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1. Anthropometry and the Risk of Lung Cancer in EPIC

Author

Dewi, Nikmah Utami, Boshuizen, Hendriek C, Johansson, Mattias, Vineis, Paolo, Kampman, Ellen, Steffen, Annika, Tjønneland, Anne, Halkjær, Jytte, Overvad, Kim, Severi, Gianluca, Fagherazzi, Guy, Boutron-Ruault, Marie-Christine, Kaaks, Rudolf, Li, Kuanrong, Boeing, Heiner, Trichopoulou, Antonia, Bamia, Christina, Klinaki, Eleni, Tumino, Rosario, Palli, Domenico, Mattiello, Amalia, Tagliabue, Giovanna, Peeters, Petra H, Vermeulen, Roel, Weiderpass, Elisabete, Torhild Gram, Inger, Huerta, José María, Agudo, Antonio, Sánchez, María-José, Ardanaz, Eva, Dorronsoro, Miren, Quirós, José Ramón, Sonestedt, Emily, Johansson, Mikael, Grankvist, Kjell, Key, Tim, Khaw, Kay-Tee, Wareham, Nick, Cross, Amanda J, Norat, Teresa, Riboli, Elio, Fanidi, Anouar, Muller, David, Bueno-de-Mesquita, H Bas, LS IRAS EEPI GRA (Gezh.risico-analyse), dIRAS RA-I&I RA, dIRAS RA-2, LS IRAS EEPI GRA (Gezh.risico-analyse), dIRAS RA-I&I RA, dIRAS RA-2, and Imperial College Trust

Subjects
Male, obesity, Lung Neoplasms, Nutrition and Disease, Epidemiology, Comorbidity, waist to hip ratio, ORIGINAL CONTRIBUTIONS, Tumours of the digestive tract Radboud Institute for Health Sciences [Radboudumc 14], 0302 clinical medicine, Waist–hip ratio, Voeding en Ziekte, Multicenter Studies as Topic, Medicine, Prospective Studies, 030212 general & internal medicine, POPULATION, Public, Environmental & Occupational Health, Human Nutrition & Health, Waist-to-height ratio, Anthropometry, Hazard ratio, Humane Voeding & Gezondheid, Confounding Factors, Epidemiologic, 11 Medical And Health Sciences, Middle Aged, waist circumference, Europe, LEANNESS, 030220 oncology & carcinogenesis, Female, Life Sciences & Biomedicine, Adult, medicine.medical_specialty, Waist, body mass index, waist-to-height ratio, Risk Assessment, smoking, 03 medical and health sciences, Journal Article, Humans, COHORT, Lung cancer, waist-to-heigh ratio, METAANALYSIS, 01 Mathematical Sciences, Aged, Proportional Hazards Models, VLAG, MODEL ANALYSIS, Science & Technology, Waist-Hip Ratio, business.industry, Proportional hazards model, CURRENT SMOKERS, Cancer, FAT DISTRIBUTION, medicine.disease, Diet, Surgery, BODY-MASS INDEX, lung cancer, business, Body mass index, Demography
Abstract

The associations of body mass index (BMI) and other anthropometric measurements with lung cancer were examined in 348,108 participants in the European Investigation Into Cancer and Nutrition (EPIC) between 1992 and 2010. The study population included 2,400 case patients with incident lung cancer, and the average length of follow-up was 11 years. Hazard ratios were calculated using Cox proportional hazard models in which we modeled smoking variables with cubic splines. Overall, there was a significant inverse association between BMI (weight (kg)/height (m)(2)) and the risk of lung cancer after adjustment for smoking and other confounders (for BMI of 30.0-34.9 versus 18.5-25.0, hazard ratio = 0.72, 95% confidence interval: 0.62, 0.84). The strength of the association declined with increasing follow-up time. Conversely, after adjustment for BMI, waist circumference and waist-to-height ratio were significantly positively associated with lung cancer risk (for the highest category of waist circumference vs. the lowest, hazard ratio = 1.25, 95% confidence interval: 1.05, 1.50). Given the decline of the inverse association between BMI and lung cancer over time, the association is likely at least partly due to weight loss resulting from preclinical lung cancer that was present at baseline. Residual confounding by smoking could also have influenced our findings.

Published
2016

2. Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry

Author

Figueroa, Jonine D, Middlebrooks, Candace D, Banday, A Rouf, Ye, Yuanqing, Garcia-Closas, Montserrat, Chatterjee, Nilanjan, Koutros, Stella, Kiemeney, Lambertus A, Rafnar, Thorunn, Bishop, Timothy, Furberg, Helena, Matullo, Giuseppe, Golka, Klaus, Gago-Dominguez, Manuela, Taylor, Jack A, Fletcher, Tony, Siddiq, Afshan, Cortessis, Victoria K, Kooperberg, Charles, Cussenot, Olivier, Benhamou, Simone, Prescott, Jennifer, Porru, Stefano, Dinney, Colin P, Malats, Núria, Baris, Dalsu, Purdue, Mark P, Jacobs, Eric J, Albanes, Demetrius, Wang, Zhaoming, Chung, Charles C, Vermeulen, Sita H, Aben, Katja K, Galesloot, Tessel E, Thorleifsson, Gudmar, Sulem, Patrick, Stefansson, Kari, Kiltie, Anne E, Harland, Mark, Teo, Mark, Offit, Kenneth, Vijai, Joseph, Bajorin, Dean, Kopp, Ryan, Fiorito, Giovanni, Guarrera, Simonetta, Sacerdote, Carlotta, Selinski, Silvia, Hengstler, Jan G, Gerullis, Holger, Ovsiannikov, Daniel, Blaszkewicz, Meinolf, Castelao, Jose Esteban, Calaza, Manuel, Martinez, Maria Elena, Cordeiro, Patricia, Xu, Zongli, Panduri, Vijayalakshmi, Kumar, Rajiv, Gurzau, Eugene, Koppova, Kvetoslava, Bueno-De-Mesquita, H Bas, Ljungberg, Börje, Clavel-Chapelon, Françoise, Weiderpass, Elisabete, Krogh, Vittorio, Dorronsoro, Miren, Travis, Ruth C, Tjønneland, Anne, Brennan, Paul, Chang-Claude, Jenny, Riboli, Elio, Conti, David, Stern, Marianna C, Pike, Malcolm C, Van Den Berg, David, Yuan, Jian-Min, Hohensee, Chancellor, Jeppson, Rebecca P, Cancel-Tassin, Geraldine, Roupret, Morgan, Comperat, Eva, Turman, Constance, De Vivo, Immaculata, Giovannucci, Edward, Hunter, David J, Kraft, Peter, Lindstrom, Sara, Carta, Angela, Pavanello, Sofia, Arici, Cecilia, Mastrangelo, Giuseppe, Kamat, Ashish M, Zhang, Liren, Gong, Yilei, Pu, Xia, Hutchinson, Amy, Burdett, Laurie, Wheeler, William A, and Karagas, Margaret R

Subjects
Male, Urologic Diseases, Medical and Health Sciences, Chromosomes, Linkage Disequilibrium, White People, Risk Factors, Genetics, Humans, 2.1 Biological and endogenous factors, Pair 13, Genetic Predisposition to Disease, Polymorphism, Aetiology, Genetic Association Studies, Cancer, Genetics & Heredity, Tumor, Prevention, Human Genome, Single Nucleotide, Biological Sciences, Urinary Bladder Neoplasms, Case-Control Studies, Female, Pair 20, Biomarkers, Human, Genome-Wide Association Study, Biotechnology
Abstract

Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 × 10(-6)), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 × 10(-11)) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 × 10(-10)). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region-the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r(2) = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case-case P ≤ 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer.

Published
2016

3. Plasma fetuin-A concentration, genetic variation in the AHSG gene and risk of colorectal cancer

Author

Nimptsch, Katharina, Aleksandrova, Krasimira, Boeing, Heiner, Janke, Jürgen, Lee, Young-Ae, Jenab, Mazda, Yeon Kong, So, Tsilidis, Konstatinos K, Weiderpass, Elisabete, Bueno-De-Mesquita, Bas H, Siersema, Peter D, Jansen, Eugène H.J.M., Trichopoulou, Antonia, Tjønneland, Anne, Olsen, Anja, Wu, Chunsen, Overvad, Kim, Boutron-Ruault, Marie-Christine, Racine, Antoine, Freisling, Heinz, Katzke, Verena, Kaaks, Rudolf, Lagiou, Pagona, Trichopoulos, Dimitrios, Severi, Gianluca, Naccarati, Alessio, Mattiello, Amalia, Palli, Domenico, Grioni, Sara, Tumino, Rosario, Peeters, Petra H, Ljuslinder, Ingrid, Nyström, Hanna, Brändstedt, Jenny, Sánchez, María-José, Barricarte Gurrea, Aurelio, Bonet Bonet, Catalina, Chirlaque, María-Dolores, Dorronsoro, Miren, Quirós, José Ramón, Travis, Ruth C, Khaw, Kay-Tee, Wareham, Nick, Riboli, Elio, Gunter, Marc J, and Pischon, Tobias

Subjects
Male, Medicine(all), Cancer Research, alpha-2-HS-Glycoprotein, colorectal cancer, Other Research Radboud Institute for Molecular Life Sciences [Radboudumc 0], Middle Aged, fetuin-A, Oncology, Cardiovascular and Metabolic Diseases, Risk Factors, AHSG, Case-Control Studies, Humans, Female, Colorectal Neoplasms, Aged
Abstract

Fetuin-A, also referred to as α2-Heremans-Schmid glycoprotein (AHSG), is a liver protein known to inhibit insulin actions. Hyperinsulinemia is a possible risk factor for colorectal cancer; however, the role of fetuin-A in the development of colorectal cancer is unclear. We investigated the association between circulating fetuin-A and colorectal cancer risk in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition. Fetuin-A concentrations were measured in prediagnostic plasma samples from 1,367 colorectal cancer cases and 1,367 matched controls. In conditional logistic regression models adjusted for potential confounders, the estimated relative risk (95% confidence interval) of colorectal cancer per 40 μg/mL higher fetuin-A concentrations (approximately one standard deviation) was 1.13 (1.02-1.24) overall, 1.21 (1.05-1.39) in men, 1.06 (0.93-1.22) in women, 1.13 (1.00-1.27) for colon cancer and 1.12 (0.94-1.32) for rectal cancer. To improve causal inference in a Mendelian Randomization approach, five tagging single nucleotide polymorphisms of the AHSG gene were genotyped in a subset of 456 case-control pairs. The AHSG allele-score explained 21% of the interindividual variation in plasma fetuin-A concentrations. In instrumental variable analysis, genetically raised fetuin-A was not associated with colorectal cancer risk (relative risk per 40 μg/mL genetically determined higher fetuin-A was 0.98, 95% confidence interval: 0.73-1.33). The findings of our study indicate a modest linear association between fetuin-A concentrations and risk of colorectal cancer but suggest that fetuin-A may not be causally related to colorectal cancer development. What's new? Fetuin-A is a liver protein associated with insulin resistance, but with no defined role yet in colorectal cancer. In this prospective study, the authors uncover a modest linear association between fetuin-A levels and higher risk of colorectal cancer, but this was only observed in male participants. In addition, no association was observed between fetuin-A variants and colorectal cancer risk in a Mendelian randomization analysis, arguing against a direct role of fetuin-A in colorectal carcinogenesis.

Published
2015

4. The Languages at Home and at School in Irun

Author

Irastorza Dorronsoro, Miren Pilar, Gorter, Durk, Didáctica de las Ciencias Sociales, and Gizarte Zientzien didaktika

Subjects
multilingualism
Abstract

It is survey about the diversity of languages spoken at school & at home in Irun.

Published
2014

5. Additional file 1: of Metabolomic profiles of hepatocellular carcinoma in a European prospective cohort

Author

Fages, Anne, Talita Duarte-Salles, Stepien, Magdalena, Ferrari, Pietro, Fedirko, Veronika, Pontoizeau, Clément, Trichopoulou, Antonia, Aleksandrova, Krasimira, Tjønneland, Anne, Olsen, Anja, Clavel-Chapelon, Françoise, Marie-Christine Boutron-Ruault, Severi, Gianluca, Kaaks, Rudolf, Kuhn, Tilman, Floegel, Anna, Boeing, Heiner, Lagiou, Pagona, Bamia, Christina, Trichopoulos, Dimitrios, Palli, Domenico, Pala, Valeria, Panico, Salvatore, Tumino, Rosario, Vineis, Paolo, H. Bueno-De-Mesquita, Peeters, Petra, Weiderpass, Elisabete, Agudo, Antonio, Molina-Montes, Esther, Huerta, José, Ardanaz, Eva, Dorronsoro, Miren, Sjöberg, Klas, Ohlsson, Bodil, Kay-Tee Khaw, Wareham, Nick, Travis, Ruth, Schmidt, Julie, Cross, Amanda, Gunter, Marc, Riboli, Elio, Scalbert, Augustin, Romieu, Isabelle, Elena-Herrmann, Benedicte, and Mazda Jenab

Subjects
3. Good health
Abstract

Supplementary methods for NMR metabolomics data acquisition, additional table (Table S1. Metabolites identified in serum samples) and additional figures (Figure S1. Validation (1000 resampling) of the O-PLS model based on 1H CPMG spectra and O-PLS metabolic signature obtained from the analysis of 1H NOESY NMR spectra. Figure S2. Validation (1000 resampling) of the O-PLS models stratified by hepatitis infection status of the cases, and liver function score. Figure S3. Validation (1000 resampling) of the O-PLS models stratified by lag time between blood collection and diagnosis). (PDF 684 kb)

6. Autoimmunity plays a role in the onset of diabetes after 40 years of age

Author

Rolandsson, Olov, Hampe, Christiane S, Sharp, Stephen J, Ardanaz, Eva, Boeing, Heiner, Fagherazzi, Guy, Mancini, Francesca Romana, Nilsson, Peter M, Overvad, Kim, Chirlaque, Maria-Dolores, Dorronsoro, Miren, Gunter, Marc J, Kaaks, Rudolf, Key, Timothy J, Khaw, Kay-Tee, Krogh, Vittorio, Kühn, Tilman, Palli, Domenico, Panico, Salvatore, Sacerdote, Carlotta, Sánchez, Maria-José, Severi, Gianluca, Spijkerman, Annemieke MW, Tumino, Rosario, Van Der Schouw, Yvonne T, Riboli, Elio, Forouhi, Nita G, Langenberg, Claudia, and Wareham, Nicholas J

Subjects
Adult, Male, Glutamate Decarboxylase, Autoimmunity, Type 2 diabetes, Middle Aged, Genetic risk score, Antibodies, 3. Good health, Autoantibody, Type 1 diabetes, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Incident diabetes, Case-Control Studies, Humans, Female, Aged
Abstract

AIMS/HYPOTHESIS: Type 1 and type 2 diabetes differ with respect to pathophysiological factors such as beta cell function, insulin resistance and phenotypic appearance, but there may be overlap between the two forms of diabetes. However, there are relatively few prospective studies that have characterised the relationship between autoimmunity and incident diabetes. We investigated associations of antibodies against the 65 kDa isoform of GAD (GAD65) with type 1 diabetes and type 2 diabetes genetic risk scores and incident diabetes in adults in European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct, a case-cohort study nested in the EPIC cohort. METHODS: GAD65 antibodies were analysed in EPIC participants (over 40 years of age and free of known diabetes at baseline) by radioligand binding assay in a random subcohort (n = 15,802) and in incident diabetes cases (n = 11,981). Type 1 diabetes and type 2 diabetes genetic risk scores were calculated. Associations between GAD65 antibodies and incident diabetes were estimated using Prentice-weighted Cox regression. RESULTS: GAD65 antibody positivity at baseline was associated with development of diabetes during a median follow-up time of 10.9 years (HR for GAD65 antibody positive vs negative 1.78; 95% CI 1.43, 2.20) after adjustment for sex, centre, physical activity, smoking status and education. The genetic risk score for type 1 diabetes but not type 2 diabetes was associated with GAD65 antibody positivity in both the subcohort (OR per SD genetic risk 1.24; 95% CI 1.03, 1.50) and incident cases (OR 1.97; 95% CI 1.72, 2.26) after adjusting for age and sex. The risk of incident diabetes in those in the top tertile of the type 1 diabetes genetic risk score who were also GAD65 antibody positive was 3.23 (95% CI 2.10, 4.97) compared with all other individuals, suggesting that 1.8% of incident diabetes in adults was attributable to this combination of risk factors. CONCLUSIONS/INTERPRETATION: Our study indicates that incident diabetes in adults has an element of autoimmune aetiology. Thus, there might be a reason to re-evaluate the present subclassification of diabetes in adulthood.

7. A Nested Case-Control Study of Metabolically Defined Body Size Phenotypes and Risk of Colorectal Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC)

Author

Murphy, Neil, Cross, Amanda J, Abubakar, Mustapha, Jenab, Mazda, Aleksandrova, Krasimira, Boutron-Ruault, Marie-Christine, Dossus, Laure, Racine, Antoine, Kühn, Tilman, Katzke, Verena A, Tjønneland, Anne, Petersen, Kristina EN, Overvad, Kim, Quirós, J Ramón, Jakszyn, Paula, Molina-Montes, Esther, Dorronsoro, Miren, Huerta, José-María, Barricarte, Aurelio, Khaw, Kay-Tee, Wareham, Nick, Travis, Ruth C, Trichopoulou, Antonia, Lagiou, Pagona, Trichopoulos, Dimitrios, Masala, Giovanna, Krogh, Vittorio, Tumino, Rosario, Vineis, Paolo, Panico, Salvatore, Bueno-De-Mesquita, H Bas, Siersema, Peter D, Peeters, Petra H, Ohlsson, Bodil, Ericson, Ulrika, Palmqvist, Richard, Nyström, Hanna, Weiderpass, Elisabete, Skeie, Guri, Freisling, Heinz, Kong, So Yeon, Tsilidis, Kostas, Muller, David C, Riboli, Elio, and Gunter, Marc J

Subjects
Male, Health Status, Risk Assessment, Body Mass Index, Risk Factors, Hyperinsulinism, Odds Ratio, Body Size, Humans, Obesity, Prospective Studies, Adiposity, 2. Zero hunger, Obesity, Metabolically Benign, Chi-Square Distribution, C-Peptide, Incidence, nutritional and metabolic diseases, Middle Aged, Protective Factors, 3. Good health, Europe, Logistic Models, Phenotype, Case-Control Studies, Multivariate Analysis, Female, Waist Circumference, Colorectal Neoplasms, Biomarkers
Abstract

BACKGROUND: Obesity is positively associated with colorectal cancer. Recently, body size subtypes categorised by the prevalence of hyperinsulinaemia have been defined, and metabolically healthy overweight/obese individuals (without hyperinsulinaemia) have been suggested to be at lower risk of cardiovascular disease than their metabolically unhealthy (hyperinsulinaemic) overweight/obese counterparts. Whether similarly variable relationships exist for metabolically defined body size phenotypes and colorectal cancer risk is unknown. METHODS AND FINDINGS: The association of metabolically defined body size phenotypes with colorectal cancer was investigated in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Metabolic health/body size phenotypes were defined according to hyperinsulinaemia status using serum concentrations of C-peptide, a marker of insulin secretion. A total of 737 incident colorectal cancer cases and 737 matched controls were divided into tertiles based on the distribution of C-peptide concentration amongst the control population, and participants were classified as metabolically healthy if below the first tertile of C-peptide and metabolically unhealthy if above the first tertile. These metabolic health definitions were then combined with body mass index (BMI) measurements to create four metabolic health/body size phenotype categories: (1) metabolically healthy/normal weight (BMI < 25 kg/m2), (2) metabolically healthy/overweight (BMI ≥ 25 kg/m2), (3) metabolically unhealthy/normal weight (BMI < 25 kg/m2), and (4) metabolically unhealthy/overweight (BMI ≥ 25 kg/m2). Additionally, in separate models, waist circumference measurements (using the International Diabetes Federation cut-points [≥80 cm for women and ≥94 cm for men]) were used (instead of BMI) to create the four metabolic health/body size phenotype categories. Statistical tests used in the analysis were all two-sided, and a p-value of

8. Autoimmunity plays a role in the onset of diabetes after 40 years of age

Author

Rolandsson, Olov, Hampe, Christiane S., Sharp, Stephen J., Ardanaz, Eva, Boeing, Heiner, Fagherazzi, Guy, Mancini, Francesca Romana, Nilsson, Peter M., Overvad, Kim, Chirlaque, Maria-Dolores, Dorronsoro, Miren, Gunter, Marc J., Kaaks, Rudolf, Key, Timothy J., Khaw, Kay-Tee, Krogh, Vittorio, Kühn, Tilman, Palli, Domenico, Panico, Salvatore, Sacerdote, Carlotta, Sánchez, Maria-José, Severi, Gianluca, Spijkerman, Annemieke M. W., Tumino, Rosario, Van Der Schouw, Yvonne T., Riboli, Elio, Forouhi, Nita G., Langenberg, Claudia, and Wareham, Nicholas J.

Subjects
Autoantibody, Type 1 diabetes, Incident diabetes, Autoimmunity, Type 2 diabetes, Article, Genetic risk score, 3. Good health
Abstract

Funder: Umea University, Aims/hypothesis: Type 1 and type 2 diabetes differ with respect to pathophysiological factors such as beta cell function, insulin resistance and phenotypic appearance, but there may be overlap between the two forms of diabetes. However, there are relatively few prospective studies that have characterised the relationship between autoimmunity and incident diabetes. We investigated associations of antibodies against the 65 kDa isoform of GAD (GAD65) with type 1 diabetes and type 2 diabetes genetic risk scores and incident diabetes in adults in European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct, a case-cohort study nested in the EPIC cohort. Methods: GAD65 antibodies were analysed in EPIC participants (over 40 years of age and free of known diabetes at baseline) by radioligand binding assay in a random subcohort (n = 15,802) and in incident diabetes cases (n = 11,981). Type 1 diabetes and type 2 diabetes genetic risk scores were calculated. Associations between GAD65 antibodies and incident diabetes were estimated using Prentice-weighted Cox regression. Results: GAD65 antibody positivity at baseline was associated with development of diabetes during a median follow-up time of 10.9 years (HR for GAD65 antibody positive vs negative 1.78; 95% CI 1.43, 2.20) after adjustment for sex, centre, physical activity, smoking status and education. The genetic risk score for type 1 diabetes but not type 2 diabetes was associated with GAD65 antibody positivity in both the subcohort (OR per SD genetic risk 1.24; 95% CI 1.03, 1.50) and incident cases (OR 1.97; 95% CI 1.72, 2.26) after adjusting for age and sex. The risk of incident diabetes in those in the top tertile of the type 1 diabetes genetic risk score who were also GAD65 antibody positive was 3.23 (95% CI 2.10, 4.97) compared with all other individuals, suggesting that 1.8% of incident diabetes in adults was attributable to this combination of risk factors. Conclusions/interpretation: Our study indicates that incident diabetes in adults has an element of autoimmune aetiology. Thus, there might be a reason to re-evaluate the present subclassification of diabetes in adulthood.

9. Autoimmunity plays a role in the onset of diabetes after 40 years of age

Author

Rolandsson, Olov, Hampe, Christiane S., Sharp, Stephen J., Ardanaz, Eva, Boeing, Heiner, Fagherazzi, Guy, Mancini, Francesca Romana, Nilsson, Peter M., Overvad, Kim, Chirlaque, Maria-Dolores, Dorronsoro, Miren, Gunter, Marc J., Kaaks, Rudolf, Key, Timothy J., Khaw, Kay-Tee, Krogh, Vittorio, Kühn, Tilman, Palli, Domenico, Panico, Salvatore, Sacerdote, Carlotta, Sánchez, Maria-José, Severi, Gianluca, Spijkerman, Annemieke M. W., Tumino, Rosario, Van Der Schouw, Yvonne T., Riboli, Elio, Forouhi, Nita G., Langenberg, Claudia, and Wareham, Nicholas J.

Subjects
Autoantibody, Type 1 diabetes, Incident diabetes, Autoimmunity, Type 2 diabetes, Article, Genetic risk score, 3. Good health
Abstract

Funder: Umea University, Aims/hypothesis: Type 1 and type 2 diabetes differ with respect to pathophysiological factors such as beta cell function, insulin resistance and phenotypic appearance, but there may be overlap between the two forms of diabetes. However, there are relatively few prospective studies that have characterised the relationship between autoimmunity and incident diabetes. We investigated associations of antibodies against the 65 kDa isoform of GAD (GAD65) with type 1 diabetes and type 2 diabetes genetic risk scores and incident diabetes in adults in European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct, a case-cohort study nested in the EPIC cohort. Methods: GAD65 antibodies were analysed in EPIC participants (over 40 years of age and free of known diabetes at baseline) by radioligand binding assay in a random subcohort (n = 15,802) and in incident diabetes cases (n = 11,981). Type 1 diabetes and type 2 diabetes genetic risk scores were calculated. Associations between GAD65 antibodies and incident diabetes were estimated using Prentice-weighted Cox regression. Results: GAD65 antibody positivity at baseline was associated with development of diabetes during a median follow-up time of 10.9 years (HR for GAD65 antibody positive vs negative 1.78; 95% CI 1.43, 2.20) after adjustment for sex, centre, physical activity, smoking status and education. The genetic risk score for type 1 diabetes but not type 2 diabetes was associated with GAD65 antibody positivity in both the subcohort (OR per SD genetic risk 1.24; 95% CI 1.03, 1.50) and incident cases (OR 1.97; 95% CI 1.72, 2.26) after adjusting for age and sex. The risk of incident diabetes in those in the top tertile of the type 1 diabetes genetic risk score who were also GAD65 antibody positive was 3.23 (95% CI 2.10, 4.97) compared with all other individuals, suggesting that 1.8% of incident diabetes in adults was attributable to this combination of risk factors. Conclusions/interpretation: Our study indicates that incident diabetes in adults has an element of autoimmune aetiology. Thus, there might be a reason to re-evaluate the present subclassification of diabetes in adulthood.

10. Additional file 2: of Reproductive factors and risk of mortality in the European Prospective Investigation into Cancer and Nutrition; a cohort study

Author

Merritt, Melissa, Riboli, Elio, Murphy, Neil, Kadi, Mai, Tjønneland, Anne, Olsen, Anja, Overvad, Kim, Dossus, Laure, Dartois, Laureen, Clavel-Chapelon, Françoise, Fortner, Renée, Katzke, Verena, Boeing, Heiner, Trichopoulou, Antonia, Lagiou, Pagona, Trichopoulos, Dimitrios, Palli, Domenico, Sieri, Sabina, Tumino, Rosario, Sacerdote, Carlotta, Panico, Salvatore, H. Bueno-De-Mesquita, Peeters, Petra, Lund, Eiliv, Nakamura, Aurelie, Weiderpass, Elisabete, J. Quirós, Agudo, Antonio, Molina-Montes, Esther, Larrañaga, Nerea, Dorronsoro, Miren, Lluís Cirera, Barricarte, Aurelio, Olsson, Åsa, Butt, Salma, Idahl, Annika, Lundin, Eva, Wareham, Nicholas, Key, Timothy, Brennan, Paul, Ferrari, Pietro, Wark, Petra, Norat, Teresa, Cross, Amanda, and Gunter, Marc

Subjects
3. Good health
Abstract

Supplemental tables that are referred to in the manuscript text. (DOCX 32 kb)

11. Determinants of non- response to a second assessment of lifestyle factors and body weight in the EPIC-PANACEA study

Author

May, Anne M, Adema, Lotte E, Romaguera, Dora, Vergnaud, Anne-Claire, Agudo, Antonio, Ekelund, Ulf, Steffen, Annika, Orfanos, Philippos, Slimani, Nadia, Rinaldi, Sabina, Mouw, Traci, Rohrmann, Sabine, Hermann, Silke, Boeing, Heiner, Bergmann, Manuela M, Jakobsen, Marianne Uhre, Overvad, Kim, Wareham, Nicholas J, Gonzalez, Carlos, Tjonneland, Anne, Halkjaer, Jytte, Key, Timothy J, Spencer, Elizabeth A, Hellstrom, Veronica, Manjer, Jonas, Hedblad, Bo, Lund, Eiliv, Braaten, Tonje, Clavel-Chapelon, Françoise, Boutron-Ruault, Marie-Christine, Rodríguez, Laudina, Sánchez, Maria J, Dorronsoro, Miren, Barricarte, Aurelio, Huerta, Jose Maria, Naska, Androniki, Trichopoulou, Antonia, Palli, Domenico, Pala, Valeria, Norat, Teresa, Mattiello, Amalia, Tumino, Rosario, van der A, Daphne, Bueno-de-Mesquita, H Bas, Riboli, Elio, and Peeters, Petra Hm

Subjects
3. Good health

12. Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.3

Author

Purdue, Mark P., Johansson, Mattias, Zelenika, Diana, Toro, Jorge R., Scelo, Ghislaine, Moore, Lee E., Prokhortchouk, Egor, Wu, Xifeng, Kiemeney, Lambertus A., Gaborieau, Valerie, Jacobs, Kevin B., Allen, Naomi E., Bueno de Mesquita, H. Bas, Peeters, Petra H. M., Trichopoulos, Dimitrios, Linseisen, Jakob, Ljungberg, Börje, Overvad, Kim, Tjønneland, Anne, Romieu, Isabelle, Riboli, Elio, Mukeria, Anush, Shangina, Oxana, Stevens, Victoria L., Thun, Michael J., Diver, W. Ryan, Gapstur, Susan M., Pharoah, Paul D. P., Easton, Douglas F., Albanes, Demetrius, Weinstein, Stephanie J., Virtamo, Jarmo, Vatten, Lars, Hveem, Kristian, Njølstad, Inger, Tell, Grethe, Stoltenberg, Camilla, Kumar, Rajiv, Koppova, Kvetoslava, Cussenot, Olivier, Benhamou, Simone, Oosterwijk, Egbert, Vermeulen, Sita H., Aben, Katja K., van der Marel, Saskia L., Ye, Yuanqing, Wood, Christopher G., Pu, Xia, Mazur, Alexander M., Boulygina, Eugenia S., Chekanov, Nikolai N., Foglio, Mario, Lechner, Doris, Gut, Ivo, Heath, Simon, Blanche, Hélène, Hutchinson, Amy, Thomas, Gilles, Wang, Zhaoming, Yeager, Meredith, Fraumeni, Joseph F., Skryabin, Konstantin G., McKay, James D., Rothman, Nathaniel, Chanock, Stephen J., Lathrop, Mark, Brennan, Paul, Chow, Wong-Ho, Zaridze, David, Matveev, Vsevolod, Lubinski, Jan, Trubicka, Joanna, Szeszenia-Dabrowska, Neonila, Lissowska, Jolanta, Rudnai, Péter, Fabianova, Eleonora, Bucur, Alexandru, Bencko, Vladimir, Foretova, Lenka, Janout, Vladimir, Boffetta, Paolo, Colt, Joanne S., Davis, Faith G., Schwartz, Kendra L., Banks, Rosamonde E., Selby, Peter J., Harnden, Patricia, Berg, Christine D., Hsing, Ann W., Grubb III, Robert L., Boeing, Heiner, Vineis, Paolo, Clavel-Chapelon, Françoise, Palli, Domenico, Tumino, Rosario, Krogh, Vittorio, Panico, Salvatore, Duell, Eric J., Quirós, J. Ramón, Sánchez, María José, Navarro, Carmen, Ardanaz, Eva, Dorronsoro, Miren, and Khaw, Kay-Tee

Subjects
Genòmica, Kidney cancer, Genomics, Càncer de ronyó
Abstract

We conducted a two-stage genome-wide association study of renal cell carcinoma (RCC) in 3,772 affected individuals (cases) and 8,505 controls of European background from 11 studies and followed up 6 SNPs in 3 replication studies of 2,198 cases and 4,918 controls. Two loci on the regions of 2p21 and 11q13.3 were associated with RCC susceptibility below genome-wide significance. Two correlated variants (r(2) = 0.99 in controls), rs11894252 (P = 1.8 x 10(-8)) and rs7579899 (P = 2.3 x 10(-9)), map to EPAS1 on 2p21, which encodes hypoxia-inducible-factor-2 alpha, a transcription factor previously implicated in RCC. The second locus, rs7105934, at 11q13.3, contains no characterized genes (P = 7.8 x 10(-14)). In addition, we observed a promising association on 12q24.31 for rs4765623, which maps to SCARB1, the scavenger receptor class B, member 1 gene (P = 2.6 x 10(-8)). Our study reports previously unidentified genomic regions associated with RCC risk that may lead to new etiological insights.

13. Association between plasma phospholipid saturated fatty acids and metabolic markers of lipid, hepatic, inflammation and glycaemic pathways in eight European countries: a cross-sectional analysis in the EPIC-InterAct study

Author

Zheng, Ju-Sheng, Sharp, Stephen J, Imamura, Fumiaki, Koulman, Albert, Schulze, Matthias B, Ye, Zheng, Griffin, Jules, Guevara, Marcela, Huerta, José María, Kröger, Janine, Sluijs, Ivonne, Agudo, Antonio, Barricarte, Aurelio, Boeing, Heiner, Colorado-Yohar, Sandra, Dow, Courtney, Dorronsoro, Miren, Dinesen, Pia T, Fagherazzi, Guy, Franks, Paul W, Feskens, Edith JM, Kühn, Tilman, Katzke, Verena Andrea, Key, Timothy J, Khaw, Kay-Tee, De Magistris, Maria Santucci, Mancini, Francesca Romana, Molina-Portillo, Elena, Nilsson, Peter M, Olsen, Anja, Overvad, Kim, Palli, Domenico, Quirós, Jose Ramón, Rolandsson, Olov, Ricceri, Fulvio, Spijkerman, Annemieke MW, Slimani, Nadia, Tagliabue, Giovanna, Tjonneland, Anne, Tumino, Rosario, Van Der Schouw, Yvonne T, Langenberg, Claudia, Riboli, Elio, Forouhi, Nita G, and Wareham, Nicholas J

Subjects
Adult, Blood Glucose, Male, Body Mass Index, Young Adult, Hepatic, Humans, Saturated fatty acids, Prospective Studies, Triglycerides, Aged, 2. Zero hunger, Inflammation, Cholesterol, HDL, Fatty Acids, Cholesterol, LDL, Middle Aged, Lipids, Dietary Fats, 3. Good health, Europe, Metabolic markers, Cross-Sectional Studies, Even-chain, lipids (amino acids, peptides, and proteins), Female, Very-long-chain, Glycaemic, Odd-chain, Biomarkers
Abstract

BACKGROUND: Accumulating evidence suggests that individual circulating saturated fatty acids (SFAs) are heterogeneous in their associations with cardio-metabolic diseases, but evidence about associations of SFAs with metabolic markers of different pathogenic pathways is limited. We aimed to examine the associations between plasma phospholipid SFAs and the metabolic markers of lipid, hepatic, glycaemic and inflammation pathways. METHODS: We measured nine individual plasma phospholipid SFAs and derived three SFA groups (odd-chain: C15:0 + C17:0, even-chain: C14:0 + C16:0 + C18:0, and very-long-chain: C20:0 + C22:0 + C23:0 + C24:0) in individuals from the subcohort of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study across eight European countries. Using linear regression in 15,919 subcohort members, adjusted for potential confounders and corrected for multiple testing, we examined cross-sectional associations of SFAs with 13 metabolic markers. Multiplicative interactions of the three SFA groups with pre-specified factors, including body mass index (BMI) and alcohol consumption, were tested. RESULTS: Higher levels of odd-chain SFA group were associated with lower levels of major lipids (total cholesterol (TC), triglycerides, apolipoprotein A-1 (ApoA1), apolipoprotein B (ApoB)) and hepatic markers (alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyl transferase (GGT)). Higher even-chain SFA group levels were associated with higher levels of low-density lipoprotein cholesterol (LDL-C), TC/high-density lipoprotein cholesterol (HDL-C) ratio, triglycerides, ApoB, ApoB/A1 ratio, ALT, AST, GGT and CRP, and lower levels of HDL-C and ApoA1. Very-long-chain SFA group levels showed inverse associations with triglycerides, ApoA1 and GGT, and positive associations with TC, LDL-C, TC/HDL-C, ApoB and ApoB/A1. Associations were generally stronger at higher levels of BMI or alcohol consumption. CONCLUSIONS: Subtypes of SFAs are associated in a differential way with metabolic markers of lipid metabolism, liver function and chronic inflammation, suggesting that odd-chain SFAs are associated with lower metabolic risk and even-chain SFAs with adverse metabolic risk, whereas mixed findings were obtained for very-long-chain SFAs. The clinical and biochemical implications of these findings may vary by adiposity and alcohol intake.

14. Circulating concentrations of vitamin D in relation to pancreatic cancer risk in European populations

Author

Van Duijnhoven, Fränzel JB, Jenab, Mazda, Hveem, Kristian, Siersema, Peter D, Fedirko, Veronika, Duell, Eric J, Kampman, Ellen, Halfweeg, Anouk, Van Kranen, Henk J, Van Den Ouweland, Jody MW, Weiderpass, Elisabete, Murphy, Neil, Langhammer, Arnulf, Ness-Jensen, Eivind, Olsen, Anja, Tjønneland, Anne, Overvad, Kim, Cadeau, Claire, Kvaskoff, Marina, Boutron-Ruault, Marie-Christine, Katzke, Verena A, Kühn, Tilman, Boeing, Heiner, Trichopoulou, Antonia, Kotanidou, Anastasia, Kritikou, Maria, Palli, Domenico, Agnoli, Claudia, Tumino, Rosario, Panico, Salvatore, Matullo, Giuseppe, Peeters, Petra, Brustad, Magritt, Olsen, Karina Standahl, Lasheras, Cristina, Obón-Santacana, Mireia, Sánchez, María-José, Dorronsoro, Miren, Chirlaque, Maria-Dolores, Barricarte, Aurelio, Manjer, Jonas, Almquist, Martin, Renström, Frida, Ye, Weimin, Wareham, Nick, Khaw, Kay-Tee, Bradbury, Kathryn E, Freisling, Heinz, Aune, Dagfinn, Norat, Teresa, Riboli, Elio, and Bueno-De-Mesquita, HB As

Subjects
2. Zero hunger, 25-Hydroxyvitamin D 2, Male, Incidence, pancreatic cancer, vitamin D, Middle Aged, Risk Assessment, 3. Good health, Europe, Pancreatic Neoplasms, nested case-control study, Case-Control Studies, Humans, Female, Prospective Studies, Seasons, cancer epidemiology, Aged, Calcifediol, Follow-Up Studies
Abstract

Evidence from in vivo, in vitro and ecological studies are suggestive of a protective effect of vitamin D against pancreatic cancer (PC). However, this has not been confirmed by analytical epidemiological studies. We aimed to examine the association between pre-diagnostic circulating vitamin D concentrations and PC incidence in European populations. We conducted a pooled nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Nord-Trøndelag Health Study's second survey (HUNT2) cohorts. In total, 738 primary incident PC cases (EPIC n = 626; HUNT2 n = 112; median follow-up = 6.9 years) were matched to 738 controls. Vitamin D [25(OH)D2 and 25(OH)D3 combined] concentrations were determined using isotope-dilution liquid chromatography-tandem mass spectrometry. Conditional logistic regression models with adjustments for body mass index and smoking habits were used to estimate incidence rate ratios (IRRs) and 95% confidence intervals (95%CI). Compared with a reference category of >50 to 75 nmol/L vitamin D, the IRRs (95% CIs) were 0.71 (0.42-1.20); 0.94 (0.72-1.22); 1.12 (0.82-1.53) and 1.26 (0.79-2.01) for clinically pre-defined categories of ≤25; >25 to 50; >75 to 100; and >100 nmol/L vitamin D, respectively (p for trend = 0.09). Corresponding analyses by quintiles of season-standardized vitamin D concentrations also did not reveal associations with PC risk (p for trend = 0.23). Although these findings among participants from the largest combination of European cohort studies to date show increasing effect estimates of PC risk with increasing pre-diagnostic concentrations of vitamin D, they are not statistically significant.

15. Additional file 1: of Metabolomic profiles of hepatocellular carcinoma in a European prospective cohort

Author

Fages, Anne, Talita Duarte-Salles, Stepien, Magdalena, Ferrari, Pietro, Fedirko, Veronika, Pontoizeau, Clément, Trichopoulou, Antonia, Aleksandrova, Krasimira, Tjønneland, Anne, Olsen, Anja, Clavel-Chapelon, Françoise, Marie-Christine Boutron-Ruault, Severi, Gianluca, Kaaks, Rudolf, Kuhn, Tilman, Floegel, Anna, Boeing, Heiner, Lagiou, Pagona, Bamia, Christina, Trichopoulos, Dimitrios, Palli, Domenico, Pala, Valeria, Panico, Salvatore, Tumino, Rosario, Vineis, Paolo, H. Bueno-De-Mesquita, Peeters, Petra, Weiderpass, Elisabete, Agudo, Antonio, Molina-Montes, Esther, Huerta, José, Ardanaz, Eva, Dorronsoro, Miren, Sjöberg, Klas, Ohlsson, Bodil, Kay-Tee Khaw, Wareham, Nick, Travis, Ruth, Schmidt, Julie, Cross, Amanda, Gunter, Marc, Riboli, Elio, Scalbert, Augustin, Romieu, Isabelle, Elena-Herrmann, Benedicte, and Mazda Jenab

Subjects
3. Good health
Abstract

Supplementary methods for NMR metabolomics data acquisition, additional table (Table S1. Metabolites identified in serum samples) and additional figures (Figure S1. Validation (1000 resampling) of the O-PLS model based on 1H CPMG spectra and O-PLS metabolic signature obtained from the analysis of 1H NOESY NMR spectra. Figure S2. Validation (1000 resampling) of the O-PLS models stratified by hepatitis infection status of the cases, and liver function score. Figure S3. Validation (1000 resampling) of the O-PLS models stratified by lag time between blood collection and diagnosis). (PDF 684 kb)

16. Long-term exposure to ambient air pollution and incidence of postmenopausal ereast cancer in 15 European cohorts within the ESCAPE project

Author

Andersen, Zorana J., Stafoggia, Massimo, Weinmayr, Gudrun, Pedersen, Marie, Galassi, Claudia, Jørgensen, Jeanette T., Oudin, Anna, Forsberg, Bertil, Olsson, David, Oftedal, Bente, Marit Aasvang, Gunn, Aamodt, Geir, Pyko, Andrei, Pershagen, Göran, Korek, Michal, De Faire, Ulf, Pedersen, Nancy L., Östenson, Claes-Göran, Fratiglioni, Laura, Eriksen, Kirsten T., Tjønneland, Anne, Peeters, Petra H., Bueno-de-Mesquita, Bas, Plusquin, Michelle, Key, Timothy J., Jaensch, Andrea, Nagel, Gabriele, Lang, Alois, Wang, Meng, Tsai, Ming-Yi, Fournier, Agnes, Boutron-Ruault, Marie-Christine, Baglietto, Laura, Grioni, Sara, Marcon, Alessandro, Krogh, Vittorio, Ricceri, Fulvio, Sacerdote, Carlotta, Migliore, Enrica, Tamayo-Uria, Ibon, Amiano, Pilar, Dorronsoro, Miren, Vermeulen, Roel, Sokhi, Rajneet, Keuken, Menno, de Hoogh, Kees, Beelen, Rob, Vineis, Paolo, Cesaroni, Giulia, Brunekreef, Bert, Hoek, Gerard, and Raaschou-Nielsen, Ole

Subjects
13. Climate action, 3. Good health

17. The association between circulating 25-hydroxyvitamin D metabolites and type 2 diabetes in European populations: A meta-analysis and Mendelian randomisation analysis

Author

Zheng, Ju-Sheng, Luan, Jian’an, Sofianopoulou, Eleni, Sharp, Stephen J., Day, Felix R., Imamura, Fumiaki, Gundersen, Thomas E., Lotta, Luca A., Sluijs, Ivonne, Stewart, Isobel D., Shah, Rupal L., Van Der Schouw, Yvonne T., Wheeler, Eleanor, Ardanaz, Eva, Boeing, Heiner, Dorronsoro, Miren, Dahm, Christina C., Dimou, Niki, El-Fatouhi, Douae, Franks, Paul W., Fagherazzi, Guy, Grioni, Sara, Huerta, José María, Heath, Alicia K., Hansen, Louise, Jenab, Mazda, Jakszyn, Paula, Kaaks, Rudolf, Kühn, Tilman, Khaw, Kay-Tee, Laouali, Nasser, Masala, Giovanna, Nilsson, Peter M., Overvad, Kim, Olsen, Anja, Panico, Salvatore, Quirós, J. Ramón, Rolandsson, Olov, Rodríguez-Barranco, Miguel, Sacerdote, Carlotta, Spijkerman, Annemieke M. W., Tong, Tammy Y. N., Tumino, Rosario, Tsilidis, Konstantinos K., Danesh, John, Riboli, Elio, Butterworth, Adam S., Langenberg, Claudia, Forouhi, Nita G., and Wareham, Nicholas J.

Subjects
Medicine and health sciences, Physical sciences, Research and analysis methods, Biology and life sciences, FOS: Physical sciences, 3. Good health, Research Article
Abstract

Funder: NIHR Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme; Grant(s): IS-BRC-1215-20014, Background: Prior research suggested a differential association of 25-hydroxyvitamin D (25(OH)D) metabolites with type 2 diabetes (T2D), with total 25(OH)D and 25(OH)D3 inversely associated with T2D, but the epimeric form (C3-epi-25(OH)D3) positively associated with T2D. Whether or not these observational associations are causal remains uncertain. We aimed to examine the potential causality of these associations using Mendelian randomisation (MR) analysis. Methods and findings: We performed a meta-analysis of genome-wide association studies for total 25(OH)D (N = 120,618), 25(OH)D3 (N = 40,562), and C3-epi-25(OH)D3 (N = 40,562) in participants of European descent (European Prospective Investigation into Cancer and Nutrition [EPIC]–InterAct study, EPIC-Norfolk study, EPIC-CVD study, Ely study, and the SUNLIGHT consortium). We identified genetic variants for MR analysis to investigate the causal association of the 25(OH)D metabolites with T2D (including 80,983 T2D cases and 842,909 non-cases). We also estimated the observational association of 25(OH)D metabolites with T2D by performing random effects meta-analysis of results from previous studies and results from the EPIC-InterAct study. We identified 10 genetic loci associated with total 25(OH)D, 7 loci associated with 25(OH)D3 and 3 loci associated with C3-epi-25(OH)D3. Based on the meta-analysis of observational studies, each 1–standard deviation (SD) higher level of 25(OH)D was associated with a 20% lower risk of T2D (relative risk [RR]: 0.80; 95% CI 0.77, 0.84; p < 0.001), but a genetically predicted 1-SD increase in 25(OH)D was not significantly associated with T2D (odds ratio [OR]: 0.96; 95% CI 0.89, 1.03; p = 0.23); this result was consistent across sensitivity analyses. In EPIC-InterAct, 25(OH)D3 (per 1-SD) was associated with a lower risk of T2D (RR: 0.81; 95% CI 0.77, 0.86; p < 0.001), while C3-epi-25(OH)D3 (above versus below lower limit of quantification) was positively associated with T2D (RR: 1.12; 95% CI 1.03, 1.22; p = 0.006), but neither 25(OH)D3 (OR: 0.97; 95% CI 0.93, 1.01; p = 0.14) nor C3-epi-25(OH)D3 (OR: 0.98; 95% CI 0.93, 1.04; p = 0.53) was causally associated with T2D risk in the MR analysis. Main limitations include the lack of a non-linear MR analysis and of the generalisability of the current findings from European populations to other populations of different ethnicities. Conclusions: Our study found discordant associations of biochemically measured and genetically predicted differences in blood 25(OH)D with T2D risk. The findings based on MR analysis in a large sample of European ancestry do not support a causal association of total 25(OH)D or 25(OH)D metabolites with T2D and argue against the use of vitamin D supplementation for the prevention of T2D.

18. The association between circulating 25-hydroxyvitamin D metabolites and type 2 diabetes in European populations: A meta-analysis and Mendelian randomisation analysis

Author

Zheng, Ju-Sheng, Luan, Jian'an, Sofianopoulou, Eleni, Sharp, Stephen J, Day, Felix R, Imamura, Fumiaki, Gundersen, Thomas E, Lotta, Luca A, Sluijs, Ivonne, Stewart, Isobel D, Shah, Rupal L, Van Der Schouw, Yvonne T, Wheeler, Eleanor, Ardanaz, Eva, Boeing, Heiner, Dorronsoro, Miren, Dahm, Christina C, Dimou, Niki, El-Fatouhi, Douae, Franks, Paul W, Fagherazzi, Guy, Grioni, Sara, Huerta, José María, Heath, Alicia K, Hansen, Louise, Jenab, Mazda, Jakszyn, Paula, Kaaks, Rudolf, Kühn, Tilman, Khaw, Kay-Tee, Laouali, Nasser, Masala, Giovanna, Nilsson, Peter M, Overvad, Kim, Olsen, Anja, Panico, Salvatore, Quirós, J Ramón, Rolandsson, Olov, Rodríguez-Barranco, Miguel, Sacerdote, Carlotta, Spijkerman, Annemieke MW, Tong, Tammy YN, Tumino, Rosario, Tsilidis, Konstantinos K, Danesh, John, Riboli, Elio, Butterworth, Adam S, Langenberg, Claudia, Forouhi, Nita G, and Wareham, Nicholas J

Subjects
Adult, Male, Mendelian Randomization Analysis, Middle Aged, White People, 3. Good health, Diabetes Mellitus, Type 2, Risk Factors, Dietary Supplements, Humans, Female, Prospective Studies, Vitamin D, Genome-Wide Association Study
Abstract

BACKGROUND: Prior research suggested a differential association of 25-hydroxyvitamin D (25(OH)D) metabolites with type 2 diabetes (T2D), with total 25(OH)D and 25(OH)D3 inversely associated with T2D, but the epimeric form (C3-epi-25(OH)D3) positively associated with T2D. Whether or not these observational associations are causal remains uncertain. We aimed to examine the potential causality of these associations using Mendelian randomisation (MR) analysis. METHODS AND FINDINGS: We performed a meta-analysis of genome-wide association studies for total 25(OH)D (N = 120,618), 25(OH)D3 (N = 40,562), and C3-epi-25(OH)D3 (N = 40,562) in participants of European descent (European Prospective Investigation into Cancer and Nutrition [EPIC]-InterAct study, EPIC-Norfolk study, EPIC-CVD study, Ely study, and the SUNLIGHT consortium). We identified genetic variants for MR analysis to investigate the causal association of the 25(OH)D metabolites with T2D (including 80,983 T2D cases and 842,909 non-cases). We also estimated the observational association of 25(OH)D metabolites with T2D by performing random effects meta-analysis of results from previous studies and results from the EPIC-InterAct study. We identified 10 genetic loci associated with total 25(OH)D, 7 loci associated with 25(OH)D3 and 3 loci associated with C3-epi-25(OH)D3. Based on the meta-analysis of observational studies, each 1-standard deviation (SD) higher level of 25(OH)D was associated with a 20% lower risk of T2D (relative risk [RR]: 0.80; 95% CI 0.77, 0.84; p < 0.001), but a genetically predicted 1-SD increase in 25(OH)D was not significantly associated with T2D (odds ratio [OR]: 0.96; 95% CI 0.89, 1.03; p = 0.23); this result was consistent across sensitivity analyses. In EPIC-InterAct, 25(OH)D3 (per 1-SD) was associated with a lower risk of T2D (RR: 0.81; 95% CI 0.77, 0.86; p < 0.001), while C3-epi-25(OH)D3 (above versus below lower limit of quantification) was positively associated with T2D (RR: 1.12; 95% CI 1.03, 1.22; p = 0.006), but neither 25(OH)D3 (OR: 0.97; 95% CI 0.93, 1.01; p = 0.14) nor C3-epi-25(OH)D3 (OR: 0.98; 95% CI 0.93, 1.04; p = 0.53) was causally associated with T2D risk in the MR analysis. Main limitations include the lack of a non-linear MR analysis and of the generalisability of the current findings from European populations to other populations of different ethnicities. CONCLUSIONS: Our study found discordant associations of biochemically measured and genetically predicted differences in blood 25(OH)D with T2D risk. The findings based on MR analysis in a large sample of European ancestry do not support a causal association of total 25(OH)D or 25(OH)D metabolites with T2D and argue against the use of vitamin D supplementation for the prevention of T2D.

19. Additional file 2: of Reproductive factors and risk of mortality in the European Prospective Investigation into Cancer and Nutrition; a cohort study

Author

Merritt, Melissa, Riboli, Elio, Murphy, Neil, Kadi, Mai, Tjønneland, Anne, Olsen, Anja, Overvad, Kim, Dossus, Laure, Dartois, Laureen, Clavel-Chapelon, Françoise, Fortner, Renée, Katzke, Verena, Boeing, Heiner, Trichopoulou, Antonia, Lagiou, Pagona, Trichopoulos, Dimitrios, Palli, Domenico, Sieri, Sabina, Tumino, Rosario, Sacerdote, Carlotta, Panico, Salvatore, H. Bueno-De-Mesquita, Peeters, Petra, Lund, Eiliv, Nakamura, Aurelie, Weiderpass, Elisabete, J. Quirós, Agudo, Antonio, Molina-Montes, Esther, Larrañaga, Nerea, Dorronsoro, Miren, Lluís Cirera, Barricarte, Aurelio, Olsson, Åsa, Butt, Salma, Idahl, Annika, Lundin, Eva, Wareham, Nicholas, Key, Timothy, Brennan, Paul, Ferrari, Pietro, Wark, Petra, Norat, Teresa, Cross, Amanda, and Gunter, Marc

Subjects
3. Good health
Abstract

Supplemental tables that are referred to in the manuscript text. (DOCX 32 kb)

20. Determination of oleanolic acid in human plasma and its association with olive oil intake in healthy Spanish adults within the EPIC Spain cohort study

Author

Miguel Rodríguez-Barranco, Noémie Travier, Eva Ardanaz, Genevieve Buckland, José Ramón Quirós, Carlos A. González, Aurelio Barricarte, Miren Dorronsoro, Rafael de la Torre, Carmen Navarro, Antoni Pastor, María José Sánchez, Maria Dolores Chirlaque, Pilar Amiano, Amaia Molinuevo, Antonio Agudo, José María Huerta, Leila Lujan-Barroso, [Buckland, Genevieve] Catalan Inst Oncol ICO IDIBELL, Canc Epidemiol Res Programme, Unit Nutr & Canc, Barcelona, Spain, [Lujan-Barroso, Leila] Catalan Inst Oncol ICO IDIBELL, Canc Epidemiol Res Programme, Unit Nutr & Canc, Barcelona, Spain, [Alberto Gonzalez, Carlos] Catalan Inst Oncol ICO IDIBELL, Canc Epidemiol Res Programme, Unit Nutr & Canc, Barcelona, Spain, [Travier, Noemie] Catalan Inst Oncol ICO IDIBELL, Canc Epidemiol Res Programme, Unit Nutr & Canc, Barcelona, Spain, [Agudo, Antonio] Catalan Inst Oncol ICO IDIBELL, Canc Epidemiol Res Programme, Unit Nutr & Canc, Barcelona, Spain, [Pastor, Antoni] Hosp del Mar, IMIM, Neurosci Res Program, Integrat Pharmacol & Syst Neurosci Res Grp,Med Re, Barcelona, Spain, [de la Torre, Rafael] Hosp del Mar, IMIM, Neurosci Res Program, Integrat Pharmacol & Syst Neurosci Res Grp,Med Re, Barcelona, Spain, [Pastor, Antoni] CIBER Fisiopatol Obesidad & Nutr CIBERobn, Santiago De Compostela, Spain, [de la Torre, Rafael] CIBER Fisiopatol Obesidad & Nutr CIBERobn, Santiago De Compostela, Spain, [Lujan-Barroso, Leila] Univ Barcelona, Sch Nursing, Dept Nursing Publ Hlth Mental Hlth & Matern & Chi, Barcelona, Spain, [Amiano, Pilar] CIBER Epidemiol & Publ Hlth CIBERESP, Madrid, Spain, [Maria Huerta, Jose] CIBER Epidemiol & Publ Hlth CIBERESP, Madrid, Spain, [Navarro, Carmen] CIBER Epidemiol & Publ Hlth CIBERESP, Madrid, Spain, [Dolores Chirlaque, Maria] CIBER Epidemiol & Publ Hlth CIBERESP, Madrid, Spain, [Sanchez, Maria-Jose] CIBER Epidemiol & Publ Hlth CIBERESP, Madrid, Spain, [Barricarte, Aurelio] CIBER Epidemiol & Publ Hlth CIBERESP, Madrid, Spain, [Ardanaz, Eva] CIBER Epidemiol & Publ Hlth CIBERESP, Madrid, Spain, [Dorronsoro, Miren] CIBER Epidemiol & Publ Hlth CIBERESP, Madrid, Spain, [Molinuevo, Amaia] CIBER Epidemiol & Publ Hlth CIBERESP, Madrid, Spain, [Amiano, Pilar] BioDonostia Res Inst, Publ Hlth Div Gipuzkoa, Donostia San Sebastian, Spain, [Dorronsoro, Miren] BioDonostia Res Inst, Publ Hlth Div Gipuzkoa, Donostia San Sebastian, Spain, [Maria Huerta, Jose] IMIB Arrixaca, Murcia Reg Hlth Council, Dept Epidemiol, Murcia, Spain, [Navarro, Carmen] IMIB Arrixaca, Murcia Reg Hlth Council, Dept Epidemiol, Murcia, Spain, [Dolores Chirlaque, Maria] IMIB Arrixaca, Murcia Reg Hlth Council, Dept Epidemiol, Murcia, Spain, [Navarro, Carmen] Univ Murcia, Dept Hlth & Social Sci, Murcia, Spain, [Dolores Chirlaque, Maria] Univ Murcia, Dept Hlth & Social Sci, Murcia, Spain, [Sanchez, Maria-Jose] Inst Invest Biosanitaria Ibs, Andaluzian Sch Publ Hlth, Granada, Spain, [Rodriguez-Barranco, Miguel] Inst Invest Biosanitaria Ibs, Andaluzian Sch Publ Hlth, Granada, Spain, [Barricarte, Aurelio] Navarra Publ Hlth Inst, Dept Epidemiol, Pamplona, Spain, [Ardanaz, Eva] Navarra Publ Hlth Inst, Dept Epidemiol, Pamplona, Spain, [Barricarte, Aurelio] Navarra Inst Hlth Res, IdiSNA, Pamplona, Spain, [Ardanaz, Eva] Navarra Inst Hlth Res, IdiSNA, Pamplona, Spain, [Ramon Quiros, Jose] Publ Hlth & Hlth Planning Directorate, Asturias, Spain, [de la Torre, Rafael] Pompeu Fabra Univ UPF, Dept Expt & Hlth Sci DCEXS, Barcelona, Spain, AGAUR, Generalitat de Catalunya, Health Research Funds, FEDER funds /European Regional Development Fund (ERDF) 'A way to buid Europe', Spanish Regional Government of Andalusia, Spanish Regional Government of Asturias, Spanish Regional Government of Basque Country, Spanish Regional Government of Murcia, Spanish Regional Government of Navarra, Catalan Institute of Oncology (ICO-IDIBELL), and CIBER Epidemiologia y Salud Publica (CIBERESP)

Subjects
Adult, Male, Risk, 0301 basic medicine, Population, Apoptosis, Oli d'oliva -- Aspectes nutricionals, Project, Disposition, EPIC, Cohort Studies, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Animal science, Humans, EPIC cohort study, Medicine, Hydroxytyrosol, 030212 general & internal medicine, education, Oleanolic acid, Aged, Cancer, education.field_of_study, 030109 nutrition & dietetics, business.industry, Biomarker, Middle Aged, Nutrition Surveys, Triterpenes, European Prospective Investigation into Cancer and Nutrition, Biotechnology, chemistry, Spain, Human plasma, Cohort, Female, business, Olive oil, Food Science, Cohort study
Abstract

cope Oleanolic acid (OA) is an important triterpenic compound found in olive oil, however little is known about its concentrations in human plasma. We aimed to determine plasma OA levels in a healthy Spanish population and compare them with estimates of dietary olive oil intake. Methods and results The final study sample included 141 individuals randomly selected from the European Prospective Investigation into Cancer and Nutrition Spanish cohort. Dietary olive oil intake was estimated using validated dietary history questionnaires. OA concentrations were determined in plasma (from the participants’ stored blood samples) using a HPLC-MS method. Correlation coefficients between OA and olive oil intake were calculated, adjusting for center; sex; age; consumption of olives, apples, grapes, and red wine; and fasting state. The mean OA concentration in olive oil nonconsumers was 0.72 ng/mL (SD 0.82), while in the high olive oil intake group it was 1.32 ng/mL (SD 1.14). The fully adjusted partial Spearman correlations coefficients reached 0.36 (p-value < 0.001) overall, varying minimally by sex and fasting state. Conclusion This is the first study providing steady-state concentrations of triterpenes in humans. The results show that there was low-to-moderate correlation between OA concentrations and olive oil intake in this population.

Published
2017

21. Pre-diagnostic copper and zinc biomarkers and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort

Author

Magdalena Czuban, Verena Katzke, Hendrik B. Bueno-de-Mesquita, Domenico Palli, Kim Overvad, Lutz Schomburg, Christina Bamia, Tilman Kühn, Francesca Mancini, Amanda J. Cross, Behany van Guelpen, Heinz Freisling, Nicholas J. Wareham, José María Huerta, Kay-Tee Khaw, Alessio Naccarati, David J. Hughes, Mazda Jenab, María José Sánchez, Magdalena Stepien, Kathryn E. Bradbury, Petra H.M. Peeters, Rosario Tumino, Sabina Sieri, Khalid Iqbal, Anja Olsen, Anne Tjønneland, Susana Merino, Aurelio Barricarte, Isabelle Savoye, Antonia Trichopoulou, Philippos Orfanos, Elisabete Weiderpass, Miren Dorronsoro, Niels-Peter Becker, Heiner Boeing, Stina Bodén, Salvatore Panico, Paula Jakszyn, Marie-Christine Boutron-Ruault, Stepien, Magdalena, Jenab, Mazda, Freisling, Heinz, Becker, Niels peter, Czuban, Magdalena, Tjã¸nneland, Anne, Olsen, Anja, Overvad, Kim, Boutron ruault, Marie christine, Mancini, Francesca Romana, Savoye, Isabelle, Katzke, Verena, Kã¼hn, Tilman, Boeing, Heiner, Iqbal, Khalid, Trichopoulou, Antonia, Bamia, Christina, Orfanos, Philippo, Palli, Domenico, Sieri, Sabina, Tumino, Rosario, Naccarati, Alessio, Panico, Salvatore, Bueno de mesquita, H. B., Peeters, Petra H., Weiderpass, Elisabete, Merino, Susana, Jakszyn, Paula, Sanchez, Maria jose, Dorronsoro, Miren, Huerta, Josã© Marã­a, Barricarte, Aurelio, Boden, Stina, Van Guelpen, Behany, Wareham, Nick, Khaw, Kay tee, Bradbury, Kathryn E., Cross, Amanda J., Schomburg, Lutz, Hughes, David J., Wareham, Nicholas [0000-0003-1422-2993], Khaw, Kay-Tee [0000-0002-8802-2903], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Oncology, Male, Cancer Research, Colorectal cancer, diagnosis, Colorectal Neoplasm, SERUM, 0302 clinical medicine, Risk Factors, follow-up, Medicine, Prospective Studies, Prospective cohort study, General Medicine, Middle Aged, Micronutrient, European Prospective Investigation into Cancer and Nutrition, Zinc, 030220 oncology & carcinogenesis, Cohort, Female, Case-Control Studie, Colorectal Neoplasms, Life Sciences & Biomedicine, HUMAN PHYSIOLOGY, biological markers, Human, medicine.medical_specialty, European Continental Ancestry Group, colorectal cancer, HEME IRON, White People, 03 medical and health sciences, RATIO, Breast cancer, nutrition in cancer, DIAGNOSTIC-VALUE, Internal medicine, SELENIUM STATUS, TRACE-ELEMENTS, Journal Article, Biomarkers, Tumor, BREAST-CANCER, Humans, Oncology & Carcinogenesis, RECTAL-CANCER, Aged, Science & Technology, copper measurement, business.industry, VDP::Medical disciplines: 700::Clinical medical disciplines: 750::Oncology: 762, Risk Factor, Case-control study, Oxidative Stre, Odds ratio, medicine.disease, VDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Onkologi: 762, Prospective Studie, Oxidative Stress, 030104 developmental biology, Case-Control Studies, Immunology, business, 1112 Oncology And Carcinogenesis, Copper
Abstract

Adequate intake of copper and zinc, two essential micronutrients, are important for antioxidant functions. Their imbalance may have implications for development of diseases like colorectal cancer (CRC), where oxidative stress is thought to be etiologically involved. As evidence from prospective epidemiologic studies is lacking, we conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort to investigate the association between circulating levels of copper and zinc, and their calculated ratio, with risk of CRC development. Copper and zinc levels were measured by reflection X-ray fluorescence spectrometer in 966 cases and 966 matched controls. Multivariable adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression and are presented for the fifth versus first quintile. Higher circulating concentration of copper was associated with a raised CRC risk (OR = 1.50; 95% CI: 1.06, 2.13; P-trend = 0.02) whereas an inverse association with cancer risk was observed for higher zinc levels (OR = 0.65; 95% CI: 0.43, 0.97; P-trend = 0.07). Consequently, the ratio of copper/zinc was positively associated with CRC (OR = 1.70; 95% CI: 1.20, 2.40; P-trend = 0.0005). In subgroup analyses by follow-up time, the associations remained statistically significant only in those diagnosed within 2 years of blood collection. In conclusion, these data suggest that copper or copper levels in relation to zinc (copper to zinc ratio) become imbalanced in the process of CRC development. Mechanistic studies into the underlying mechanisms of regulation and action are required to further examine a possible role for higher copper and copper/zinc ratio levels in CRC development and progression.

Published
2018
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22. Tobacco smoking-associated genome-wide DNA methylation changes in the EPIC study

Author

Androniki Naska, Rosario Tumino, Salvatore Panico, Eva Ardanaz, Bas Bueno-de-Mesquita, Krasimira Aleksandrova, Akram Ghantous, Paolo Vineis, Timothy J. Key, Neil Murphy, Florence Le Calvez-Kelm, Petra H.M. Peeters, Heiner Boeing, Antonia Trichopoulou, José Ramón Quirós, Cyrille Cuenin, Isabelle Romieu, Elio Riboli, Miren Dorronsoro, Carmen Navarro, Silvia Polidoro, Myrto Barrdahl, Srikant Ambatipudi, Domenico Palli, Pagona Lagiou, Hector Hernandez-Vargas, Vittorio Krogh, Zdenko Herceg, Rudolf Kaaks, Ambatipudi, Srikant, Cuenin, Cyrille, Hernandez Vargas, Hector, Ghantous, Akram, Le Calvez Kelm, Florence, Kaaks, Rudolf, Barrdahl, Myrto, Boeing, Heiner, Aleksandrova, Krasimira, Trichopoulou, Antonia, Lagiou, Pagona, Naska, Androniki, Palli, Domenico, Krogh, Vittorio, Polidoro, Silvia, Tumino, Rosario, Panico, Salvatore, Bueno de Mesquita, Ba, Peeters, Petra Hm, Quirós, José Ramón, Navarro, Carmen, Ardanaz, Eva, Dorronsoro, Miren, Key, Tim, Vineis, Paolo, Murphy, Neil, Riboli, Elio, Romieu, Isabelle, Herceg, Zdenko, Commission of the European Communities, University Medical Center Utrecht, and Imperial College Trust

Subjects
0301 basic medicine, Adult, Male, tobacco smoking, prospective cohort, epigenetic signature, DNA methylome, Cancer Research, medicine.medical_treatment, Physiology, Biology, Tobacco smoke, Epigenesis, Genetic, 03 medical and health sciences, medicine, Genetics, Journal Article, Tobacco Smoking, Humans, Epigenetics, Prospective Studies, Aged, Environmental exposure, Epigenome, Methylation, Sequence Analysis, DNA, DNA Methylation, Middle Aged, 030104 developmental biology, CpG site, DNA methylation, Smoking cessation, CpG Islands, Female, Smoking Cessation
Abstract

Aim: Epigenetic changes may occur in response to environmental stressors, and an altered epigenome pattern may represent a stable signature of environmental exposure. Materials & methods: Here, we examined the potential of DNA methylation changes in 910 prediagnostic peripheral blood samples as a marker of exposure to tobacco smoke in a large multinational cohort. Results: We identified 748 CpG sites that were differentially methylated between smokers and nonsmokers, among which we identified novel regionally clustered CpGs associated with active smoking. Importantly, we found a marked reversibility of methylation changes after smoking cessation, although specific genes remained differentially methylated up to 22 years after cessation. Conclusion: Our study has comprehensively cataloged the smoking-associated DNA methylation alterations and showed that these alterations are reversible after smoking cessation.

Published
2016

23. A Nested Case-Control Study of Metabolically Defined Body Size Phenotypes and Risk of Colorectal Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC)

Author

Murphy, N, Cross, A, Abubakar, M, Jenab, M, Aleksandrova, K, Boutron-Ruault, M, Dossus, L, Racine, A, Kühn, T, Katzke, V, Tjønneland, A, Petersen, K, Overvad, K, Quirós, JR, Jakszyn, P, Molina-Montes, E, Dorronsoro, M, Huerta, J, Barricarte, A, Khaw, K, Wareham, N, Travis, R, Trichopoulou, A, Lagiou, P, Trichopoulos, D, Masala, G, Krogh, V, Tumino, R, Vineis, P, Panico, S, Bueno-de-Mesquita, H, Siersema, P, Peeters, P, Ohlsson, B, Ericson, U, Palmqvist, R, Nyström, H, Weiderpass, E, Skeie, G, Freisling, H, Kong, S, Tsilidis, K, Muller, D, Riboli, E, Gunter, M, [Murphy,N, Cross,AJ, Vineis,P, Bueno-de-Mesquita,HB, Tsilidis,K, Riboli,E, Gunter,MJ] Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.[Abubakar,M] Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, United Kingdom. [Jenab,M, Freisling,M, Kong,SY, Mulle,DC, Gunter,MJ] International Agency for Research on Cancer, World Health Organization, Lyon, France. [Aleksandrova,K] Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Potsdam, Germany. [Boutron-Ruault,M, Dossus,L, Racine,A] Inserm, Nutrition, Hormones and Women’s Health, Centre for Research in Epidemiology and Population Health (CESP), U1018, Villejuif, France. Université Paris Sud, UMRS 1018, Villejuif, France. Institut Gustave Roussy, Villejuif, France. [Kühn,T, Katzke,VA] Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. [Tjønneland,A, Petersen,KEN] Danish Cancer Society Research Center, Copenhagen, Denmark. [Overvad,K] Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark. [Quirós,JR] Public Health Directorate, Asturias, Spain. [Jakszyn,P] Unit of Nutrition, Environment and Cancer, Catalan Institute of Oncology, Barcelona, Spain. [Molina-Montes,E] Andalusian School of Public Health, Granada, Spain. [Molina-Montes,E, Huerta,J, Barricarte,A] Biomedical Research Centre Network for Epidemiology and Public Health (CIBERESP), Madrid, Spain. [Dorronsoro,M] Public Health Direction and Biodonostia–CIBERESP, Basque Regional Health Department, Vitoria, Spain. [Huerta,J] Department of Epidemiology, Murcia Regional Health Council, Murcia, Spain. [Barricarte,A] Navarre Public Health Institute, Pamplona, Spain. [Khaw,K] University of Cambridge, Cambridge, United Kingdom. [Wareham,N] MRC Epidemiology Unit, Cambridge, United Kingdom. [Travis,RC] Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom. [Trichopoulou,A, Trichopoulos,D] Hellenic Health Foundation, Athens, Greece. [Trichopoulou,A, Lagiou,P] Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece. [Trichopoulou,A, Lagiou,P, Trichopoulos,D] Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece. [Lagiou,P, Trichopoulos,D] Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America. [Masala,G] Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), Florence, Italy. [Krogh,V] Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. [Tumino,R] Cancer Registry and Histopathology Unit, Civic–M.P.Arezzo Hospital, Azienda Sanitaria Provinciale di Ragusa, Italy. [Vineis,P] HuGeF Foundation, Torino, Italy. [Panico,S] Dipartimento di Medicina Clinica e Sperimentale, Federico II University, Naples, Italy. [Bueno-de- Mesquita,HB] Department of Determinants of Chronic Diseases, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia [Bueno-de-Mesquita,HB, Siersema,PD] Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, The Netherlands. [Peeters,PH] Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands. [Ohlsson,B] Division of Internal Medicine, Department of Clinical Sciences, Skåne University Hospital, Lund University, Malmö, Sweden. [Ericson,U] Diabetes and Cardiovascular Disease–Genetic Epidemiology, Department of Clinical Sciences, Skåne University Hospital, Lund University, Malmö, Lund University, Sweden. [Palmqvist,R, Nyström,H] Medical Bioscience, Umeå University, Umeå, Sweden. [Weiderpass,E, Skeie,G] Department of Community Medicine, Faculty of Health Sciences, University of Tromsø–The Arctic University of Norway, Tromsø, Norway. [Weiderpass,E] Cancer Registry of Norway, Oslo, Norway. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. Department of Genetic Epidemiology, Folkhälsan Research Center, Helsinki, Finland. [Tsilidis,K] Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece., Funding: The coordination of EPIC is financially supported by the European Commission (DGSANCO), and the International Agency for Research on Cancer., University Medical Center Utrecht, Imperial College Trust, Murphy, Neil, Cross, Amanda J, Abubakar, Mustapha, Jenab, Mazda, Aleksandrova, Krasimira, Boutron Ruault, Marie Christine, Dossus, Laure, Racine, Antoine, Kühn, Tilman, Katzke, Verena A, Tjønneland, Anne, Petersen, Kristina E. N, Overvad, Kim, Quirós, J. Ramón, Jakszyn, Paula, Molina Montes, Esther, Dorronsoro, Miren, Huerta, José María, Barricarte, Aurelio, Khaw, Kay Tee, Wareham, Nick, Travis, Ruth C, Trichopoulou, Antonia, Lagiou, Pagona, Trichopoulos, Dimitrio, Masala, Giovanna, Krogh, Vittorio, Tumino, Rosario, Vineis, Paolo, Panico, Salvatore, Bueno de Mesquita, H. Ba, Siersema, Peter D, Peeters, Petra H, Ohlsson, Bodil, Ericson, Ulrika, Palmqvist, Richard, Nyström, Hanna, Weiderpass, Elisabete, Skeie, Guri, Freisling, Heinz, Kong, So Yeon, Tsilidis, Kosta, Muller, David C, Riboli, Elio, Gunter, Marc J., Khaw, Kay-Tee [0000-0002-8802-2903], Wareham, Nicholas [0000-0003-1422-2993], and Apollo - University of Cambridge Repository

Subjects
Male, Phenomena and Processes::Genetic Phenomena::Phenotype [Medical Subject Headings], Cell- och molekylärbiologi, Obesidad, Biochemistry, Body Mass Index, Tumours of the digestive tract Radboud Institute for Health Sciences [Radboudumc 14], Endocrinology, Odds Ratio, Insulin, Prospective Studies, Diseases::Pathological Conditions, Signs and Symptoms::Signs and Symptoms::Body Weight::Overweight [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Vital Statistics::Morbidity::Prevalence [Medical Subject Headings], Adiposity, VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, C-Peptide, Incidence, 11 Medical And Health Sciences, Oncology, Medicine, Waist Circumference, Fenotipo, Human, Logistic Model, Colon, Risk Assessment, Hyperinsulinism, Gastrointestinal Tumors, Neoplasias Colorrectales, Humans, Comparative Study, Diseases::Cardiovascular Diseases [Medical Subject Headings], Protective Factor, Cancer och onkologi, Chi-Square Distribution, Biology and Life Sciences, nutritional and metabolic diseases, Diseases::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms [Medical Subject Headings], Biomarker, Hormones, Diseases::Nutritional and Metabolic Diseases::Nutrition Disorders::Overnutrition::Obesity [Medical Subject Headings], Prospective Studie, Logistic Models, Case-Control Studies, Cancer and Oncology, Digestive System, Biomarkers, Cell and Molecular Biology, Metabolic Processes, Physiology, Health Status, Colorectal Neoplasm, Health Statu, Risk Factors, Medicine and Health Sciences, Body Size, Multivariate Analysi, Tamaño Corporal, Enfermedades Cardiovasculares, Medicine(all), Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Case-Control Studies [Medical Subject Headings], Research Support, Non-U.S. Gov't, Estudios de Casos y Controles, Estudios Prospectivos, Middle Aged, Multicenter Study, Europe, Phenotype, Physiological Parameters, Female, Anatomy, Colorectal Neoplasms, Case-Control Studie, Research Article, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies::Longitudinal Studies::Prospective Studies [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Physical Examination::Body Constitution::Body Weights and Measures::Body Size [Medical Subject Headings], Rectal Cancer, Research Support, N.I.H., Extramural, General & Internal Medicine, Journal Article, Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Glucose Metabolism Disorders::Hyperinsulinism [Medical Subject Headings], Obesity, Colorectal Cancer, Diabetic Endocrinology, Obesity, Metabolically Benign, Hiperinsulinismo, Risk Factor, Body Weight, Cancers and Neoplasms, Protective Factors, Gastrointestinal Tract, Metabolism, Sobrepeso, Multivariate Analysis, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, Prevalencia
Abstract

Background Obesity is positively associated with colorectal cancer. Recently, body size subtypes categorised by the prevalence of hyperinsulinaemia have been defined, and metabolically healthy overweight/obese individuals (without hyperinsulinaemia) have been suggested to be at lower risk of cardiovascular disease than their metabolically unhealthy (hyperinsulinaemic) overweight/obese counterparts. Whether similarly variable relationships exist for metabolically defined body size phenotypes and colorectal cancer risk is unknown. Methods and Findings The association of metabolically defined body size phenotypes with colorectal cancer was investigated in a case–control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Metabolic health/body size phenotypes were defined according to hyperinsulinaemia status using serum concentrations of C-peptide, a marker of insulin secretion. A total of 737 incident colorectal cancer cases and 737 matched controls were divided into tertiles based on the distribution of C-peptide concentration amongst the control population, and participants were classified as metabolically healthy if below the first tertile of C-peptide and metabolically unhealthy if above the first tertile. These metabolic health definitions were then combined with body mass index (BMI) measurements to create four metabolic health/body size phenotype categories: (1) metabolically healthy/normal weight (BMI < 25 kg/m2), (2) metabolically healthy/overweight (BMI ≥ 25 kg/m2), (3) metabolically unhealthy/normal weight (BMI < 25 kg/m2), and (4) metabolically unhealthy/overweight (BMI ≥ 25 kg/m2). Additionally, in separate models, waist circumference measurements (using the International Diabetes Federation cut-points [≥80 cm for women and ≥94 cm for men]) were used (instead of BMI) to create the four metabolic health/body size phenotype categories. Statistical tests used in the analysis were all two-sided, and a p-value of, Gunter and colleagues analyse a large European dataset to determine how body size and metabolic profile associates with the risk of developing colorectal cancer., Editors' Summary Background Colorectal cancer is the third most common cancer worldwide and is a leading cause of cancer-related death, killing around 700,000 people every year. It develops when cells in the colon (the final part of the digestive system, which is also known as the large intestine or large bowel) or the rectum (the lower end of the colon) acquire genetic changes that allow them to divide uncontrollably to form a tumor and to move around the body (metastasize). Symptoms of colorectal cancer include blood in the stool, a change in bowel habits, and unexplained weight loss. Treatments for colorectal cancer include surgery, chemotherapy, and radiation. As with other types of cancer, these treatments are more likely to be successful if started when the tumor is very small. Consequently, many countries run screening programs that use colonoscopy, the fecal occult blood test, and other tests to detect the earliest signs of colorectal cancer in apparently healthy people. Why Was This Study Done? Being obese—having too much body fat—is associated with an increased colorectal cancer risk (other risk factors include age, having a family history of colorectal cancer, and eating a high-fat, low-fiber diet). Obesity is also associated with several other chronic diseases, and recent evidence suggests that some obese individuals have a higher risk of developing these diseases than others. For example, overweight/obese individuals who have hyperinsulinemia (abnormally high blood levels of insulin; “metabolically unhealthy”) seem to have a higher risk of cardiovascular disease than their non-hyperinsulinemic (“metabolically healthy”) overweight counterparts. If certain combinations of metabolic health status and body size (“metabolically defined body size phenotypes”) are also associated with colorectal cancer, measurement of insulin levels in conjunction with body fat (adiposity) measurements such as body mass index (BMI; an indicator of body fat calculated by dividing a person’s weight in kilograms by their height in meters squared) might improve colorectal cancer risk assessment. In this nested case–control study, the researchers assess the associations between metabolically defined body size phenotypes and colorectal cancer risk. A nested case–control study identifies everyone in a group (here, participants in the European Prospective Investigation into Cancer and Nutrition [EPIC] study) who has a specific condition, identifies matched individuals in the same group without the condition, and asks whether these controls and the cases differ in terms of a specific characteristic or outcome. What Did the Researchers Do and Find? The researchers matched 737 participants in the EPIC study who developed colorectal cancer after study enrollment with 737 controls and used serum concentrations of C-peptide, a marker of insulin secretion, and BMI measurements to classify each individual as metabolically healthy/normal weight, metabolically healthy/overweight, metabolically unhealthy/normal weight, or metabolically unhealthy/overweight. Specifically, the researchers categorized people as metabolically unhealthy if they had a C-peptide level above an arbitrarily chosen cut-off value based on the distribution of C-peptide levels in the control participants and as overweight if they had a BMI of ≥25 kg/m2 (the standard definition of overweight). Compared to metabolically healthy normal weight individuals, metabolically unhealthy normal weight and overweight individuals had an increased colorectal cancer risk; metabolically healthy overweight individuals had a similar colorectal cancer risk to metabolically healthy normal weight individuals. Among overweight individuals, metabolically healthy individuals had a lower colorectal cancer risk than metabolically unhealthy individuals. Finally, similar associations were seen when the researchers used waist circumference instead of BMI as the measure of adiposity. What Do These Findings Mean? These findings suggest that normal weight individuals with hyperinsulinemia (the metabolically unhealthy normal weight phenotype) have a higher risk of colorectal cancer than normal weight individuals without hyperinsulinemia. They also suggest that metabolically unhealthy overweight individuals have a higher risk of colorectal cancer than metabolically healthy overweight individuals. The accuracy of these findings may be limited by the method the researchers used to classify individuals as hyperinsulinemic—there is no universally accepted clinical definition for using C-peptide level to diagnose hyperinsulinemia. Nevertheless, these findings suggest that the assessment of insulin levels in conjunction with adiposity measures might be a better way to assess an individual’s colorectal cancer risk than simply measuring adiposity, and might help to identify those individuals at high risk of colorectal cancer who are most likely to benefit from targeted interventions designed to prevent the onset of clinical disease. Additional Information This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001988. The US National Cancer Institute provides information for patients about all aspects of colorectal cancer; it also provides more detailed information colorectal cancer for health professionals and information on cancer risk and obesity The UK National Health Service Choices website has information and personal stories about colorectal cancer and information on obesity The not-for-profit organization Cancer Research UK provides information about colorectal cancer and about the association between cancer and obesity MedlinePlus provides links to further resources about colorectal cancer and about obesity Wikipedia has a page on hyperinsulinemia (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages) More information about the EPIC study is available

Published
2016

24. A prospective study of the immune system activation biomarker neopterin and colorectal cancer risk

Author

So Yeon J. Kong, Yunxia Lu, Heinz Freisling, Krasimira Aleksandrova, Mazda Jenab, Ingrid Ljuslinder, Paula Jakszyn, Hui Zuo, Pagona Lagiou, Rudolf Kaaks, Marie-Christine Boutron-Ruault, Grethe S. Tell, Elio Riboli, Sabina Sieri, Ruth C. Travis, Shu Chun Chuang, J. Ramón Quirós, Miren Dorronsoro, Gianluca Severi, Richard Palmqvist, Salvatore Panico, Eva Ardanaz, Stein Emil Vollset, Bas Bueno-de-Mesquita, Tilman Kühn, María José Sánchez, Kim Overvad, Marc J. Gunter, Nicholas J. Wareham, Øivind Midttun, Antoine Racine, María Dolores Chirlaque, Paolo Vineis, Heiner Boeing, Anne M. May, Rosario Tumino, Elisabete Weiderpass, Mattias Johansson, Kay-Tee Khaw, Amanda J. Cross, Antonia Trichopoulou, Dimitrios Trichopoulos, Per Magne Ueland, Tobias Pischon, Anne Tjønneland, Domenico Palli, Veronika Fedirko, Aleksandrova, Krasimira, Chuang, Shu Chun, Boeing, Heiner, Zuo, Hui, Tell, Grethe S, Pischon, Tobia, Jenab, Mazda, Bueno de Mesquita, Ba, Vollset, Stein Emil, Midttun, Øivind, Ueland, Per Magne, Fedirko, Veronika, Johansson, Mattia, Weiderpass, Elisabete, Severi, Gianluca, Racine, Antoine, Boutron Ruault, Marie Christine, Kaaks, Rudolf, Kühn, Tilman, Tjønneland, Anne, Overvad, Kim, Quirós, J. Ramón, Jakszyn, Paula, Sánchez, María José, Dorronsoro, Miren, Chirlaque, Maria Dolore, Ardanaz, Eva, Khaw, Kay Tee, Wareham, Nicholas J, Travis, Ruth C, Trichopoulou, Antonia, Lagiou, Pagona, Trichopoulos, Dimitrio, Palli, Domenico, Sieri, Sabina, Tumino, Rosario, Panico, Salvatore, May, Anne M, Palmqvist, Richard, Ljuslinder, Ingrid, Kong, So Yeon J, Freisling, Heinz, Gunter, Marc J, Lu, Yunxia, Cross, Amanda J, Riboli, Elio, and Vineis, Paolo

Subjects
Male, Cancer Research, Cellular immunity, Helper-Inducer, Colorectal cancer, T-Lymphocytes, Colorectal Neoplasm, cancer risk, medicine.disease_cause, immunology, chemistry.chemical_compound, analogs and derivatives, immune system diseases, Tandem Mass Spectrometry, Odds Ratio, Prospective Studies, Prospective cohort study, Chromatography, Liquid, Colonic Neoplasm, Immunity, Cellular, Tumor, nutrition in cancer, oxidative stress, colorectal cancer, biological markers, inflammation, neopterin, plasma drug concentration, colon, immune system, rectal carcinoma, follow-up, colon tumor, risk assessment, Neopterin, T-Lymphocytes, Helper-Inducer, Middle Aged, tumor marker, adult, biological marker, unclassified drug, Europe, priority journal, risk factor, Oncology, Colonic Neoplasms, Biomarker (medicine), Female, medicine.symptom, Colorectal Neoplasms, Case-Control Studie, prospective study, Human, Adult, Inflammation, cellular immunity, 8 dihydroneopterin, Sensitivity and Specificity, Article, Immune system, blood, medicine, Biomarkers, Tumor, liquid chromatography, Humans, 8-dihydroneopterin, controlled study, human, 7,8-dihydroneopterin, Aged, helper cell, rectum tumor, Rectal Neoplasm, Rectal Neoplasms, business.industry, Immunity, case control study, medicine.disease, major clinical study, 7,8 dihydroneopterin, Prospective Studie, chemistry, Case-Control Studies, tumor marker, Immunology, Cancer research, tandem mass spectrometry, Adult, Cellular, business, Biomarkers, Oxidative stress, colorectal tumor, Chromatography, Liquid
Abstract

Background: Neopterin may be relevant for colorectal cancer (CRC) development, as a biomarker of cellular immune activity exerting pleiotropic effects on cellular ageing, oxidative stress, and inflammation. So far, the association between prediagnostic neopterin and colon and rectal cancer risk has not been evaluated in human populations. Methods: A nested case-control study was conducted within the European Prospective Investigation into Cancer and Nutrition cohort using data on plasma concentrations of total neopterin (T-N, sum of neopterin and 7,8-dihydroneopterin) in 830 incident CRC case patients (561 colon and 269 rectal) matched within risk sets to 830 control participants. A subsequent replication study used data from the Hordaland Health Study, where 173 CRC case patients have been diagnosed among 6594 healthy participants over 12 years of follow-up. Results: After multivariable adjustment for a priori chosen CRC risk factors, a "U-shaped" association of T-N with CRC was revealed. Compared with the second quintile of the T-N distribution, the relative risks for the first, third, fourth, and fifth quintiles were 2.37 (95% CI = 1.66 to 3.39), 1.24 (95% CI = 0.87 to 1.77), 1.55 (95% CI = 1.08 to 2.22), and 2.31 (95% CI = 1.63 to 3.27), respectively. Replication of these associations within the Hordaland Health Study yielded similar results. No differences have been observed when the associations were explored by colon and rectal cancer site (two-sided P difference =. 87) and after excluding case patients diagnosed within the first four follow-up years. Conclusions: These novel findings provide evidence of the role of both suppressed and activated cell-mediated immunity as reflected by prediagnostic T-N concentrations in the development of CRC. © 2015 The Author. Published by Oxford University Press. All rights reserved.

Published
2015

25. Pre-diagnostic concordance with the WCRF/AICR guidelines and survival in European colorectal cancer patients: a cohort study

Author

Carla H. van Gils, E. Riboli, Christos Tsironis, Anne-Claire Vergnaud, H. Bas Bueno-de-Mesquita, Laureen Dartois, José Ramón Quirós, Veronika Fedirko, Pietro Ferrari, Teresa Norat, Pagona Lagiou, Christina C. Dahm, Giovanna Masala, Timothy J. Key, Mark J. Gunter, Maria Wennberg, Kay-Tee Khaw, Verena Katzke, Petra H.M. Peeters, Aurelio Barricarte, Heather Ward, Nicholas J. Wareham, Anne Tjønneland, Lena Maria Nilsson, Bodil Ohlsson, Valeria Pala, Laure Dossus, Antonia Trichopoulou, Tilman Kühn, Heiner Boeing, Elisabete Weiderpass, Petra A. Wark, M. Dorronsoro, Carmen Navarro, Camilla Plambeck Hansen, Genevieve Buckland, Salvatore Panico, Marie-Christine Boutron-Ruault, María José Sánchez, Paolo Vineis, Peter D. Siersema, Karin Jirström, Dora Romaguera, Rosario Tumino, Mazda Jenab, Romaguera, Dora, Ward, Heather, Wark, Petra A, Vergnaud, Anne Claire, Peeters, Petra H, van Gils, Carla H, Ferrari, Pietro, Fedirko, Veronika, Jenab, Mazda, Boutron Ruault, Marie Christine, Dossus, Laure, Dartois, Laureen, Hansen, Camilla Plambeck, Dahm, Christina Catherine, Buckland, Genevieve, Sánchez, María José, Dorronsoro, Miren, Navarro, Carmen, Barricarte, Aurelio, Key, Timothy J, Trichopoulou, Antonia, Tsironis, Christo, Lagiou, Pagona, Masala, Giovanna, Pala, Valeria, Tumino, Rosario, Vineis, Paolo, Panico, Salvatore, Bueno de Mesquita, H. Ba, Siersema, Peter D, Ohlsson, Bodil, Jirström, Karin, Wennberg, Maria, Nilsson, Lena M, Weiderpass, Elisabete, Kühn, Tilman, Katzke, Verena, Khaw, Kay Tee, Wareham, Nick J, Tjønneland, Anne, Boeing, Heiner, Quirós, José R, Gunter, Marc J, Riboli, Elio, Norat, Teresa, Department of Medical and Clinical Genetics, Medicum, BMC, BMC, Department of Epidemiology and Public Health, Imperial College London, Instituto de Investigación Sanitaria de Palma (IdISPa), Hospital Universitario Son Espases, CIBER Fisiopatología de la Obesidad y Nutrición ( (CIBEROBN)), Instituto de Salud Carlos III [Madrid] (ISC), Department of Primary Care and Public Health, Department of Epidemiology, University Medical Center [Utrecht]-Julius Center for Health Sciences and Primary Care, Nutrition and Metabolism Section, International Agency for Cancer Research (IACR), Emory University [Atlanta, GA]-Rollins School of Public Health-Winship Cancer Institute, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Section for Epidemiology, Aarhus University [Aarhus], Unit of Nutrition, Environment and Cancer, Catalan Institute of Oncology (ICO-IDIBELL)-Cancer Epidemiology Research Programme, Granada Cancer Registry, Andalusian School of Public Health [Granada], Consorcio de Investigación Biomédica en Red especializado en Epidemiología y Salud Pública (CIBERESP), Los Centros de Investigación Biomédica en Red (CIBER), Murcia Regional Health Council [Murcia], Department of Health and Social Sciences, Universidad de Murcia, Navarre Public Health Institute, Cancer Epidemiology Unit, University of Oxford, Hellenic Health Foundation, Bureau of Epidemiologic Research, Academy of Athens, Department of Hygiene, Epidemiology and Medical Statistics, Harvard School of Public Health, Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute-ISPO, Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan], Cancer Registry and Histopathology Unit, Department of Oncology-Civile - M.P.Arezzo Hospital, Human Genetics Foundation (HuGeF), Università degli studi di Torino = University of Turin (UNITO), Dipartimento di Medicina Clinica e Chirurgia, University of Naples Federico II = Università degli studi di Napoli Federico II, Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya = Universiti Malaya [Kuala Lumpur, Malaisie] (UM), Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment [Bilthoven] (RIVM), Department of Gastroenterology and Hepatology, University Medical Center [Utrecht], Division of Internal Medicine, Skane University Hospital [Malmo], Lund University [Lund]-Lund University [Lund], Division of Oncology and Pathology, Lund University [Lund], Department of Public Health and Clinical Medicine, Nutritional Research, Umeå University, Arctic Research Centre, Department of Community Medicine, The Arctic University of Norway [Tromsø, Norway] (UiT), Department of Research, Cancer Registry of Norway, Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Genetic Epidemiology Group [Helsinki], Folkhälsan Research Center, Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Division of Cancer Epidemiology, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Clinical Gerontology Unit, University of Cambridge [UK] (CAM), MRC Epidemiology Unit, University of Cambridge [UK] (CAM)-Institute of Metabolic Science, Danish Cancer Society Research Center, German Institute of Human Nutrition (DIfE) Potsdam-Rehbrücke, Public Health Directorate, Khaw, Kay-Tee [0000-0002-8802-2903], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), University of Oxford [Oxford], Università degli studi di Torino (UNITO), University of Naples Federico II, University of Malaya, The Arctic University of Norway, University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, [Romaguera,D, Ward,H, Vergnaud,A, Peeters,PH, Vineis,P, Bueno-de-Mesquita,HB, Gunter, MJ, Riboli,E, Norat,T] Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK. [Romaguera,D] Instituto de Investigación Sanitaria de Palma (IdISPa), Hospital Universitario Son Espases, Palma de Mallorca, Spain. [Romaguera,D] CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain. [Wark,PA] Global eHealth Unit, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, UK. [Peeters,PH, Gils, CH] Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands. [Ferrari,P, Jenab,M] International Agency for Cancer Research (IARC), Lyon CEDEX, France. [Fedirko,V] Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, USA. [Fedirko,V] Winship Cancer Institute, Emory University, Atlanta, USA. [Boutron-Ruault,M, Dossus,L, Dartois,L] Inserm (Institut National de la Santé et de la Recherche Médicale), Centre for Research in Epidemiology and Population Health (CESP), Vaillant, Villejuif, Cedex, France. [Boutron-Ruault,M, Dartois,L] Univ Paris Sud, Villejuif, France. [Boutron-Ruault,M, Dartois,L] Gustave Roussy, Villejuif, France. [Hansen,CP, Dahm,CC] Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus C, Denmark. [Buckland,G] Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Programme, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain. [Sánchez,MJ] Escuela Andaluza de Salud Pública, Instituto de Investigación Biosanitaria ibs. GRANADA, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain. [Sánchez,MJ, Dorronsoro,M, Navarro,C, Barricarte,A] CIBER de Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain. [Dorronsoro,M] Public Health Direction and Biodonostia Basque Regional Health Department, San Sebastian, Spain. [Navarro,C] Department of Epidemiology, Murcia Regional Health Council, Murcia, Spain. Department of Health and Social Sciences, Universidad de Murcia, Campus Universitario de Espinardo, Murcia, Spain. [Barricarte,A] Navarre Public Health Institute, Pamplona, Spain. [Key,TJ] Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford UK. [Trichopoulou,A, Tsironis,C] Hellenic Health Foundation, Athens, Greece . [Trichopoulou,A, Lagiou,P] Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece. [Lagiou,P] Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece. [Lagiou,P] Department of Epidemiology, Harvard School of Public Health, Boston, USA. [Masala,G] Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute – ISPO, Florence, Italy. [Pala,V] Epidemiology and Prevention Unit, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy. [Tumino,R] Cancer Registry and Histopathology Unit, 'Civic – M.P. Arezzo' Hospital, Ragusa, Italy. [Vineis,P] HuGeF Foundation, Turin, Italy. [Panico,S] Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy. [Bueno-de-Mesquita,HB] Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven The Netherlands. [Bueno-de-Mesquita,HB, Siersema,PD] Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands. [Bueno-de-Mesquita,HB] Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. [Ohlsson,B] Division of Internal Medicine, Department of Clinical Sciences, Skane University Hospital, Malmo, Lund University, Lund, Sweden. [Jirström,K] Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden. [Wennberg,M] Public Health and Clinical Medicine, Nutritional Research, Umeå University, Umeå, Sweden. [Nilsson,LM] Arctic Research Centre, Umeå University, Umeå, Sweden. [Weiderpass,E] Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, ISM - Universitetet i Tromsø, Tromsø, Norway. Department of Research, Cancer Registry of Norway, Majorstuen Oslo, Norway. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. Department of Genetic Epidemiology, Folkhälsan Research Center, Folkhälsan Research Center, Biomedicum 1, University of Helsinki, Helsinki, Finland. [Kühn,T, Katzke,V] German Cancer Research Center (DKFZ), Division of Cancer Epidemiology Im Neuenheimer Feld 581, Heidelberg, Germany. [Khaw,K] University of Cambridge School of Clinical Medicine, Clinical Gerontology Unit Box 251, Addenbrooke’s Hospital, Cambridge, UK. [Wareham,NJ] MRC Epidemiology Unit, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK. [Tjønneland,A] Danish Cancer Society Research Center, Copenhagen, Denmark. [Boeing,H] Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. [Quirós,JR] Public Health Directorate, Oviedo Asturias, Spain., This study was funded by the World Cancer Research Fund (WCRF) International Regular Grant Programme (Grant number 2009/44). Dora Romaguera holds a Ramon y Cajal contract (Ministerio de Economía y Competitividad, Spain and European Regional Development Fund, RYC-2011-08796). In addition, EPIC investigators acknowledge funding from the following agencies: Europe Against Cancer Program of the European Commission (SANCO), German Cancer Aid, German Cancer Research Center (DKFZ), German Federal Ministry of Education and Research (BMBF), Danish Cancer Society, Catalan Institute of Oncology, Spain, Health Research Fund (FIS) of the Spanish Ministry of Health, Spanish Regional Governments of Andalucía, Asturias, Basque Country, Murcia (no. 6236) and Navarra, ISCIII RCESP exp. C03/09 and ISCIII RETICC RD06/0020/0091, Spain, Cancer Research UK, Medical Research Council, United Kingdom, The Hellenic Health Foundation, Greece, Italian Association for Research on Cancer (AIRC), Italian National Research Council, Fondazione-Istituto Banco Napoli, Italy, Dutch Ministry of Public Health, Welfare and Sports, Dutch Prevention Funds, LK Research Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), The Netherlands, Swedish Cancer Society, Swedish Scientific Council, Regional Government of Skåne, Sweden, Helga—Nordic Center of Excellence Programme in Nutrition and Health, French League against Cancer (LNCC), National Institute for Health and Medical Research (INSERM), France, Mutuelle Générale de l'Education Romaguera et al. BMC Medicine (2015) 13:107 Page 10 of 12 Nationale (MGEN), France, 3 M Co., France, Gustave Roussy Institute (IGR), France, and and General Councils of France. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Subjects
Male, physical activity, 0302 clinical medicine, estudios prospectivos, Prospective Studies, estudios de cohortes, mediana edad, Aged, 80 and over, anciano, Psychiatry and Psychology::Behavior and Behavior Mechanisms::Behavior::Motor Activity [Medical Subject Headings], dieta, Incidence, Hazard ratio, COLON-CANCER, General Medicine, adulto, 3. Good health, Näringslära, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, estilo de vida, Cohort, Dieta, Estilo de Vida, RESEARCH FUND/AMERICAN INSTITUTE, Cohort study, Human, medicine.medical_specialty, Concordance, European Continental Ancestry Group, DIAGNOSIS, incidencia, White People, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Càncer colorectal, Neoplasias Colorrectales, BREAST-CANCER, Humans, Life Style, Aged, Cancer prevention, Proportional hazards model, Physical activity, Diseases::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms [Medical Subject Headings], Psychiatry and Psychology::Behavior and Behavior Mechanisms::Psychology, Social::Life Style [Medical Subject Headings], weight, LIFE-STYLE FACTORS, Colorectal cancer, REPRODUCTIVE HISTORY, Prospective Studie, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies [Medical Subject Headings], Cancer and Oncology, Proportional Hazards Model, grupo de ascendencia continental europea, Estudios de Cohortes, Gerontology, cumplimiento del paciente, Survival, modelos de riesgos proporcionales, VDP::Medisinske Fag: 700::Helsefag: 800::Epidemiologi medisinsk og odontologisk statistikk: 803, [SDV]Life Sciences [q-bio], humanos, Colorectal Neoplasm, Alcohol consumption, Breast cancer, Prospective study, Named Groups::Persons::Survivors [Medical Subject Headings], Cohort Studies, 030212 general & internal medicine, Prospective cohort study, Non-U.S. Gov't, 2. Zero hunger, Medicine(all), RISK, Nutrition and Dietetics, Healthy lifestyle, Diet, Weight, Research Support, Non-U.S. Gov't, Public Health, Global Health, Social Medicine and Epidemiology, Middle Aged, European Prospective Investigation into Cancer and Nutrition, VDP::Medical disciplines: 700::Health sciences: 800::Epidemiology medical and dental statistics: 803, NUTRITION, Female, Colorectal Neoplasms, Research Article, Adult, neoplasias colorrectales, 3122 Cancers, RECREATIONAL PHYSICAL-ACTIVITY, Other Research Radboud Institute for Molecular Life Sciences [Radboudumc 0], colorectal cancer, Phenomena and Processes::Physiological Phenomena::Nutritional Physiological Phenomena::Diet [Medical Subject Headings], Research Support, survival, Sobrevivientes, healthy lifestyle, Internal medicine, medicine, Journal Article, Proportional Hazards Models, Actividad Motora, business.industry, Physical fitness, BODY-MASS INDEX, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Other Clinical Medicine, 3121 General medicine, internal medicine and other clinical medicine, Patient Compliance, Cohort Studie, business, diet, Condició física
Abstract

Background: Cancer survivors are advised to follow lifestyle recommendations on diet, physical activity, and body fatness proposed by the World Cancer Research Fund/American Institute of Cancer Research (WCRF/AICR) for cancer prevention. Previous studies have demonstrated that higher concordance with these recommendations measured using an index score (the WCRF/AICR score) was associated with lower cancer incidence and mortality. The aim of this study was to evaluate the association between pre-diagnostic concordance with WCRF/AICR recommendations and mortality in colorectal cancer (CRC) patients. Methods: The association between the WCRF/AICR score (score range 0-6 in men and 0-7 in women; higher scores indicate greater concordance) assessed on average 6.4 years before diagnosis and CRC-specific (n = 872) and overall mortality (n = 1,113) was prospectively examined among 3,292 participants diagnosed with CRC in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (mean follow-up time after diagnosis 4.2 years). Multivariable Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality. Results: The HRs (95% CIs) for CRC-specific mortality among participants in the second (score range in men/women: 2.25-2.75/3.25-3.75), third (3-3.75/4-4.75), and fourth (4-6/5-7) categories of the score were 0.87 (0.72-1.06), 0.74 (0.61-0.90), and 0.70 (0.56-0.89), respectively (P for trend, We would like to acknowledge the contribution of all participants in the study. This study was funded by the World Cancer Research Fund (WCRF) International Regular Grant Programme (Grant number 2009/44). Dora Romaguera holds a Ramon y Cajal contract (Ministerio de Economia y Competitividad, Spain and European Regional Development Fund; RYC-2011-08796). In addition, EPIC investigators acknowledge funding from the following agencies: Europe Against Cancer Program of the European Commission (SANCO); German Cancer Aid; German Cancer Research Center (DKFZ); German Federal Ministry of Education and Research (BMBF); Danish Cancer Society; Catalan Institute of Oncology, Spain; Health Research Fund (FIS) of the Spanish Ministry of Health; Spanish Regional Governments of Andalucia, Asturias, Basque Country, Murcia (no. 6236) and Navarra; ISCIII RCESP exp. C03/09 and ISCIII RETICC RD06/0020/0091, Spain; Cancer Research UK; Medical Research Council, United Kingdom; The Hellenic Health Foundation, Greece; Italian Association for Research on Cancer (AIRC); Italian National Research Council; Fondazione-Istituto Banco Napoli, Italy; Dutch Ministry of Public Health, Welfare and Sports, Dutch Prevention Funds, LK Research Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), The Netherlands; Swedish Cancer Society; Swedish Scientific Council; Regional Government of Skane, Sweden; Helga-Nordic Center of Excellence Programme in Nutrition and Health; French League against Cancer (LNCC); National Institute for Health and Medical Research (INSERM), France; Mutuelle Generale de l'Education Nationale (MGEN), France; 3 M Co., France; Gustave Roussy Institute (IGR), France; and General Councils of France.

Published
2014

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