Associations between Fatty Acid Intakes and Plasma Phospholipid Fatty Acid Concentrations in the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: The aim of this study is to determine the correlations between dietary fatty acid (FA) intakes and plasma phospholipid (PL) FA levels in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. METHODS: The dietary intake of 60 individual FAs was estimated using centre-specific validated dietary questionnaires. Plasma PL FA concentrations of these FAs were measured in non-fasting venous plasma samples in nested case-control studies within the EPIC cohort (n = 4923, using only non-cases). Spearman rank correlations were calculated to determine associations between FA intakes and plasma PL FA levels. RESULTS: Correlations between FA intakes and circulating levels were low to moderately high (-0.233 and 0.554). Moderate positive correlations were found for total long-chain n-3 poly-unsaturated FA (PUFA) (r = 0.354) with the highest (r = 0.406) for n-3 PUFA docosahexaenoic acid (DHA). Moderate positive correlations were also found for the non-endogenously synthesized trans-FA (r = 0.461 for total trans-FA C16-18; r = 0.479 for industrial trans-FA (elaidic acid)). CONCLUSIONS: Our findings indicate that dietary FA intakes might influence the plasma PL FA status to a certain extent for several specific FAs. The stronger positive correlations for health-enhancing long-chain PUFAs and the health-deteriorating trans-FA that are not endogenously produced are valuable for future cancer prevention public health interventions.

The association between dietary intakes of methionine, choline and betaine and breast cancer risk: A systematic review and meta-analysis.

BACKGROUND AND AIM: This study evaluates the associations between dietary intakes and circulating blood levels of methionine, choline or betaine and breast cancer risk, which remains currently unclear. METHODS: Systematic searches for observational epidemiological studies were performed of the MEDLINE, Embase, and Web of Science databases through July, 2022. Two review authors independently screened titles and abstracts against the eligibility criteria at a first stage, and screened full texts of potentially eligible records at a second stage, followed by data extraction from qualified studies. Quality of evidence was assessed using the Newcastle-Ottawa scale quality assessment tool. Risk estimates were calculated using random-effects meta-analysis. RESULTS: In total, 21 studies were selected for qualitative analyses and 18 studies were included in the meta-analyses. Random-effects analysis combining prospective cohort (N = 8) or case-control studies (N = 10) showed little evidence of an association between dietary intake of methionine or betaine and the risk of breast cancer. However, inconclusive evidence for a significant inverse association between choline intake and breast cancer risk was found in case-control studies (odds ratio [OR] estimates for highest vs. lowest intakes = 0.38; 95 % CI: 0.16-0.86) but not in prospective cohort studies (hazard ratio [HR] estimates for highest vs. lowest intakes = 1.01; 95 % CI: 0.92-1.12). CONCLUSION: This study did not suggest an effect of dietary intake of methionine, choline, nor betaine on breast cancer risk, mainly due to the lack of precision of the combined risk estimates as few studies are available. To overcome this uncertainty, more well-designed studies with relevant individual-level covariates are needed.

Blood cell DNA methylation biomarkers in preclinical malignant pleural mesothelioma: The EPIC prospective cohort.

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer mainly caused by asbestos exposure. Specific and sensitive noninvasive biomarkers may facilitate and enhance screening programs for the early detection of cancer. We investigated DNA methylation (DNAm) profiles in MPM prediagnostic blood samples in a case-control study nested in the European Prospective Investigation into Cancer and nutrition (EPIC) cohort, aiming to characterise DNAm biomarkers associated with MPM. From the EPIC cohort, we included samples from 135 participants who developed MPM during 20 years of follow-up and from 135 matched, cancer-free, controls. For the discovery phase we selected EPIC participants who developed MPM within 5 years from enrolment (n = 36) with matched controls. We identified nine differentially methylated CpGs, selected by 10-fold cross-validation and correlation analyses: cg25755428 (MRI1), cg20389709 (KLF11), cg23870316, cg13862711 (LHX6), cg06417478 (HOOK2), cg00667948, cg01879420 (AMD1), cg25317025 (RPL17) and cg06205333 (RAP1A). Receiver operating characteristic (ROC) analysis showed that the model including baseline characteristics (age, sex and PC1wbc) along with the nine MPM-related CpGs has a better predictive value for MPM occurrence than the baseline model alone, maintaining some performance also at more than 5 years before diagnosis (area under the curve [AUC] < 5 years = 0.89; AUC 5-10 years = 0.80; AUC >10 years = 0.75; baseline AUC range = 0.63-0.67). DNAm changes as noninvasive biomarkers in prediagnostic blood samples of MPM cases were investigated for the first time. Their application can improve the identification of asbestos-exposed individuals at higher MPM risk to possibly adopt more intensive monitoring for early disease identification.

Biomarkers of the transsulfuration pathway and risk of renal cell carcinoma in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

Previous studies have suggested that components of one-carbon metabolism, particularly circulating vitamin B6, have an etiological role in renal cell carcinoma (RCC). Vitamin B6 is a cofactor in the transsulfuration pathway. We sought to holistically investigate the role of the transsulfuration pathway in RCC risk. We conducted a nested case-control study (455 RCC cases and 455 matched controls) within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Plasma samples from the baseline visit were analyzed for metabolites of the transsulfuration pathway, including pyridoxal 5'-phosphate (PLP, the biologically active form of vitamin B6), homocysteine, serine, cystathionine, and cysteine, in addition to folate. Bayesian conditional logistic regression was used to estimate associations of metabolites with RCC risk as well as interactions with established RCC risk factors. Circulating PLP and cysteine were inversely associated with RCC risk, and these associations were not attenuated after adjustment for other transsulfuration metabolites (odds ratio (OR) and 90% credible interval (CrI) per 1 SD increase in log concentration: 0.76 [0.66, 0.87]; 0.81 [0.66, 0.96], respectively). A comparison of joint metabolite profiles suggested substantially greater RCC risk for the profile representative of low overall transsulfuration function compared to high function (OR 2.70 [90% CrI 1.26, 5.70]). We found some statistical evidence of interactions of cysteine with body mass index, and PLP and homocysteine with smoking status, on their associations with RCC risk. In conclusion, we found evidence suggesting that the transsulfuration pathway may play a role in metabolic dysregulation leading to RCC development.

Evaluation of protein and amino acid intake estimates from the EPIC dietary questionnaires and 24-h dietary recalls using different food composition databases.

BACKGROUND AND AIMS: This study aimed to expand the European Prospective Investigation into Cancer and Nutrition (EPIC) nutrient database (ENDB) by adding amino acid (AA) values, using the U.S. nutrient database (USNDB). Additionally, we aimed to evaluate these new protein and AA intake estimates from the EPIC dietary questionnaires (DQ) and 24-h dietary recalls (24-HDR) using different matching procedures. METHODS AND RESULTS: Dietary energy, protein and AA intakes were assessed via DQ and 24-HDR by matching with the USNDB food composition table. Energy and protein intakes calculated using USNDB matching were compared with those calculated using ENDB, that uses country specific food composition tables. Pearson correlations, Cohen's weighted kappa statistic and Bland-Altman plots were used to compare data resulting from USNDB matching with our reference from ENDB matching. Very high correlations were found when comparing daily energy (r = 0.99) and dietary protein intakes (r = 0.97) assessed via USNDB with those obtained via ENDB (matching for DQ and 24-HDR). Significant positive correlations were also found with energy and protein intakes acquired via 24-HDRs in the EPIC calibration sample. CONCLUSION: Very high correlations between total energy and protein intake obtained via the USDA matching and those available in ENDB suggest accuracy in the food matching. Individual AA have been included in the extended EPIC Nutrient database that will allow important analyses on AA disease prospective associations in the EPIC study.

Dietary Methyl-Group Donor Intake and Breast Cancer Risk in the European Prospective Investigation into Cancer and Nutrition (EPIC).

(1) Background: Methyl-group donors (MGDs), including folate, choline, betaine, and methionine, may influence breast cancer (BC) risk through their role in one-carbon metabolism; (2) Methods: We studied the relationship between dietary intakes of MGDs and BC risk, adopting data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort; (3) Results: 318,686 pre- and postmenopausal women were followed between enrolment in 1992-2000 and December 2013-December 2015. Dietary MGD intakes were estimated at baseline through food-frequency questionnaires. Multivariable Cox proportional hazards regression models were used to quantify the association between dietary intake of MGDs, measured both as a calculated score based on their sum and individually, and BC risk. Subgroup analyses were performed by hormone receptor status, menopausal status, and level of alcohol intake. During a mean follow-up time of 14.1 years, 13,320 women with malignant BC were identified. No associations were found between dietary intakes of the MGD score or individual MGDs and BC risk. However, a potential U-shaped relationship was observed between dietary folate intake and overall BC risk, suggesting an inverse association for intakes up to 350 µg/day compared to a reference intake of 205 µg/day. No statistically significant differences in the associations were observed by hormone receptor status, menopausal status, or level of alcohol intake; (4) Conclusions: There was no strong evidence for an association between MGDs involved in one-carbon metabolism and BC risk. However, a potential U-shaped trend was suggested for dietary folate intake and BC risk. Further research is needed to clarify this association.

Associations between dietary amino acid intakes and blood concentration levels.

BACKGROUND AND AIMS: Emerging evidence suggests a role of amino acids (AAs) in the development of various diseases including renal failure, liver cirrhosis, diabetes and cancer. However, mechanistic pathways and the effects of dietary AA intakes on circulating levels and disease outcomes are unclear. We aimed to compare protein and AA intakes, with their respective blood concentrations in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. METHODS: Dietary protein and AA intakes were assessed via the EPIC dietary questionnaires (DQ) and 24-h dietary recalls (24-HDR). A subsample of 3768 EPIC participants who were free of cancer had blood AA concentrations measured. To investigate how circulating levels relate to their respective intakes, dietary AA intake was examined in quintiles and ANOVA tests were run. Pearson correlations were examined for continous associations between intakes and blood concentrations. RESULTS: Dietary AA intakes (assessed with the DQ) and blood AA concentrations were not strongly correlated (-0.15 ≤ r ≤ 0.17) and the direction of the correlations depended on AA class: weak positive correlations were found for most essential AAs (isoleucine, leucine, lysine, methionine, threonine, tryptophan, and valine) and conditionally essential AAs (arginine and tyrosine), while negative associations were found for non-essential AAs. Similar results were found when using the 24-HDR. When conducting ANOVA tests for essential AAs, higher intake quintiles were linked to higher blood AA concentrations, except for histidine and phenylalanine. For non-essential AAs and glycine, an inverse relationship was observed. Conditionally-essential AAs showed mixed results. CONCLUSIONS: Weak positive correlations and dose responses were found between most essential and conditionally essential AA intakes, and blood concentrations, but not for the non-essential AAs. These results suggest that intake of dietary AA might be related to physiological AA status, particularly for the essential AAs. However, these results should be further evaluated and confirmed in large-scale prospective studies.

A comparison of complementary measures of vitamin B6 status, function, and metabolism in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

BACKGROUND: Vitamin B6 insufficiency has been linked to increased risk of cancer and other chronic diseases. The circulating concentration of pyridoxal 5'-phosphate (PLP) is a commonly used measure of vitamin B6 status. Ratios of substrates indicating PLP coenzymatic function and metabolism may be useful complementary measures to further explore the role of vitamin B6 in health. OBJECTIVES: We explored the sensitivity of 5 outcomes, namely PLP concentration, homocysteine:cysteine (Hcy:Cys), cystathionine:cysteine (Cysta:Cys), the 3´-hydroxykynurenine ratio (HKr), and the 4-pyridoxic acid ratio (PAr) to vitamin B6 intake as well as personal and lifestyle characteristics. MEDTHODS: Dietary intake and biomarker data were collected from participants from 3 nested case-control studies within the European Prospective Investigation into Cancer and Nutrition (EPIC). Bayesian regression models assessed the associations of the 5 biomarker outcomes with vitamin B6 intake and personal and lifestyle covariates. Analogous models examined the relations of Hcy:Cys, Cysta:Cys, and HKr with PLP. RESULTS: In total, 4608 participants were included in the analyses. Vitamin B6 intake was most strongly associated with PLP, moderately associated with Hcy:Cys, Cysta:Cys, and HKr, and not associated with PAr (fold change in marker given a doubling of vitamin B6 intake: PLP 1.60 [95% credible interval (CrI): 1.50, 1.71]; Hcy:Cys 0.87 [95% CrI: 0.84, 0.90]; Cysta:Cys 0.89 [95% CrI: 0.84, 0.94]; HKr 0.88 [95% CrI: 0.85, 0.91]; PAr 1.00 [95% CrI: 0.95, 1.05]). PAr was most sensitive to age, and HKr was least sensitive to BMI and alcohol intake. Sex and menopause status were strongly associated with all 5 markers. CONCLUSIONS: We found that 5 different markers, capturing different aspects of vitamin B6-related biological processes, varied in their associations with vitamin B6 intake and personal and lifestyle predictors.

Comparing Calculated Nutrient Intakes Using Different Food Composition Databases: Results from the European Prospective Investigation into Cancer and Nutrition (EPIC) Cohort.

This study aimed to compare calculated nutrient intakes from two different food composition databases using data from the European prospective investigation into cancer and nutrition (EPIC) cohort. Dietary intake data of the EPIC cohort was recently matched to 150 food components from the U.S. nutrient database (USNDB). Twenty-eight of these nutrients were already included in the EPIC nutrient database (ENDB-based upon country specific food composition tables), and used for comparison. Paired sample t-tests, Pearson's correlations (r), weighted kappa's (κ) and Bland-Altman plots were used to compare the dietary intake of 28 nutrients estimated by the USNDB and the ENDB for 476,768 participants. Small but significant differences were shown between the USNDB and the ENDB for energy and macronutrient intakes. Moderate to very strong correlations (r = 0.60-1.00) were found for all macro- and micronutrients. A strong agreement (κ > 0.80) was found for energy, water, total fat, carbohydrates, sugar, alcohol, potassium and vitamin C, whereas a weak agreement (κ < 0.60) was found for starch, vitamin D and vitamin E. Dietary intakes estimated via the USNDB compare adequately with those obtained via the ENDB for most macro- and micronutrients, although the agreement was weak for starch, vitamin D and vitamin E. The USNDB will allow exposure assessments for 150 nutrients to investigate associations with disease outcomes within the EPIC cohort.

Methodological approaches to compile and validate a food composition database for methyl-group carriers in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

A standardised methodology was used to compile and validate a methyl-group carrier database (MGDB) including folate, choline, betaine and methionine, for use in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Compilation was performed by following structured guidelines to match the EPIC dietary intake data to food items from four food composition databases, according to their assigned priority of use. To assess relative validity, calculated dietary folate intakes were compared between the MGDB and the EPIC nutrient database (ENDB), used as the reference database. Folate intakes based on the MGDB and those generated using the ENDB showed good agreement (weighted κ = 0.63) and were strongly correlated (r = 0.81). This MGDB can be used for investigating potential associations between methyl-group carrier intakes and risk or prognosis of cancer and other diseases in the EPIC study population.