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OBJECTIVES: Beyond the quantity of carbohydrate intake, further research is needed on the relevance of carbohydrate quality and chronic conditions. No previous longitudinal study has assessed the association between an integrated multi-dimensional index for carbohydrate intake quality and the risk of breast cancer (BC). Thus, we evaluated the association between an a priori defined carbohydrate quality index (CQI) and the incidence of BC in a Mediterranean cohort study. METHODS: We used a validated semi-quantitative 136-item food-frequency questionnaire (FFQ) to evaluate the CQI at baseline, as previously described (PMID: 31,868,210), based on 4 criteria: dietary fiber intake, glycemic index, whole grain/total grain ratio, and solid carbohydrate/total carbohydrate ratio), in 10,812 middle-aged women. RESULTS: During a median follow-up of 11.8 years, we confirmed 101 incident cases of BC. A higher CQI (fourth quartile) was associated with a lower risk of BC [HR (Q4 vs. Q1) 0.39 (95% CI 0.17, 0.87) p for trend: 0.049]. When we additionally included probable incident cases (n = 190) this association between CQI and BC persisted with a relative risk reduction of 48% for the overall sample of women [HR (Q4 vs. Q1) 0.52, 95% CI 0.31, 0.89; p for trend: 0.034]. Furthermore, when we stratified by menopausal status, we found a significant inverse association between the CQI and premenopausal BC for both confirmed (HR (T3 vs. T1) 0.32, 95% CI 0.10, 1.00) and probable (HR (T3 vs. T1) 0.46, 95% CI 0.22, 0.96) cases. CONCLUSIONS: In this Mediterranean cohort, a better quality of dietary carbohydrate intake showed a significant inverse association with the incidence of BC, particularly among premenopausal women, which suggests that strategies for cancer prevention should focus, in relation to diet, on the quality of this macronutrient. FUNDING SOURCES: The SUN Project has been supported by the Institute of Health Carlos III, the European Regional Development Fund, the Navarra Regional Government, and the University of Navarra.

OBJECTIVES: Dietary patterns may have a greater influence on human health than individual foods or nutrients and they are also being widely studied in the field of breast cancer prevention. Beyond the adequate balance of macronutrients, evidence shows that the quality of fat sources may play an important role in health outcomes. Our aim was to assess the relationship between healthful and less healthful low-fat dietary patterns in relation to breast cancer in a Mediterranean cohort (the SUN project). METHODS: The SUN Project is a Mediterranean dynamic prospective follow-up cohort study assessing participants every 2 years. We evaluated 10,930 middle-aged women initially free of breast cancer during a median of follow-up of 12.1 years. Dietary variables were evaluated through a previously validated 136-item FFQ. We calculated an overall, an unhealthful, and a healthful low-fat-diet score (rang: 0–30 points) based on the percentage of energy from total and subtypes of carbohydrate, fat, and protein. Participants were then categorized into tertiles. Incident breast cancer was de primary outcome. We fitted Cox regression models adjusted for potential confounders to investigate the relationship between baseline categories of low-fat-diet scores and the incidence of breast cancer- overall and stratified by menopausal status-. RESULTS: During 123,297 person-years of follow-up, 119 cases of incident breast cancer were confirmed. Among postmenopausal women, a significant direct association with postmenopausal breast cancer (comparing tertile 2 vs. tertile 1, HR = 2.60; 95% CI 1.24–5.45, P value = 0.012) was found. None of the other associations was statistically significant. CONCLUSIONS: In this Mediterranean prospective cohort study, a moderate adherence to an unhealthy low-fat-diet-score might increase the risk of postmenopausal breast cancer. These results must be further confirmed in future studies. FUNDING SOURCES: The SUN project received funding from the Spanish Government-Instituto de Salud Carlos III, and the ...

This article belongs to the Section Epidemiology & Public Health. ; Limited longitudinal studies have been conducted to evaluate colorectal cancer (CRC) incidence based on the updated 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) recommendations or other global lifestyle indices, and none in aged populations at high cardiovascular risk. We aimed to assess the association between CRC incidence and adherence to two emerging lifestyles indices (2018 WCRF/AICR score and another low-risk lifestyle (LRL) score comprising smoking status, alcohol consumption, physical activity, diet, and body mass index) in the Spanish PREvencion con DIeta MEDiterranea (PREDIMED) cohort. We studied 7216 elderly men and women at high cardiovascular risk. The 2018 WCRF/AICR and LRL scores were calculated. Multivariable Cox proportional regression models were fitted to estimate the HRs (hazard ratios) and 95% confidence intervals (CIs) for incident CRC events. During a median interquartile range (IQR) follow-up of 6.0 (4.4–7.3) years, 97 CRC events were considered. A significant linear association was observed between each 1-point increment in the WCRF/AICR score (score range from 0 to 7) and CRC risk (HR (95% CI) = 0.79 (0.63–0.99)). Similarly, each 1-point increment in the LRL score (score range from 0 to 5) was associated with a 22% reduction in CRC risk (0.78 (0.64–0.96)). Adhering to emergent lifestyle scores might substantially reduce CRC incidence in elderly individuals. Further longitudinal studies, which take different lifestyle indexes into account, are warranted in the future. ; The Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBEROBN) is an initiative of the Spanish Instituto de Salud Carlos III (ISCIII) which is funded by FEDER "A way to make Europe"/"Investing in your future" (CB06/03). It is supported by the official funding agency for biomedical research of the Spanish government, ISCIII, through grants provided to research networks specifically developed for the trial (RTIC G03/140 and RD 06/0045) through CIBEROBN, and by grants from the Centro Nacional de Investigaciones Cardiovasculares (CNIC 06/2007), Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo Regional (PI04–2239, PI05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI07/0473, PI10/01407, PI10/02658, PI11/01647, and PI11/02505; PI13/00462), Ministerio de Ciencia e Innovación (AGL-2009–13906-C02 and AGL2010–22319-C03), Fundación Mapfre 2010, Consejería de Salud de la Junta de Andalucía (PI0105/2007), Public Health Division of the Department of Health of the Autonomous Government of Catalonia, Generalitat Valenciana (PROMETEO17/2017), and the Navarra Regional Government (27/2011). The Fundación Patrimonio Comunal Olivarero and Hojiblanca SA (Málaga, Spain), California Walnut Commission (Sacramento, CA), Borges SA (Reus, Spain), and Morella Nuts SA (Reus, Spain) donated the olive oil, walnuts, almonds, and hazelnuts, respectively, used in the study. J. Salas-Salvadó, the senior author/gratefully acknowledges the financial support by ICREA under the ICREA Academia program. Dr. P.H.-A. is supported by a postdoctoral fellowship (Juan de la Cierva-Formación, FJCI-2017-32205). L. Barrubés has been awarded a grant by the Spanish Ministry of Education, Culture, and Sports (FPU 16/00165). M.M.-G. was the recipient of the Nicolas Monardes Programme from the "Servicio Andaluz de Salud, Junta de Andalucía", Spain (RC-0001-2018 and C-0029-2023).

Limited longitudinal studies have been conducted to evaluate colorectal cancer (CRC) incidence based on the updated 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) recommendations or other global lifestyle indices, and none in aged populations at high cardiovascular risk. We aimed to assess the association between CRC incidence and adherence to two emerging lifestyles indices (2018 WCRF/AICR score and another low-risk lifestyle (LRL) score comprising smoking status, alcohol consumption, physical activity, diet, and body mass index) in the Spanish PREvencion con DIeta MEDiterranea (PREDIMED) cohort. We studied 7216 elderly men and women at high cardiovascular risk. The 2018 WCRF/AICR and LRL scores were calculated. Multivariable Cox proportional regression models were fitted to estimate the HRs (hazard ratios) and 95% confidence intervals (CIs) for incident CRC events. During a median interquartile range (IQR) follow-up of 6.0 (4.4-7.3) years, 97 CRC events were considered. A significant linear association was observed between each 1-point increment in the WCRF/AICR score (score range from 0 to 7) and CRC risk (HR (95% CI) = 0.79 (0.63-0.99)). Similarly, each 1-point increment in the LRL score (score range from 0 to 5) was associated with a 22% reduction in CRC risk (0.78 (0.64-0.96)). Adhering to emergent lifestyle scores might substantially reduce CRC incidence in elderly individuals. Further longitudinal studies, which take different lifestyle indexes into account, are warranted in the future. ; The Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBEROBN) is an initiative of the Spanish Instituto de Salud Carlos III (ISCIII) which is funded by FEDER "A way to make Europe"/"Investing in your future" (CB06/03). It is supported by the official funding agency for biomedical research of the Spanish government, ISCIII, through grants provided to research networks specifically developed for the trial (RTIC G03/140 and RD 06/0045) through CIBEROBN, and by grants from the Centro Nacional de Investigaciones Cardiovasculares (CNIC 06/2007), Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo Regional (PI04–2239, PI05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI07/0473, PI10/01407, PI10/02658, PI11/01647, and PI11/02505; PI13/00462), Ministerio de Ciencia e Innovación (AGL-2009–13906-C02 and AGL2010–22319-C03), Fundación Mapfre 2010, Consejería de Salud de la Junta de Andalucía (PI0105/2007), Public Health Division of the Department of Health of the Autonomous Government of Catalonia, Generalitat Valenciana (PROMETEO17/2017), and the Navarra Regional Government (27/2011). The Fundación Patrimonio Comunal Olivarero and Hojiblanca SA (Málaga, Spain), California Walnut Commission (Sacramento, CA), Borges SA (Reus, Spain), and Morella Nuts SA (Reus, Spain) donated the olive oil, walnuts, almonds, and hazelnuts, respectively, used in the study. J. Salas-Salvadó, the senior author/gratefully acknowledges the financial support by ICREA under the ICREA Academia program. Dr. P.H.-A. is supported by a postdoctoral fellowship (Juan de la Cierva-Formación, FJCI-2017-32205). L. Barrubés has been awarded a grant by the Spanish Ministry of Education, Culture, and Sports (FPU 16/00165). M.M.-G. was the recipient of the Nicolas Monardes Programme from the "Servicio Andaluz de Salud, Junta de Andalucía", Spain (RC-0001-2018 and C-0029-2023). None of the funding sources played a role in the design, collection, analysis or interpretation of the data or in the decision to submit the manuscript for publication.

BACKGROUND: Glutamate metabolism may play a role in the pathophysiology of cardiometabolic disorders. However, there is limited evidence of an association between glutamate-related metabolites and, moreover, changes in these metabolites, and risk of cardiovascular disease (CVD). METHODS AND RESULTS: Plasma levels of glutamate and glutamine were measured at baseline and 1-year follow-up in a case-cohort study including 980 participants (mean age 68 years; 46% male) from the PREvención con DIeta MEDiterránea (PREDIMED) randomized trial, which assessed a Mediterranean diet intervention in the primary prevention of CVD. During median 4.8 years of follow-up, there were 229 incident CVD events (nonfatal stroke, nonfatal myocardial infarction, or CVD death). In fully adjusted models, per 1-SD, baseline glutamate was associated with 43% (95% CI: 16% to 76%) and 81% (39% to 137%) increased risk of composite CVD and stroke alone, respectively, and baseline glutamine-to-glutamate ratio with 25% (6% to 40%) and 44% (25% to 58%) decreased risk of composite CVD and stroke alone, respectively. Associations appeared linear for stroke (both Plinear trend≤0.005). Among participants with high baseline glutamate, the interventions lowered CVD risk by 37% compared to the control diet; the intervention effects were not significant when baseline glutamate was low (Pinteraction=0.02). No significant effect of the intervention on year-1 changes in metabolites was observed, and no effect of changes themselves on CVD risk was apparent. CONCLUSIONS: Baseline glutamate was associated with increased CVD risk, particularly stroke, and glutamine-to-glutamate ratio was associated with decreased risk. Participants with high glutamate levels may obtain greater benefits from the Mediterranean diet than those with low levels. ; This work was supported by the National Institutes of Health, 1R01HL118264. The PREDIMED trial was supported by the official funding agency for Biomedical Research of the Spanish Government, Instituto de Salud Carlos III, through grants provided to research networks specifically developed for the trial: RTIC G03/140 (Period 2003–2006, Coordinator: R. Estruch, MD, PhD), and RTIC RD 06/0045 (Period 2007–2013, Coordinator: M. A. Martinez-Gonzalez, MD, PhD). We also acknowledge the grants from Centro Nacional de Investigaciones Cardiovasculares CNIC06/2007,Fondo de Investigaci on Sanitaria—Fondo Europeo de Desarrollo Regional (PI04-2239, PI05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI08/1259, PI10/01407, PI11/01647, PI11/01791), and Consejer ıa de Salud de la Junta de Andaluc ıa (PI0105/2007). Ministerio de Ciencia e Innovaci on (AGL-2009- 13906-C02, AGL2010-22319-C03), Fundaci on Mapfre 2010, Consejeria de Salud de la Junta de Andalucia (PI0105/2007), Agencia Canaria de Investigaci on, Innovaci on y Sociedad de la Informaci on-EU FEDER (PI 2007/050), Public Health Division of the Department of Health of the Autonomous Government of Catalonia and Generalitat Valenciana (ACOMP06109, GVACOMP2010-181, GVACOMP2011-151, CS2010-AP-111, CS2011-AP-042, AP-042/11 and BEST11-263) and Ministerio de Econom ıa (PI07-0954, CNIC-06, AGL2010-22319-C03-03, PI11/02505). CIBEROBN is an initiative of ISCIII, Spain.

BACKGROUND: Eggs are a major source of dietary cholesterol and their consumption has been sometimes discouraged. A relationship between egg consumption and the incidence of cardiovascular disease (CVD) has been suggested to be present exclusively among patients with type2 diabetes. AIMS: To assess the association between egg consumption and CVD in a large Mediterranean cohort where approximately 50% of participants had type 2 diabetes. METHODS: We prospectively followed 7216 participants (55-80 years old) at high cardiovascular risk from the PREDIMED (PREvención con DIeta MEDiterránea) study for a mean of 5.8 years. All participants were initially free of CVD. Yearly repeated measurements of dietary information with a validated 137-item food-frequency questionnaire were used to assess egg consumption and other dietary exposures. The endpoint was the rate of major cardiovascular events (myocardial infarction, stroke or death from cardiovascular causes). RESULTS: A major cardiovascular event occurred in 342 participants. Baseline egg consumption was not significantly associated with cardiovascular events in the total population. Non-diabetic participants who ate on average >4 eggs/week had a hazard ratio (HR) of 0.96 (95% confidence interval, 0.33-2.76) in the fully adjusted multivariable model when compared with non-diabetic participants who reported the lowest egg consumption (<2 eggs/week). Among diabetic participants, the HR was 1.33 (0.72-2.46). There was no evidence of interaction by diabetic status. HRs per 500 eggs of cumulative consumption during follow-up were 0.94 (0.66-1.33) in non-diabetics and 1.18 (0.90-1.55) in diabetics. CONCLUSIONS: Low to moderated egg consumption was not associated with an increased CVD risk in diabetic or non-diabetic individuals at high cardiovascular risk. This trial was registered at controlled-trials.com as ISRCTN35739639. ; Supported by the official funding agency for biomedical research of the Spanish Government, Instituto de Salud Carlos III (ISCIII), through grants provided to research networks specifically developed for the trial (RTIC G03/140, to RE; RTIC RD 06/0045, to Miguel A. Martínez-Gonzalez) and through Centro de Investigaci on Biomedica en Red de Fisiopatología de la Obesidad y Nutrici on (CIBERobn), and by grants from Centro Nacional de Investigaciones Cardiovasculares (CNIC 06/2007), the Fondo de Investigacion Sanitaria eFondo Europeo de Desarrollo Regional (Proyecto de Investigacion (PI) 04-2239, PI 05/2584, CP06/00100, PI07/0240, PI07/ 1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505 and PI13/00462), the Ministerio de Ciencia e Innovacion (Recursos y teconologia agroalimentarias (AGL)-2009-13906-C02 and AGL2010-22319-C03 and AGL2013-49083-C3-1-R), the Fundacion Mapfre 2010, the Consejería de Salud de la Junta de Andalucía (PI0105/2007), the Public Health Division of the Department of Health of the Autonomous Government of Catalonia, the Generalitat Valenciana (Generalitat Valenciana Ayuda Complementaria (GVACOMP) 06109, GVACOMP2010-181, GVACOMP2011-151), Conselleria de Sanitat y AP; Atencion Primaria (CS) 2010-AP-111, and CS2011-AP-042, and Regional Government of Navarra (P27/2011).

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; P<0.001 for trend) and a 2.27-fold higher risk of stroke (95% confidence interval, 1.24-4.16; P<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 (P=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. ; This work was supported by NIH research grant HL118264. The PREDIMED trial was supported by the official funding agency for biomedical research of the Spanish Government, Instituto de Salud Carlos III, through grants provided to research networks specifically developed for the trial (RTIC G03/140 to Estruch; RTIC RD 06/0045 to Martínez‐González) and through Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición; and by grants from Centro Nacional de Investigaciones Cardiovasculares (06/2007), Fondo de Investigación Sanitaria–Fondo Europeo de Desarrollo Regional (PI04–2239, PI05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505, and PI13/00462), Ministerio de Ciencia e Innovación (AGL‐2009–13906‐C02 and AGL2010–22319‐C03), Fundación Mapfre 2010, Consejería de Salud de la Junta de Andalucía (PI0105/2007), Public Health Division of the Department of Health of the Autonomous Government of Catalonia, Generalitat Valenciana (ACOMP06109, GVA‐COMP2010–181, GVACOMP2011–151, CS2010‐AP‐111, and CS2011‐AP‐042), and Regional Government of Navarra (P27/2011). Guasch‐Ferré was supported by a postdoctoral fellowship granted by the Agency for Administration of University and Research Grants of the Autonomous Government of Catalonia (2014‐BP‐A 00017).

Few studies have examined the association of a wide range of metabolites with total and subtypes of coffee consumption. The aim of this study was to investigate associations of plasma metabolites with total, caffeinated, and decaffeinated coffee consumption. We also assessed the ability of metabolites to discriminate between coffee consumption categories. This is a cross-sectional analysis of 1664 participants from the PREDIMED study. Metabolites were semiquantitatively profiled using a multiplatform approach. Consumption of total coffee, caffeinated coffee and decaffeinated coffee was assessed by using a validated food frequency questionnaire. We assessed associations between 387 metabolite levels with total, caffeinated, or decaffeinated coffee consumption (≥50 mL coffee/day) using elastic net regression analysis. Ten-fold cross-validation analyses were used to estimate the discriminative accuracy of metabolites for total and subtypes of coffee. We identified different sets of metabolites associated with total coffee, caffeinated and decaffeinated coffee consumption. These metabolites consisted of lipid species (e.g., sphingomyelin, phosphatidylethanolamine, and phosphatidylcholine) or were derived from glycolysis (alpha-glycerophosphate) and polyphenol metabolism (hippurate). Other metabolites included caffeine, 5-acetylamino-6-amino-3-methyluracil, cotinine, kynurenic acid, glycocholate, lactate, and allantoin. The area under the curve (AUC) was 0.60 (95% CI 0.56–0.64), 0.78 (95% CI 0.75–0.81) and 0.52 (95% CI 0.49–0.55), in the multimetabolite model, for total, caffeinated, and decaffeinated coffee consumption, respectively. Our comprehensive metabolic analysis did not result in a new, reliable potential set of metabolites for coffee consumption. ; This study was funded by the National Institutes of Health (R01DK102896, F31DK114938, NIH/NHLBI 1R01HL118264, NIH/NHLBI 2R01HL118264), the Spanish Ministry of Health (Instituto de Salud Carlos III, RD 06/0045- Coordinator: MAM-G), the Ministerio de Economía y Competitividad-Fondo Europeo de Desarrollo Regional (Projects CNIC-06/2007, RTIC G03/140, CIBER 06/03, PI06-1326, PI07-0954, PI11/02505, SAF2009-12304 and AGL2010-22319-C03-03), and by the Generalitat Valenciana (ACOMP2010-181, AP111/10, AP-042/11, ACOM2011/145, ACOMP/2012/190, ACOMP/2013/159 and ACOMP/213/165). Dr. Christopher Papandreou was supported by a postdoctoral fellowship granted by the Autonomous Government of Catalonia (PERIS2016-2020 Incorporació de Científics I Tecnòlegs, SLT002/0016/00428). Dr. Marta Guasch-Ferré was supported by EFSD (European Foundation for the Study of Diabetes)/Lilly through the Institut d'Investigacions Sanitàries Pere I Virgili (IISPV).