Proteomic insights into the associations between obesity, lifestyle factors, and coronary artery disease

Abstract

Background: We aimed to investigate the protein pathways linking obesity and lifestyle factors to coronary artery disease (CAD).

Methods: Summary-level genome-wide association statistics of CAD were obtained from the CARDIoGRAMplusC4D consortium (60,801 cases and 123,504 controls) and the FinnGen study (R8, 39,036 cases and 303,463 controls). Proteome-wide Mendelian randomization (MR) analysis was conducted to identify CAD-associated blood proteins, supplemented by colocalization analysis to minimize potential bias caused by linkage disequilibrium. Two-sample MR analyses were performed to assess the associations of genetically predicted four obesity measures and 13 lifestyle factors with CAD risk and CAD-associated proteins' levels. A two-step network MR analysis was conducted to explore the mediating effects of proteins in the associations between these modifiable factors and CAD.

Results: Genetically predicted levels of 41 circulating proteins were associated with CAD, and 17 of them were supported by medium to high colocalization evidence. PTK7 (protein tyrosine kinase-7), RGMB (repulsive guidance molecule BMP co-receptor B), TAGLN2 (transgelin-2), TIMP3 (tissue inhibitor of metalloproteinases 3), and VIM (vimentin) were identified as promising therapeutic targets. Several proteins were found to mediate the associations between some modifiable factors and CAD, with PCSK9, C1S, AGER (advanced glycosylation end product-specific receptor), and MST1 (mammalian Ste20-like kinase 1) exhibiting highest frequency among the mediating networks.

Conclusions: This study suggests pathways explaining the associations of obesity and lifestyle factors with CAD from alterations in blood protein levels. These insights may be used to prioritize therapeutic intervention for further study.

Keywords: Blood protein; Coronary artery disease; Lifestyle factor; Mediation; Mendelian randomization; Obesity.

Fig. 1

Schematic overview of the study design. Abbreviations: CAD, coronary artery disease; IVs, instrumental variables

Fig. 2

The associations of genetically predicted circulating proteins with CAD risk. A The volcano plot. The color of circle indicates the direction of association. B The forest plot. Odds ratios are scaled to per 1 standard deviation (SD) increase in the genetically predicted circulating proteins levels. C Colocalization analysis. Circle size indicates the colocalization p value for H4 and the color of circle indicates the classification of the evidence. Abbreviations: CAD, coronary artery disease; CI, confidence interval; OR, odds ratio

Fig. 3

Two-sample Mendelian randomization analyses for the associations of genetically predicted obesity measures and lifestyle factors with the risk of coronary artery disease. Abbreviations: BMI, body mass index; CI, confidence interval; MVPA, moderate to vigorous physical activity; OR, odds ratio; VAT, visceral adipose tissue; VPA, vigorous physical activity; WC, waist circumference; WHR, waist-to-hip ratio

Fig. 4

Two-step network mediation analysis connecting the obesity measures and lifestyle factors to coronary artery disease through the modulation of specific circulating proteins. A The overview of potential causal mediating network. B The proportion of the association between obesity and coronary artery disease mediated by circulating proteins. C The proportion of the association between of physical activity and sedentary behaviors with coronary artery disease mediated by circulating proteins. D The frequency of circulating proteins involved in the mediating network connecting modifiable factors to CAD risk. Abbreviations: BMI, body mass index; VAT, visceral adipose tissue; VPA, vigorous physical activity; WHR, waist-to-hip ratio; WC, waist circumference