@article{Tzoulaki2019, abstract = {Abstract Aims To characterize serum metabolic signatures associated with atherosclerosis in the coronary or carotid arteries and subsequently their association with incident cardiovascular disease (CVD). Methods and results We used untargeted one-dimensional (1D) serum metabolic profiling by proton nuclear magnetic resonance spectroscopy (1H NMR) among 3867 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), with replication among 3569 participants from the Rotterdam and LOLIPOP studies. Atherosclerosis was assessed by coronary artery calcium (CAC) and carotid intima-media thickness (IMT). We used multivariable linear regression to evaluate associations between NMR features and atherosclerosis accounting for multiplicity of comparisons. We then examined associations between metabolites associated with atherosclerosis and incident CVD available in MESA and Rotterdam and explored molecular networks through bioinformatics analyses. Overall, 30 1H NMR measured metabolites were associated with CAC and/or IMT, P = 1.3 × 10−14 to 1.0 × 10−6 (discovery) and P = 5.6 × 10−10 to 1.1 × 10−2 (replication). These associations were substantially attenuated after adjustment for conventional cardiovascular risk factors. Metabolites associated with atherosclerosis revealed disturbances in lipid and carbohydrate metabolism, branched chain, and aromatic amino acid metabolism, as well as oxidative stress and inflammatory pathways. Analyses of incident CVD events showed inverse associations with creatine, creatinine, and phenylalanine, and direct associations with mannose, acetaminophen-glucuronide, and lactate as well as apolipoprotein B (P < 0.05). Conclusion Metabolites associated with atherosclerosis were largely consistent between the two vascular beds (coronary and carotid arteries) and predominantly tag pathways that overlap with the known cardiovascular risk factors. We present an integrated systems network that highlights a series of inter-connected pathways underlying atherosclerosis. }, author = {Tzoulaki, Ioanna and Castagné, Raphaële and Boulangé, Claire L. and Karaman, Ibrahim and Chekmeneva, Elena and Evangelou, Evangelos and Ebbels, Timothy M. D. and Kaluarachchi, Manuja R. and Chadeau-Hyam, Marc and Mosen, David and Dehghan, Abbas and Moayyeri, Alireza and Ferreira, Diana L. Santos and de Vries, Paul S. and Guo, Xiuqing and Rotter, Jerome I. and Taylor, Kent D. and Lehne, Benjamin and Santos Ferreira, Diana L. and Kavousi, Maryam and Loh, Marie and Hofman, Albert and Nicholson, Jeremy K. and Chambers, John and Gieger, Christian and Holmes, Elaine and Tracy, Russell and Kooner, Jaspal and Greenland, Philip and Franco, Oscar H. and Herrington, David and Lindon, John C. and Elliott, Paul}, doi = {10.1093/eurheartj/ehz235}, journal = {European Heart Journal}, month = {may}, pages = {2883-2896}, title = {Serum metabolic signatures of coronary and carotid atherosclerosis and subsequent cardiovascular disease}, url = {https://academic.oup.com/eurheartj/article-pdf/40/34/2883/46639083/ehz235.pdf}, volume = {40}, year = {2019} }