Jun Li1,2, Marta Guasch-Ferré1,3, Wonil Chung2,4, Miguel Ruiz-Canela5,6,7, Estefanía Toledo5,6,7, Dolores Corella7,8, Shilpa N Bhupathiraju1,3, Deirdre K Tobias1,9, Fred K Tabung1,10, Jie Hu11, Tong Zhao4, Constance Turman2, Yen-Chen Anne Feng2,12, Clary B Clish12, Lorelei Mucci2, A Heather Eliassen2,3, Karen H Costenbader13, Elizabeth W Karlson13, Brian M Wolpin14, Alberto Ascherio1,2,3, Eric B Rimm1,2,3, JoAnn E Manson2,9,15, Lu Qi1,3,16, Miguel Ángel Martínez-González1,5,6,7, Jordi Salas-Salvadó7,17, Frank B Hu1,2,3, Liming Liang2,4. 1. Department of Nutrition, Harvard T.H. Chan School of Public Health, 655 Huntington Avenue, Building II 3rd Floor, Boston, MA 02115, USA. 2. Department of Epidemiology, Harvard T.H. Chan School of Public Health, 655 Huntington Avenue, Building II 2nd Floor, Boston, MA 02115, USA. 3. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA. 4. Department of Biostatistics, Harvard T.H. Chan School of Public Health, 655 Huntington Avenue, Building II 4th Floor, Boston, MA 02115, USA. 5. Department of Preventive Medicine and Public Health, University of Navarra, Irunlarrea 1, Pamplona 31008, Spain. 6. IdiSNA (Instituto de Investigación Sanitaria de Navarra), Edificio LUNA-Navarrabiomed, Irunlarrea 3, Pamplona 31008, Spain. 7. CIBER Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III, C/Monforte de Lemos 3-5, Pabellón 11, Madrid 28029, Spain. 8. Department of Preventive Medicine, University of Valencia, Valencia 46010, Spain. 9. Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 900 Commonwealth Avenue, Boston, MA 02115, USA. 10. Division of Medical Oncology, Department of Internal Medicine, The Ohio State University College of Medicine and Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute, 410 W 12th Ave Columbus, OH 43210, USA. 11. Division of Women's Health, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 1620 Tremont St, 3rd floor, Boston, MA 02120, USA. 12. Metabolomics Platform,Broad Institute of Harvard and MIT, 415 Main St, Cambridge, MA 02142, USA. 13. Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 75 Francis St, Boston, MA 02115, USA. 14. Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. 15. Mary Horrigan Connors Center for Women's Health and Gender Biology, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. 16. Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, 1440 Canal Street, New Orleans, LA 70112, USA. 17. Human Nutrition Unit, Faculty of Medicine and Health Sciences, Institut d'Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, C/Sant Llorenç 21, Reus 43201, Spain.
Abstract
AIMS: To investigate whether metabolic signature composed of multiple plasma metabolites can be used to characterize adherence and metabolic response to the Mediterranean diet and whether such a metabolic signature is associated with cardiovascular disease (CVD) risk. METHODS AND RESULTS: Our primary study cohort included 1859 participants from the Spanish PREDIMED trial, and validation cohorts included 6868 participants from the US Nurses' Health Studies I and II, and Health Professionals Follow-up Study (NHS/HPFS). Adherence to the Mediterranean diet was assessed using a validated Mediterranean Diet Adherence Screener (MEDAS), and plasma metabolome was profiled by liquid chromatography-tandem mass spectrometry. We observed substantial metabolomic variation with respect to Mediterranean diet adherence, with nearly one-third of the assayed metabolites significantly associated with MEDAS (false discovery rate < 0.05). Using elastic net regularized regressions, we identified a metabolic signature, comprised of 67 metabolites, robustly correlated with Mediterranean diet adherence in both PREDIMED and NHS/HPFS (r = 0.28-0.37 between the signature and MEDAS; P = 3 × 10-35 to 4 × 10-118). In multivariable Cox regressions, the metabolic signature showed a significant inverse association with CVD incidence after adjusting for known risk factors (PREDIMED: hazard ratio [HR] per standard deviation increment in the signature = 0.71, P < 0.001; NHS/HPFS: HR = 0.85, P = 0.001), and the association persisted after further adjustment for MEDAS scores (PREDIMED: HR = 0.73, P = 0.004; NHS/HPFS: HR = 0.85, P = 0.004). Further genome-wide association analysis revealed that the metabolic signature was significantly associated with genetic loci involved in fatty acids and amino acids metabolism. Mendelian randomization analyses showed that the genetically inferred metabolic signature was significantly associated with risk of coronary heart disease (CHD) and stroke (odds ratios per SD increment in the genetically inferred metabolic signature = 0.92 for CHD and 0.91 for stroke; P < 0.001). CONCLUSIONS: We identified a metabolic signature that robustly reflects adherence and metabolic response to a Mediterranean diet, and predicts future CVD risk independent of traditional risk factors, in Spanish and US cohorts. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: To investigate whether metabolic signature composed of multiple plasma metabolites can be used to characterize adherence and metabolic response to the Mediterranean diet and whether such a metabolic signature is associated with cardiovascular disease (CVD) risk. METHODS AND RESULTS: Our primary study cohort included 1859 participants from the Spanish PREDIMED trial, and validation cohorts included 6868 participants from the US Nurses' Health Studies I and II, and Health Professionals Follow-up Study (NHS/HPFS). Adherence to the Mediterranean diet was assessed using a validated Mediterranean Diet Adherence Screener (MEDAS), and plasma metabolome was profiled by liquid chromatography-tandem mass spectrometry. We observed substantial metabolomic variation with respect to Mediterranean diet adherence, with nearly one-third of the assayed metabolites significantly associated with MEDAS (false discovery rate < 0.05). Using elastic net regularized regressions, we identified a metabolic signature, comprised of 67 metabolites, robustly correlated with Mediterranean diet adherence in both PREDIMED and NHS/HPFS (r = 0.28-0.37 between the signature and MEDAS; P = 3 × 10-35 to 4 × 10-118). In multivariable Cox regressions, the metabolic signature showed a significant inverse association with CVD incidence after adjusting for known risk factors (PREDIMED: hazard ratio [HR] per standard deviation increment in the signature = 0.71, P < 0.001; NHS/HPFS: HR = 0.85, P = 0.001), and the association persisted after further adjustment for MEDAS scores (PREDIMED: HR = 0.73, P = 0.004; NHS/HPFS: HR = 0.85, P = 0.004). Further genome-wide association analysis revealed that the metabolic signature was significantly associated with genetic loci involved in fatty acids and amino acids metabolism. Mendelian randomization analyses showed that the genetically inferred metabolic signature was significantly associated with risk of coronary heart disease (CHD) and stroke (odds ratios per SD increment in the genetically inferred metabolic signature = 0.92 for CHD and 0.91 for stroke; P < 0.001). CONCLUSIONS: We identified a metabolic signature that robustly reflects adherence and metabolic response to a Mediterranean diet, and predicts future CVD risk independent of traditional risk factors, in Spanish and US cohorts. Published on behalf of the European Society of Cardiology. All rights reserved.
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