Tzoulaki, IITzoulakiCastagné, RRCastagnéBoulangé, CLCLBoulangéKaraman, IIKaramanChekmeneva, EEChekmenevaEvangelou, EEEvangelouEbbels, TMDTMDEbbelsKaluarachchi, MRMRKaluarachchiChadeau-Hyam, MMChadeau-HyamMosen, DDMosenDehghan, AADehghanMoayyeri, AAMoayyeriFerreira, DLSDLSFerreiraGuo, XXGuoRotter, JIJIRotterTaylor, KDKDTaylorKavousi, MMKavousiDe Vries, PSPSDe VriesLehne, BBLehneLoh, MMLohHofman, AAHofmanNicholson, JKJKNicholsonChambers, JJChambersGieger, CCGiegerHolmes, EEHolmesTracy, RRTracyKooner, JJKoonerGreenland, PPGreenlandFranco, OHOHFrancoHerrington, DDHerringtonLindon, JCJCLindonElliott, PPElliott2019-04-042019-09-07European Heart Journal, 2019, 40 (34), pp.2883-28961522-9645http://hdl.handle.net/10044/1/68576Aims: To characterise 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 (1H) nuclear magnetic resonance (NMR) spectroscopy among 3,867 participants from the Multi-Ethnic Study of Atherosclerosis (MESA), with replication among 3,569 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 NMR measured metabolites were associated with CAC and/or IMT, P =1.3x10-14 to 6.5x10-6 (discovery), P =4.2x10-14 to 4.4x10-2 (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.© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.Science & TechnologyLife Sciences & BiomedicineCardiac & Cardiovascular SystemsCardiovascular System & CardiologyAtherosclerosisMetabolomicsMetabolic phenotypingCoronary artery calciumIntima-media thicknessEpidemiological studiesWIDE ASSOCIATIONMYOCARDIAL-INFARCTIONRISK-FACTORSQUANTIFICATIONSPECTROSCOPYOBJECTIVESPREDICTIONBIOMARKERSMORTALITYRECOVERYAtherosclerosisCoronary artery calciumEpidemiological studiesIntima-media thicknessMetabolic phenotypingMetabolomics1102 Cardiorespiratory Medicine and HaematologyCardiovascular System & HematologyJournal Articlehttps://www.dx.doi.org/10.1093/eurheartj/ehz235305422RDB03 79560RO1HL133932Health Data Research UKR03CA211631MR/L01341X/1MR/L01632X/1MR/L01632X/1