Lysine pathway metabolites and the risk of type 2 diabetes and cardiovascular disease in the PREDIMED study: results from two case-cohort studies.

Emilio Ros, Miguel A Martínez-González, Frank B Hu, Jordi Salas-Salvadó, Lluis Serra-Majem, Angel Alonso-Gómez, Dora Romaguera, Jose Lapetra, Montse Fitó, Enrique Gómez-Gracia, Ramon Estruch, Cristina Razquin, Dolores Corella, Marta Guasch-Ferré, Kerry A Pierce, Albert Salas-Huetos, Liming Liang, Courtney Dennis, Estefania Toledo, Jun Li, Clary B Clish, Miguel Ruiz-Canela

Journal: Cardiovascular diabetology 2020;18(1):151

PMID: 31722714

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Abstract

BACKGROUND

The pandemic of cardiovascular disease (CVD) and type 2 diabetes (T2D) requires the identification of new predictor biomarkers. Biomarkers potentially modifiable with lifestyle changes deserve a special interest. Our aims were to analyze: (a) The associations of lysine, 2-aminoadipic acid (2-AAA) or pipecolic acid with the risk of T2D or CVD in the PREDIMED trial; (b) the effect of the dietary intervention on 1-year changes in these metabolites, and (c) whether the Mediterranean diet (MedDiet) interventions can modify the effects of these metabolites on CVD or T2D risk.

METHODS

Two unstratified case-cohort studies nested within the PREDIMED trial were used. For CVD analyses, we selected 696 non-cases and 221 incident CVD cases; for T2D, we included 610 non-cases and 243 type 2 diabetes incident cases. Metabolites were quantified using liquid chromatography-tandem mass spectrometry, at baseline and after 1-year of intervention.

RESULTS

In weighted Cox regression models, we found that baseline lysine (HR = 1.26; 95% CI 1.06-1.51) and 2-AAA (HR = 1.28; 95% CI 1.05-1.55) were both associated with a higher risk of T2D, but not with CVD. A significant interaction (p = 0.032) between baseline lysine and T2D on the risk of CVD was observed: subjects with prevalent T2D and high levels of lysine exhibited the highest risk of CVD. The intervention with MedDiet did not have a significant effect on 1-year changes of the metabolites.

CONCLUSIONS

Our results provide an independent prospective replication of the association of 2-AAA with future risk of T2D. We show an association of lysine with subsequent CVD risk, which is apparently diabetes-dependent. No evidence of effects of MedDiet intervention on lysine, 2-AAA or pipecolic acid changes was found. Trial registration ISRCTN35739639; registration date: 05/10/2005; recruitment start date 01/10/2003.

Address: Department of Preventive Medicine and Public Health, University of Navarra, Pamplona, Spain.; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III, Madrid, Spain.; Broad Institute of MIT and Harvard University, Cambridge, USA.; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Spain.; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, USA.; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, USA.; Human Nutrition Unit, Faculty of Medicine and Health Sciences, Institut d'Investigació Sanitària Pere Virgili, Rovira i Virgili University, Reus, Spain.; Department of Preventive Medicine, University of Valencia, Valencia, Spain.; Lipid Clinic, Department of Endocrinology and Nutrition, Institut d'Investigacions Biomediques August Pi Sunyer (IDI- BAPS), Hospital Clinic, University of Barcelona, Barcelona, Spain.; Department of Internal Medicine, Institut d'Investigacions Biomediques August Pi Sunyer (IDI-BAPS), Barcelona, Spain.; Department of Preventive Medicine, University of Malaga, Malaga, Spain.; Cardiovascular and Nutrition Research Group, Institut de Recerca Hospital del Mar (IMIM), Barcelona, Spain.; Department of Family Medicine, Research Unit, Distrito Sanitario Atención Primaria Sevilla, Seville, Spain.; Instituto de Investigación Sanitaria de Palma (IdISPa), University Hospital of Son Espases, Palma de Mallorca, Spain.; Department of Cardiology, University Hospital of Alava, Vitoria, Spain.; Research Institute of Biomedical and Health Sciences, University of Las Palmas de Gran Canaria, Las Palmas, Spain.; Channing Division for Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.; Department of Preventive Medicine and Public Health, University of Navarra, Pamplona, Spain. [email protected].; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain. [email protected].; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III, Madrid, Spain. [email protected].; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Spain. [email protected].

DOI: 10.1186/s12933-019-0958-2

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MeSH Terms: 2-Aminoadipic Acid, Aged, Aged, 80 and over, Biomarkers, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Diet, Mediterranean, Female, Humans, Incidence, Lysine, Male, Middle Aged, Pipecolic Acids, Primary Prevention, Prospective Studies, Randomized Controlled Trials as Topic, Risk Assessment, Risk Factors, Risk Reduction Behavior, Time Factors, Treatment Outcome