Plasma Metabolites From Choline Pathway and Risk of Cardiovascular Disease in the PREDIMED (Prevention With Mediterranean Diet) Study.

Marta Guasch-Ferré, Frank B Hu, Miguel Ruiz-Canela, Mònica Bulló, Estefanía Toledo, Dong D Wang, Dolores Corella, Enrique Gómez-Gracia, Miquel Fiol, Ramon Estruch, José Lapetra, Montserrat Fitó, Fernando Arós, Lluís Serra-Majem, Emilio Ros, Courtney Dennis, Liming Liang, Clary B Clish, Miguel A Martínez-González, Jordi Salas-Salvadó

Journal: Journal of the American Heart Association 2018;6(11):e006524

PMID: 29080862

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Abstract

BACKGROUND

The relationship between plasma concentrations of betaine and choline metabolism and major cardiovascular disease (CVD) end points remains unclear. We have evaluated the association between metabolites from the choline pathway and risk of incident CVD and the potential modifying effect of Mediterranean diet interventions.

METHODS AND RESULTS

We designed a case-cohort study nested within the PREDIMED (Prevention With Mediterranean Diet) trial, including 229 incident CVD cases and 751 randomly selected participants at baseline, followed up for 4.8 years. We used liquid chromatography-tandem mass spectrometry to measure, at baseline and at 1 year of follow-up, plasma concentrations of 5 metabolites in the choline pathway: trimethylamine N-oxide, betaine, choline, phosphocholine, and α-glycerophosphocholine. We have calculated a choline metabolite score using a weighted sum of these 5 metabolites. We used weighted Cox regression models to estimate CVD risk. The multivariable hazard ratios (95% confidence intervals) per 1-SD increase in choline and α-glycerophosphocholine metabolites were 1.24 (1.05-1.46) and 1.24 (1.03-1.50), respectively. The baseline betaine/choline ratio was inversely associated with CVD. The baseline choline metabolite score was associated with a 2.21-fold higher risk of CVD across extreme quartiles (95% confidence interval, 1.36-3.59; <0.001 for trend) and a 2.27-fold higher risk of stroke (95% confidence interval, 1.24-4.16; <0.001 for trend). Participants in the higher quartiles of the score who were randomly assigned to the control group had a higher risk of CVD compared with participants in the lower quartile and assigned to the Mediterranean diet groups (=0.05 for interaction). No significant associations were observed for 1-year changes in individual plasma metabolites and CVD.

CONCLUSIONS

A metabolite score combining plasma metabolites from the choline pathway was associated with an increased risk of CVD in a Mediterranean population at high cardiovascular risk.

CLINICAL TRIAL REGISTRATION

URL: http://www.controlled-trials.com. Unique identifier: ISRCTN35739639.

Address: Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA [email protected] [email protected].; Human Nutrition Unit, Faculty of Medicine and Health Sciences, Institut d'Investigació Sanitària Pere Virgili, Rovira i Virgili University, Reus, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA.; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.; Department of Preventive Medicine and Public Health, Instituto de Investigación Sanitaria de Navarra, University of Navarra, Pamplona, Spain.; Human Nutrition Unit, Faculty of Medicine and Health Sciences, Institut d'Investigació Sanitària Pere Virgili, Rovira i Virgili University, Reus, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA.; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.; Department of Preventive Medicine, University of Valencia, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.; Department of Preventive Medicine, University of Málaga, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.; Institute of Health Sciences IUNICS, University of Balearic Islands and Hospital Son Espases, Palma de Mallorca, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.; Department of Internal Medicine, Department of Endocrinology and Nutrition, Institut d'Investigacions Biomediques August Pi Sunyer, Hospital Clinic, University of Barcelona, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.; Department of Family Medicine, Research Unit, Primary Care Division of Sevilla, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.; Cardiovascular and Nutrition Research Group (Regicor Study Group), Institut de Recerca Hospital del Mar, Barcelona, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.; Department of Cardiology, University Hospital of Alava, Vitoria, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.; Department of Clinical Sciences, University of Las Palmas de Gran Canaria, Las Palmas, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.; Lipid Clinic, Department of Endocrinology and Nutrition, Institut d'Investigacions Biomediques August Pi Sunyer, Hospital Clinic, University of Barcelona, Spain.; Broad Institute of MIT and Harvard University, Cambridge, MA.; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA.; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA.; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA.; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.; Department of Preventive Medicine and Public Health, Instituto de Investigación Sanitaria de Navarra, University of Navarra, Pamplona, Spain.; Human Nutrition Unit, Faculty of Medicine and Health Sciences, Institut d'Investigació Sanitària Pere Virgili, Rovira i Virgili University, Reus, Spain [email protected] [email protected].; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.

DOI: 10.1161/JAHA.117.006524

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MeSH Terms: Aged, Aged, 80 and over, Betaine, Biomarkers, Cardiovascular Diseases, Case-Control Studies, Chi-Square Distribution, Choline, Chromatography, Liquid, Diet, Mediterranean, Female, Humans, Incidence, Male, Metabolomics, Methylamines, Middle Aged, Multivariate Analysis, Phospholipid Ethers, Phosphorylcholine, Proportional Hazards Models, Prospective Studies, Risk Factors, Spain, Tandem Mass Spectrometry, Time Factors, Treatment Outcome