TY - JOUR

T1 - The Mediterranean diet, plasma metabolome, and cardiovascular disease risk

AU - Li, Jun

AU - Guasch-Ferré, Marta

AU - Chung, Wonil

AU - Ruiz-Canela, Miguel

AU - Toledo, Estefaniá

AU - Corella, Dolores

AU - Bhupathiraju, Shilpa N.

AU - Tobias, Deirdre K.

AU - Tabung, Fred K.

AU - Hu, Jie

AU - Zhao, Tong

AU - Turman, Constance

AU - Feng, Yen Chen Anne

AU - Clish, Clary B.

AU - Mucci, Lorelei

AU - Eliassen, A. Heather

AU - Costenbader, Karen H.

AU - Karlson, Elizabeth W.

AU - Wolpin, Brian M.

AU - Ascherio, Alberto

AU - Rimm, Eric B.

AU - Manson, Jo Ann E.

AU - Qi, Lu

AU - Martínez-González, Miguel Ángel

AU - Salas-Salvadó, Jordi

AU - Hu, Frank B.

AU - Liang, Liming

N1 - Publisher Copyright: © 2020 Published on behalf of the European Society of Cardiology. All rights reserved.

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - Cardiovascular disease

KW - Dietary metabolic response

KW - Mediterranean diet

KW - Mendelian randomization analysis

KW - Metabolomics

KW - Risk prediction

U2 - 10.1093/eurheartj/ehaa209

DO - 10.1093/eurheartj/ehaa209

M3 - Journal article

C2 - 32406924

AN - SCOPUS:85088610256

VL - 41

SP - 2645

EP - 2656

JO - European Heart Journal

JF - European Heart Journal

SN - 0195-668X

IS - 28

ER -