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00925njm 22002777a 4500 dc Razquin, Cristina author Ruiz-Canela, Miguel author Clish, Clary B author Li, Jun author Toledo, Estefanía author Dennis, Courtney author Liang, Liming author Salas-Huetos, Albert author Pierce, Kerry A author Guasch-Ferre, Marta author Corella, Dolores author Ros, Emilio author Estruch, Ramon author Gomez-Gracia, Enrique author Fito, Montserrat author Lapetra, Jose author Romaguera, Dora author Alonso-Gomez, Angel author Serra-Majem, Lluis author Salas-Salvado, Jordi author Hu, Frank B author Martinez-Gonzalez, Miguel A author 2019-11-13 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 SD increase = 1.26; 95% CI 1.06-1.51) and 2-AAA (HR+1 SD increase = 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 Razquin C, Ruiz-Canela M, Clish CB, Li J, Toledo E, Dennis C, et al. Lysine pathway metabolites and the risk of type 2 diabetes and cardiovascular disease in the PREDIMED study: results from two case-cohort studies. Cardiovasc Diabetol. 2019 Nov 13;18(1):151. http://hdl.handle.net/20.500.13003/13075 https://hdl.handle.net/20.500.12105/22664 31722714 10.1186/s12933-019-0958-2 1475-2840 Cardiovascular Diabetology 2-s2.0-85074961499 497753100001 L629863561 Biomarkers Metabolites Cardiovascular disease Type 2 diabetes Dietary intervention Lysine pathway metabolites and the risk of type 2 diabetes and cardiovascular disease in the PREDIMED study: results from two case-cohort studies