Metabolites Associated With the Risk of Incident Venous Thromboembolism: A Metabolomic Analysis

Abstract

Background Venous thromboembolism ( VTE ) is a complex thrombotic disorder that constitutes a major source of mortality and morbidity. To improve understanding of the cause of VTE , we conducted a metabolomic analysis in a case‐control study including 240 incident VTE cases and 6963 controls nested within 3 large prospective population‐based cohorts, the Nurses’ Health Study, the Nurses’ Health Study II , and the Health Professionals Follow‐Up Study. Methods and Results For each individual, we measured 211 metabolites and collected detailed information on lifestyle factors. We performed logistic regression and enrichment analysis to identify metabolites and biological categories associated with incident VTE risk, accounting for key confounders, such as age, sex, smoking, alcohol consumption, body mass index, and comorbid diseases (eg, cancers). We performed analyses of all VTEs and separate analyses of pulmonary embolism. Using the basic model controlling for age, sex, and primary disease, we identified 60 nominally significant VTE ‐ or pulmonary embolism–associated metabolites ( P <0.05). These metabolites were enriched for diacylglycerols ( P permutation <0.05). However, after controlling for multiple testing, only 1 metabolite (C5 carnitine; odds ratio, 1.25; 95% confidence interval, 1.10–1.41; P corrected =0.03) remained significantly associated with VTE . After further adjustment for body mass index, no metabolites were significantly associated with disease after accounting for multiple testing, and no metabolite classes were enriched for nominally significant associations. Conclusions Although our findings suggest that circulating metabolites may influence the risk of incident VTE , the associations we observed were confounded by body mass index. Larger studies involving additional individuals and with broader metabolomics coverage are needed to confirm our findings.

Metabolomics Analytics Workflow for Epidemiological Research: Perspectives from the Consortium of Metabolomics Studies (COMETS)

“…Given that application of metabolomics technology to epidemiological studies is an emerging field, we conducted a survey of participating COMETS cohort representatives to gain insights into the strategies and procedures used for analyzing metabolomics data, including data pre-processing, analysis, and reporting of results. With a range of experience levels analyzing metabolomics data, participating COMETS cohorts have analyzed and published on both targeted and untargeted metabolomics data from a variety of study designs in relation to disease risk factors [8,18,19,20,21,22,23,24,25,26,27] and many disease outcomes, predominantly cancer, CVD, and diabetes [28,29,30,31,32,33,34,35,36,37,38,39,40]. However, there was little consensus on approaches to data pre-processing, statistical analysis or reporting of results, which is echoed in the broader metabolomics community [13].…”

Metabolomic Profile in Venous Thromboembolism (VTE)

“…Significantly diminished levels of many long-chain ACs in VTE patients (values below the 20th percentile of controls) could suggest that some patients had the deficiency of plasma anticoagulant lipids resulting from a shortage of multiple long-chain ACs. Similarly, Jiang et al [ 1 ] who studied 240 incident VTE cases (including 125 incident PE cases) and 6963 controls revealed that C5 carnitine was significantly associated with incident VTE. They demonstrated that diacylglycerols were increased in both VTE and PE patients, but their exact role in the pathomechanism of VTE is unknown.…”

“…The study of metabolites can reveal the physiologic state before disease onset as well as the complex interplay between genes, environmental risk factors, and VTE [ 1 ]. This technique has been used in the study of cardiovascular disease risk, however, there are just a few publications concerning metabolic profiling in VTE.…”

“…Venous thromboembolism (VTE) is a condition comprising deep venous thrombosis (DVT) and pulmonary embolism (PE) [ 1 ]. In the United States, VTE affects ~300,000–600,000 individuals and it is responsible for approximately 100,000 deaths per year [ 2 ].…”

Predicting the Risk of Recurrent Venous Thromboembolism: Current Challenges and Future Opportunities

“…Uncovering these alterations in the plasma and platelet lipidome in arterial thrombosis has further highlighted the importance of lipids in thrombosis, and it is hoped that novel approaches may also show promise in the prediction of venous thrombosis. In this regard, recent studies suggest that several lipid and metabolites pathways are altered in acute VTE [149][150][151]. Deguchi et al have demonstrated an association between low plasma acylcarnitine levels and venous thrombosis and determined that acylcarnitines have anticoagulant activity by way of their ability to bind to, and inhibit, factor Xa, establishing a potential factor in the pathogenesis of venous thrombosis [144].…”