein expression values on a log2 scale. Effect estimates and p-values were derived from Cox regression analysis adjusted for age, sex, total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, antihypertensive medication use, and current smoking (Model 1). The red triangles represent the validated proteins in the validation study, identified using the false discovery rate (p_FDR < 0.05). The black dots represent significant proteins at the uncorrected level (p < 0.05) in the discovery study which were not replicated in the validation study. (c) Forest plot of validated proteins in KORA S4 and KORA-Age1 cohorts stratified by T2D status

Fig. 3
Fig. 3

Mendelian Randomization analysis results of the validated proteins as exposure and coronary heart disease as outcome.* The protein remained significant after correction for multiple testing using the Bonferroni method (psignificant = 0.05/29 = 0.00172)

Fig. 4
Fig. 4

Protein-protein interaction network of validated coronary heart disease-associated proteins among participants without type 2 diabetes at baseline. The edges between protein nodes represent the interaction score between the proteins from the STRING database considering all types of evidence. Only edges featuring interaction scores > 0.15 are displayed. The thickness of edges corresponds to the strength of data support. Node color signifies the Reactome pathway the protein is associated with. The 5 most enriched Reactome pathways are displayed

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