Publications by authors named "Agnetha Linn Rostgaard-Hansen"

10 Publications

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Associations between dietary amino acid intakes and blood concentration levels.

Clin Nutr 2021 Jun 27;40(6):3772-3779. Epub 2021 Apr 27.

International Agency for Research on Cancer, Nutrition and Metabolism Section, 69372, Lyon CEDEX 08, France.

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.
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June 2021

Pepper Alkaloids and Processed Meat Intake: Results from a Randomized Trial and the European Prospective Investigation into Cancer and Nutrition (EPIC) Cohort.

Mol Nutr Food Res 2021 04 2;65(7):e2001141. Epub 2021 Mar 2.

Nutrition and Metabolism Branch, International Agency for Research on Cancer, 150 cours Albert Thomas, Lyon, France.

Scope: Processed meat intake has been associated with adverse health outcomes. However, little is known about the type of processed meat more particularly responsible for these effects. This study aims to identify novel biomarkers for processed meat intake.

Methods And Results: In a controlled randomized cross-over dietary intervention study, 12 healthy volunteers consume different processed and non-processed meats for 3 consecutive days each. Metabolomics analyses are applied on post-intervention fasting blood and urine samples to identify discriminating molecular features of processed meat intake. Nine and five pepper alkaloid metabolites, including piperine, are identified as major discriminants of salami intake in urine and plasma, respectively. The associations with processed meat intake are tested for replication in a cross-sectional study (n = 418) embedded within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Three of the serum metabolites including piperine are associated with habitual intake of sausages and to a lesser extent of total processed meat.

Conclusion: Pepper alkaloids are major discriminants of intake for sausages that contain high levels of pepper used as ingredient. Further work is needed to assess if pepper alkaloids in combination with other metabolites may serve as biomarkers of processed meat intake.
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April 2021

Association between nutritional profiles of foods underlying Nutri-Score front-of-pack labels and mortality: EPIC cohort study in 10 European countries.

BMJ 2020 09 16;370:m3173. Epub 2020 Sep 16.

AOU Federico II, Naples, Italy.

Objective: To determine if the Food Standards Agency nutrient profiling system (FSAm-NPS), which grades the nutritional quality of food products and is used to derive the Nutri-Score front-of-packet label to guide consumers towards healthier food choices, is associated with mortality.

Design: Population based cohort study.

Setting: European Prospective Investigation into Cancer and Nutrition (EPIC) cohort from 23 centres in 10 European countries.

Participants: 521 324 adults; at recruitment, country specific and validated dietary questionnaires were used to assess their usual dietary intakes. A FSAm-NPS score was calculated for each food item per 100 g content of energy, sugars, saturated fatty acids, sodium, fibre, and protein, and of fruit, vegetables, legumes, and nuts. The FSAm-NPS dietary index was calculated for each participant as an energy weighted mean of the FSAm-NPS score of all foods consumed. The higher the score the lower the overall nutritional quality of the diet.

Main Outcome Measure: Associations between the FSAm-NPS dietary index score and mortality, assessed using multivariable adjusted Cox proportional hazards regression models.

Results: After exclusions, 501 594 adults (median follow-up 17.2 years, 8 162 730 person years) were included in the analyses. Those with a higher FSAm-NPS dietary index score (highest versus lowest fifth) showed an increased risk of all cause mortality (n=53 112 events from non-external causes; hazard ratio 1.07, 95% confidence interval 1.03 to 1.10, P<0.001 for trend) and mortality from cancer (1.08, 1.03 to 1.13, P<0.001 for trend) and diseases of the circulatory (1.04, 0.98 to 1.11, P=0.06 for trend), respiratory (1.39, 1.22 to 1.59, P<0.001), and digestive (1.22, 1.02 to 1.45, P=0.03 for trend) systems. The age standardised absolute rates for all cause mortality per 10 000 persons over 10 years were 760 (men=1237; women=563) for those in the highest fifth of the FSAm-NPS dietary index score and 661 (men=1008; women=518) for those in the lowest fifth.

Conclusions: In this large multinational European cohort, consuming foods with a higher FSAm-NPS score (lower nutritional quality) was associated with a higher mortality for all causes and for cancer and diseases of the circulatory, respiratory, and digestive systems, supporting the relevance of FSAm-NPS to characterise healthier food choices in the context of public health policies (eg, the Nutri-Score) for European populations. This is important considering ongoing discussions about the potential implementation of a unique nutrition labelling system at the European Union level.
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September 2020

Metabolic perturbations prior to hepatocellular carcinoma diagnosis: Findings from a prospective observational cohort study.

Int J Cancer 2021 02 28;148(3):609-625. Epub 2020 Aug 28.

Public Health Directorate, Asturias, Spain.

Hepatocellular carcinoma (HCC) development entails changes in liver metabolism. Current knowledge on metabolic perturbations in HCC is derived mostly from case-control designs, with sparse information from prospective cohorts. Our objective was to apply comprehensive metabolite profiling to detect metabolites whose serum concentrations are associated with HCC development, using biological samples from within the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (>520 000 participants), where we identified 129 HCC cases matched 1:1 to controls. We conducted high-resolution untargeted liquid chromatography-mass spectrometry-based metabolomics on serum samples collected at recruitment prior to cancer diagnosis. Multivariable conditional logistic regression was applied controlling for dietary habits, alcohol consumption, smoking, body size, hepatitis infection and liver dysfunction. Corrections for multiple comparisons were applied. Of 9206 molecular features detected, 220 discriminated HCC cases from controls. Detailed feature annotation revealed 92 metabolites associated with HCC risk, of which 14 were unambiguously identified using pure reference standards. Positive HCC-risk associations were observed for N1-acetylspermidine, isatin, p-hydroxyphenyllactic acid, tyrosine, sphingosine, l,l-cyclo(leucylprolyl), glycochenodeoxycholic acid, glycocholic acid and 7-methylguanine. Inverse risk associations were observed for retinol, dehydroepiandrosterone sulfate, glycerophosphocholine, γ-carboxyethyl hydroxychroman and creatine. Discernible differences for these metabolites were observed between cases and controls up to 10 years prior to diagnosis. Our observations highlight the diversity of metabolic perturbations involved in HCC development and replicate previous observations (metabolism of bile acids, amino acids and phospholipids) made in Asian and Scandinavian populations. These findings emphasize the role of metabolic pathways associated with steroid metabolism and immunity and specific dietary and environmental exposures in HCC development.
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February 2021

Intake of whole grain and associations with lifestyle and demographics: a cross-sectional study based on the Danish Diet, Cancer and Health-Next Generations cohort.

Eur J Nutr 2021 Mar 4;60(2):883-895. Epub 2020 Jun 4.

Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark.

Purpose: The aim was to analyze the intake of whole grain (WG) and associations with lifestyle and demographics in a newly established cohort of Danish adults.

Methods: Between 2015 and 2019, Danes were enrolled into The Diet, Cancer and Health-Next Generations cohort. A total of 38,553 persons were included in the current cross-sectional study, where all completed a 376-item food frequency questionnaire, a lifestyle questionnaire, and a physical examination in a study center where physical measurements and biological samples were collected.

Results: The median intake of WG was 79 g/10 mega joule (MJ) and 54% of the participants consumed the amount of WG recommended in Denmark, which is 75 g/10 MJ. The probability of consuming the recommended amount of WG was highest among men, persons < 30 years, students, persons with body mass index (BMI) < 25 kg/m, persons participating in sports, who did not exceed the recommended maximum intake of alcohol and did not smoke. The probability of having a low intake of WG defined as < 25 g/10 MJ was highest among persons with short education, BMI ≥ 25 kg/m, persons not participating in sports, persons having an alcohol intake above the recommended maximum level and persons being active smokers.

Conclusion: The median intake of WG was 79 g/10 MJ. The probability of consuming at least 75 g WG/10 MJ was highest among persons who also adhered to healthy lifestyle measured by other factors. Only 6% of the cohort participants consumed < 25 g WG/10 MJ, these persons were more likely to have a general less healthy lifestyle.
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March 2021

A metabolomic study of red and processed meat intake and acylcarnitine concentrations in human urine and blood.

Am J Clin Nutr 2020 08;112(2):381-388

Nutrition and Metabolism Section, International Agency for Research on Cancer, Lyon, France.

Background: Acylcarnitines (ACs) play a major role in fatty acid metabolism and are potential markers of metabolic dysfunction with higher blood concentrations reported in obese and diabetic individuals. Diet, and in particular red and processed meat intake, has been shown to influence AC concentrations but data on the effect of meat consumption on AC concentrations is limited.

Objectives: To investigate the effect of red and processed meat intake on AC concentrations in plasma and urine using a randomized controlled trial with replication in an observational cohort.

Methods: In the randomized crossover trial, 12 volunteers successively consumed 2 different diets containing either pork or tofu for 3 d each. A panel of 44 ACs including several oxidized ACs was analyzed by LC-MS in plasma and urine samples collected after the 3-d period. ACs that were associated with pork intake were then measured in urine (n = 474) and serum samples (n = 451) from the European Prospective Investigation into Cancer and nutrition (EPIC) study and tested for associations with habitual red and processed meat intake derived from dietary questionnaires.

Results: In urine samples from the intervention study, pork intake was positively associated with concentrations of 18 short- and medium-chain ACs. Eleven of these were also positively associated with habitual red and processed meat intake in the EPIC cross-sectional study. In blood, C18:0 was positively associated with red meat intake in both the intervention study (q = 0.004, Student's t-test) and the cross-sectional study (q = 0.033, linear regression).

Conclusions: AC concentrations in urine and blood were associated with red meat intake in both a highly controlled intervention study and in subjects of a cross-sectional study. Our data on the role of meat intake on this important pathway of fatty acid and energy metabolism may help understanding the role of red meat consumption in the etiology of some chronic diseases. This trial was registered at as NCT03354130.
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August 2020

Circulating Metabolites Associated with Alcohol Intake in the European Prospective Investigation into Cancer and Nutrition Cohort.

Nutrients 2018 May 22;10(5). Epub 2018 May 22.

Danish Cancer Society Research Center, 2100 Copenhagen, Denmark.

Identifying the metabolites associated with alcohol consumption may provide insights into the metabolic pathways through which alcohol may affect human health. We studied associations of alcohol consumption with circulating concentrations of 123 metabolites among 2974 healthy participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Alcohol consumption at recruitment was self-reported through dietary questionnaires. Metabolite concentrations were measured by tandem mass spectrometry (BIOCRATES AbsoluteIDQTM p180 kit). Data were randomly divided into discovery (2/3) and replication (1/3) sets. Multivariable linear regression models were used to evaluate confounder-adjusted associations of alcohol consumption with metabolite concentrations. Metabolites significantly related to alcohol intake in the discovery set (FDR -value < 0.05) were further tested in the replication set (Bonferroni-corrected -value < 0.05). Of the 72 metabolites significantly related to alcohol intake in the discovery set, 34 were also significant in the replication analysis, including three acylcarnitines, the amino acid citrulline, four lysophosphatidylcholines, 13 diacylphosphatidylcholines, seven acyl-alkylphosphatidylcholines, and six sphingomyelins. Our results confirmed earlier findings that alcohol consumption was associated with several lipid metabolites, and possibly also with specific acylcarnitines and amino acids. This provides further leads for future research studies aiming at elucidating the mechanisms underlying the effects of alcohol in relation to morbid conditions.
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May 2018

Metabolic Mediators of the Association Between Adult Weight Gain and Colorectal Cancer: Data From the European Prospective Investigation into Cancer and Nutrition (EPIC) Cohort.

Am J Epidemiol 2017 05;185(9):751-764

Evidence indicates that gaining weight in adult life is associated with an elevated risk of colorectal cancer; however, biological mechanisms that may explain this association remain unclear. We evaluated the mediation effect of 20 different biomarkers on the relationship between adult weight gain and colorectal cancer, using data from a prospective nested case-control study of 452 incident cases diagnosed between 1992 and 2003 and matched within risk sets to 452 controls within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The proportions of mediated effects (%) were estimated on the basis of differences in percent effect changes in conditional logistic regression models with and without additional adjustment for individual biomarkers. Greater adult weight gain (≥300 g/year vs. <300 g/year) was associated with a higher risk of colon cancer (multivariable-adjusted relative risk = 1.54, 95% confidence interval: 1.07, 2.24) but not rectal cancer (relative risk = 1.07, 95% confidence interval: 0.68, 1.66). This association was accounted for mostly by attained waist circumference (reduction of 61%) and by the biomarkers soluble leptin receptor (reduction of 43%) and glycated hemoglobin (reduction of 28%). These novel data suggest that the observed association between adult weight gain and colon cancer could be primarily explained by attained abdominal fatness and biomarkers of metabolic dysfunction.
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May 2017

Vitamin E metabolite 13'-carboxychromanols inhibit pro-inflammatory enzymes, induce apoptosis and autophagy in human cancer cells by modulating sphingolipids and suppress colon tumor development in mice.

Free Radic Biol Med 2016 06 23;95:190-9. Epub 2016 Mar 23.

Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA. Electronic address:

Vitamin E forms are substantially metabolized to various carboxychromanols including 13'-carboxychromanols (13'-COOHs) that are found at high levels in feces. However, there is limited knowledge about functions of these metabolites. Here we studied δT-13'-COOH and δTE-13'-COOH, which are metabolites of δ-tocopherol and δ-tocotrienol, respectively. δTE-13'-COOH is also a natural constituent of a traditional medicine Garcinia Kola. Both 13'-COOHs are much stronger than tocopherols in inhibition of pro-inflammatory and cancer promoting cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX), and in induction of apoptosis and autophagy in colon cancer cells. The anticancer effects by 13'-COOHs appeared to be partially independent of inhibition of COX-2/5-LOX. Using liquid chromatography tandem mass spectrometry, we found that 13'-COOHs increased intracellular dihydrosphingosine and dihydroceramides after short-time incubation in HCT-116 cells, and enhanced ceramides while decreased sphingomyelins during prolonged treatment. Modulation of sphingolipids by 13'-COOHs was observed prior to or coinciding with biochemical manifestation of cell death. Pharmaceutically blocking the increase of these sphingolipids partially counteracted 13'-COOH-induced cell death. Further, 13'-COOH inhibited dihydroceramide desaturase without affecting the protein expression. In agreement with these mechanistic findings, δTE-13'-COOH significantly suppressed the growth and multiplicity of colon tumor in mice. Our study demonstrates that 13'-COOHs have anti-inflammatory and anticancer activities, may contribute to in vivo anticancer effect of vitamin E forms and are promising novel cancer prevention agents.
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June 2016

Energy and macronutrient intake and risk of differentiated thyroid carcinoma in the European Prospective Investigation into Cancer and Nutrition study.

Int J Cancer 2016 Jan 30;138(1):65-73. Epub 2015 Jul 30.

CIBER Epidemiología Y Salud Pública (CIBERESP), Madrid, Spain.

Incidence rates of differentiated thyroid carcinoma (TC) have increased in many countries. Adiposity and dietary risk factors may play a role, but little is known on the influence of energy intake and macronutrient composition. The aim of this study was to investigate the associations between TC and the intake of energy, macronutrients, glycemic index (GI) and glycemic load in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The study included 477,274 middle-age participants (70.2% women) from ten European countries. Dietary data were collected using country-specific validated dietary questionnaires. Total carbohydrates, proteins, fats, saturated, monounsaturated and polyunsaturated fats (PUFA), starch, sugar, and fiber were computed as g/1,000 kcal. Multivariable Cox regression was used to calculate multivariable adjusted hazard ratios (HR) and 95% confidence interval (CI) by intake quartile (Q). After a mean follow-up time of 11 years, differentiated TC was diagnosed in 556 participants (90% women). Overall, we found significant associations only with total energy (HRQ4 vs .Q1 , 1.29; 95% CI, 1.00-1.68) and PUFA intakes (HRQ4 vs .Q1 , 0.74; 95% CI, 0.57-0.95). However, the associations with starch and sugar intake and GI were significantly heterogeneous across body mass index (BMI) groups, i.e., positive associations with starch and GI were found in participants with a BMI ≥ 25 and with sugar intake in those with BMI < 25. Moreover, inverse associations with starch and GI were observed in subjects with BMI < 25. In conclusion, our results suggest that high total energy and low PUFA intakes may increase the risk of differentiated TC. Positive associations with starch intake and GI in participants with BMI ≥ 25 suggest that those persons may have a greater insulin response to high starch intake and GI than lean people.
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January 2016