Integrative Metabolomics Differentiate Coronary Artery Disease, Peripheral Artery Disease, and Venous Thromboembolism Risks

Abstract

Background: Arterial and venous cardiovascular conditions, such as coronary artery disease (CAD), peripheral artery disease (PAD), and venous thromboembolism (VTE), are genetically correlated. Interrogating underlying mechanisms may shed light on disease mechanisms. In this study, we aimed to identify (1) epidemiological and (2) causal, genetic relationships between metabolites and CAD, PAD, and VTE.

Methods: We used metabolomic data from 95 402 individuals in the UK Biobank, excluding individuals with prevalent cardiovascular disease. Cox proportional-hazards models estimated the associations of 249 metabolites with incident disease. Bidirectional 2-sample Mendelian randomization (MR) estimated the causal effects between metabolites and outcomes using genome-wide association summary statistics for metabolites (n=118 466 from the UK Biobank), CAD (n=184 305 from CARDIoGRAMplusC4D 2015), PAD (n=243 060 from the Million Veterans Project), and VTE (n=650 119 from the Million Veterans Project). Multivariable MR was performed in subsequent analyses.

Results: We found that 196, 115, and 74 metabolites were associated (P<0.001) with CAD, PAD, and VTE, respectively. Further interrogation of these metabolites with MR revealed 94, 34, and 9 metabolites with potentially causal effects on CAD, PAD, and VTE, respectively. There were 21 metabolites common to CAD and PAD and 4 common to PAD and VTE. Many putatively causal metabolites included lipoprotein traits with heterogeneity across different sizes and lipid subfractions. Small VLDL (very-low-density lipoprotein) particles increased the risk for CAD while large VLDL particles decreased the risk for VTE. We identified opposing directions of CAD and PAD effects for cholesterol and triglyceride concentrations within HDLs (high-density lipoproteins). Subsequent sensitivity analyses including multivariable MR revealed several metabolites with robust, potentially causal effects of VLDL particles on CAD.

Conclusions: While common vascular conditions are associated with overlapping metabolomic profiles, MR prioritized the role of specific lipoprotein species for potential pharmacological targets to maximize benefits in both arterial and venous beds.

Keywords: Mendelian randomization; lipoproteins; vascular disease.

Figure 1.

Study schematic. A, Epidemiological association analysis was performed using individual-level data from the UK Biobank, regressing incident coronary artery disease (CAD)/peripheral artery disease (PAD)/venous thromboembolism (VTE) events on metabolite levels. B, Bidirectional Mendelian randomization analysis was performed using metabolite summary statistics from the UK Biobank as exposures and CAD/PAD/VTE summary statistics from either CARDIoGRAMplusC4D 2015 or Million Veterans Program (MVP) as outcomes and (C) vice versa. D, Taking only the metabolite with significant causal effects from B, multivariable Mendelian randomization analysis was performed using metabolite summary statistics from the UK Biobank as exposures and CAD/PAD/VTE summary statistics from either CARDIoGRAMplusC4D 2015 or MVP as outcomes. GWAS indicates genome-wide association study.

Figure 2.

Venn diagram of metabolites with shared causal effects between coronary artery disease (CAD), peripheral artery disease (PAD), and venous thromboembolism (VTE) estimated using bidirectional Mendelian randomization. Bidirectional, inverse-variance weighted 2-sample Mendelian randomization using summary statistics from the UK Biobank and CARDIoGRAMplusC4D 2015 or Million Veterans Program was performed to estimate causal effects of metabolites on CAD, PAD, and VTE (P<0.001). Metabolites that had causal effects on >1 cardiovascular phenotype but demonstrated an opposite direction of effect were indicated with white asterisks. Metabolites that maintained significant associations after applying a Bonferroni-corrected P value threshold (P<0.0002) are bolded.

Figure 3.

Forest plots of estimated epidemiological associations and causal effects of lipoprotein particles and cardiovascular outcomes. Points are effect estimates per SD change of metabolites, and error bars represent 95% CIs. Transparent bars represent associations that were not significant based on a multiple testing correction of P<0.001. C indicates cholesterol content; CAD, coronary artery disease; HDL, high-density lipoprotein; L, lipid content; LDL, low-density lipoprotein; PAD, peripheral artery disease; TG, triglyceride content; VLDL, very-low-density lipoprotein; and VTE, venous thromboembolism.