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

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.