Publications by authors named "Verena A Katzke"

42 Publications

Are Circulating Immune Cells a Determinant of Pancreatic Cancer Risk? A Prospective Study Using Epigenetic Cell Count Measures.

Cancer Epidemiol Biomarkers Prev 2021 Sep 20. Epub 2021 Sep 20.

International Agency for Research on Cancer, World Health Organization, Lyon, France.

Background: Evidence is accumulating that immune cells play a prominent role in pancreatic cancer etiology but prospective investigations are missing.

Methods: We conducted a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) study with 502 pairs of incident pancreatic cancer cases and matched controls. Relative counts of circulating immune cells (neutrophils and lymphocyte sublineages: total CD3, CD8, CD4, and FOXP3 regulatory T cells (Tregs) relative to nucleated cells, (white blood cells) were measured by qRT-PCR. ORs with 95% confidence intervals were estimated using logistic regressions, modeling relative counts of immune cells on a continuous scale.

Results: Neither relative counts of immune cell types taken individually, nor mutually adjusted for each other were associated with pancreatic cancer risks. However, in subgroup analyses by strata of lag-time, higher relative counts of Tregs and lower relative counts of CD8 were significantly associated with an increased pancreatic cancer risks in participants diagnosed within the first 5 years of follow-up.

Conclusions: These results might reflect reverse causation, due to higher relative counts of Tregs and lower counts of CD8 cells among individuals with more advanced stages of latent pancreatic cancer, who are closer to the point of developing clinical manifest disease.

Impact: We have shown, for the first time, that increased relative counts of regulatory T cells and lower relative counts of CD8, cytotoxic T cells may be associated with pancreatic cancer risk or relatively late-stage tumor development.
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http://dx.doi.org/10.1158/1055-9965.EPI-21-0169DOI Listing
September 2021

Interaction Between GAD65 Antibodies and Dietary Fish Intake or Plasma Phospholipid n-3 Polyunsaturated Fatty Acids on Incident Adult-Onset Diabetes: The EPIC-InterAct Study.

Diabetes Care 2021 02 10;44(2):416-424. Epub 2020 Dec 10.

Medical Research Council Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, U.K.

Objective: Islet autoimmunity is associated with diabetes incidence. We investigated whether there was an interaction between dietary fish intake or plasma phospholipid n-3 polyunsaturated fatty acid (PUFA) concentration with the 65-kDa isoform of GAD (GAD65) antibody positivity on the risk of developing adult-onset diabetes.

Research Design And Methods: We used prospective data on 11,247 incident cases of adult-onset diabetes and 14,288 noncases from the EPIC-InterAct case-cohort study conducted in eight European countries. Baseline plasma samples were analyzed for GAD65 antibodies and phospholipid n-3 PUFAs. Adjusted hazard ratios (HRs) for incident diabetes in relation to GAD65 antibody status and tertiles of plasma phospholipid n-3 PUFA or fish intake were estimated using Prentice-weighted Cox regression. Additive (proportion attributable to interaction [AP]) and multiplicative interactions between GAD65 antibody positivity (≥65 units/mL) and low fish/n-3 PUFA were assessed.

Results: The hazard of diabetes in antibody-positive individuals with low intake of total and fatty fish, respectively, was significantly elevated (HR 2.52 [95% CI 1.76-3.63] and 2.48 [1.79-3.45]) compared with people who were GAD65 antibody negative and had high fish intake, with evidence of additive (AP 0.44 [95% CI 0.16-0.72] and 0.48 [0.24-0.72]) and multiplicative ( = 0.0465 and 0.0103) interactions. Individuals with high GAD65 antibody levels (≥167.5 units/mL) and low total plasma phospholipid n-3 PUFAs had a more than fourfold higher hazard of diabetes (HR 4.26 [2.70-6.72]) and an AP of 0.46 (0.12-0.80) compared with antibody-negative individuals with high n-3 PUFAs.

Conclusions: High fish intake or relative plasma phospholipid n-3 PUFA concentrations may partially counteract the increased diabetes risk conferred by GAD65 antibody positivity.
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http://dx.doi.org/10.2337/dc20-1463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818317PMC
February 2021

Citrus intake and risk of skin cancer in the European Prospective Investigation into Cancer and Nutrition cohort (EPIC).

Eur J Epidemiol 2020 Nov 24;35(11):1057-1067. Epub 2020 Jul 24.

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

Citrus intake has been suggested to increase the risk of skin cancer. Although this relation is highly plausible biologically, epidemiologic evidence is lacking. We aimed to examine the potential association between citrus intake and skin cancer risk. EPIC is an ongoing multi-center prospective cohort initiated in 1992 and involving ~ 520,000 participants who have been followed-up in 23 centers from 10 European countries. Dietary data were collected at baseline using validated country-specific dietary questionnaires. We used Cox proportional hazards regression models to compute hazard ratios (HR) and 95% confidence intervals (CI). During a mean follow-up of 13.7 years, 8448 skin cancer cases were identified among 270,112 participants. We observed a positive linear dose-response relationship between total citrus intake and skin cancer risk (HR = 1.10, 95% CI 1.03-1.18 in the highest vs. lowest quartile; P = 0.001), particularly with basal cell carcinoma (BCC) (HR = 1.11, 95% CI 1.02-1.20, P = 0.007) and squamous cell carcinoma (SCC) (HR = 1.23, 95% CI 1.04-1.47, P = 0.01). Citrus fruit intake was positively associated with skin cancer risk (HR = 1.08, 95% CI 1.01-1.16, P = 0.01), particularly with melanoma (HR = 1.23, 95% CI 1.02-1.48; P = 0.01), although with no heterogeneity across skin cancer types (P = 0.21). Citrus juice was positively associated with skin cancer risk (P = 0.004), particularly with BCC (P = 0.008) and SCC (P = 0.004), but not with melanoma (P = 0.02). Our study suggests moderate positive linear dose-response relationships between citrus intake and skin cancer risk. Studies with available biomarker data and the ability to examine sun exposure behaviors are warranted to clarify these associations and examine the phototoxicity mechanisms of furocoumarin-rich foods.
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http://dx.doi.org/10.1007/s10654-020-00666-9DOI Listing
November 2020

Glycemic index, glycemic load, and risk of coronary heart disease: a pan-European cohort study.

Am J Clin Nutr 2020 09;112(3):631-643

Center for Research in Epidemiology and Population Health, University Paris-South, Faculty of Medicine, University Versailles-St Quentin, National Institute for Health and Medical Research, Université Paris-Saclay, Villejuif, France.

Background: High carbohydrate intake raises blood triglycerides, glucose, and insulin; reduces HDLs; and may increase risk of coronary heart disease (CHD). Epidemiological studies indicate that high dietary glycemic index (GI) and glycemic load (GL) are associated with increased CHD risk.

Objectives: The aim of this study was to determine whether dietary GI, GL, and available carbohydrates are associated with CHD risk in both sexes.

Methods: This large prospective study-the European Prospective Investigation into Cancer and Nutrition-consisted of 338,325 participants who completed a dietary questionnaire. HRs with 95% CIs for a CHD event, in relation to intake of GI, GL, and carbohydrates, were estimated using covariate-adjusted Cox proportional hazard models.

Results: After 12.8 y (median), 6378 participants had experienced a CHD event. High GL was associated with greater CHD risk [HR 1.16 (95% CI: 1.02, 1.31) highest vs. lowest quintile, p-trend 0.035; HR 1.18 (95% CI: 1.07, 1.29) per 50 g/day of GL intake]. The association between GL and CHD risk was evident in subjects with BMI (in kg/m2) ≥25 [HR: 1.22 (95% CI: 1.11, 1.35) per 50 g/d] but not in those with BMI <25 [HR: 1.09 (95% CI: 0.98, 1.22) per 50 g/d) (P-interaction = 0.022). The GL-CHD association did not differ between men [HR: 1.19 (95% CI: 1.08, 1.30) per 50 g/d] and women [HR: 1.22 (95% CI: 1.07, 1.40) per 50 g/d] (test for interaction not significant). GI was associated with CHD risk only in the continuous model [HR: 1.04 (95% CI: 1.00, 1.08) per 5 units/d]. High available carbohydrate was associated with greater CHD risk [HR: 1.11 (95% CI: 1.03, 1.18) per 50 g/d]. High sugar intake was associated with greater CHD risk [HR: 1.09 (95% CI: 1.02, 1.17) per 50 g/d].

Conclusions: This large pan-European study provides robust additional support for the hypothesis that a diet that induces a high glucose response is associated with greater CHD risk.
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http://dx.doi.org/10.1093/ajcn/nqaa157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458777PMC
September 2020

Circulating Immune Cell Composition and Cancer Risk: A Prospective Study Using Epigenetic Cell Count Measures.

Cancer Res 2020 05 19;80(9):1885-1892. Epub 2020 Feb 19.

Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Although ample evidence indicates that immune cell homeostasis is an important prognostic outcome determinant in patients with cancer, few studies have examined whether it also determines cancer risk among initially healthy individuals. We performed a case-cohort study including incident cases of breast ( = 207), colorectal ( = 111), lung ( = 70), and prostate ( = 201) cancer as well as a subcohort ( = 465) within the European Prospective Investigation into Cancer and Nutrition-Heidelberg cohort. Relative counts of neutrophils, monocytes, and lymphocyte sublineages were measured by qRT-PCR. HRs and 95% confidence intervals were used to measure the associations between relative counts of immune cell and cancer risks. When relative counts of immune cell types were taken individually, a significant positive association was observed between relative counts of FOXP3 regulatory T cells (Tregs) and lung cancer risk, and significant inverse associations were observed between relative CD8 counts and risks of lung and breast cancer (overall and ER+ subtype). Multivariable models with mutual adjustments across immune markers showed further significant positive associations between higher relative FOXP3 T-cell counts and increased risks of colorectal and breast cancer (overall and ER- subtype). No associations were found between immune cell composition and prostate cancer risk. These results affirm the relevance of elevated FOXP3 Tregs and lower levels of cytotoxic (CD8) T cells as risk factors for tumor development. SIGNIFICANCE: This epidemiologic study supports a role for both regulatory and cytotoxic T cells in determining cancer risk among healthy individuals..
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http://dx.doi.org/10.1158/0008-5472.CAN-19-3178DOI Listing
May 2020

Inflammatory potential of the diet and risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition study.

Int J Cancer 2020 08 31;147(4):1027-1039. Epub 2020 Jan 31.

CESP, Faculté de Médecine, Université Paris-Sud, UVSQ, INSERM, Université Paris-Saclay, Villejuif, France.

Proinflammatory diets are associated with risk of developing colorectal cancer (CRC), however, inconsistencies exist in subsite- and sex-specific associations. The relationship between CRC and combined lifestyle-related factors that contribute toward a low-grade inflammatory profile has not yet been explored. We examined the association between the dietary inflammatory potential and an inflammatory profile and CRC risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. This cohort included 476,160 participants followed-up of 14 years and 5,991 incident CRC cases (3,897 colon and 2,094 rectal tumors). Dietary inflammatory potential was estimated using an Inflammatory Score of the Diet (ISD). An Inflammatory Profile Score (IPS) was constructed, incorporating the ISD, physical activity level and abdominal obesity. The associations between the ISD and CRC and IPS and CRC were assessed using multivariable regression models. More proinflammatory diets were related to a higher CRC risk, particularly for colon cancer; hazard ratio (HR) for highest versus lowest ISD quartile was 1.15 (95% confidence interval [CI] 1.04-1.27) for CRC, 1.24 (95% CI 1.09-1.41) for colon cancer and 0.99 (95% CI 0.83-1.17) for rectal cancer. Associations were more pronounced in men and not significant in women. The IPS was associated with CRC risk, particularly colon cancer among men; HRs for the highest versus lowest IPS was 1.62 (95% CI 1.31-2.01) for colon cancer overall and 2.11 (95% CI 1.50-2.97) for colon cancer in men. Our study shows that more proinflammatory diets and a more inflammatory profile are associated with higher risk of CRC, principally colon cancer and in men.
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http://dx.doi.org/10.1002/ijc.32870DOI Listing
August 2020

Mitochondrial DNA Copy-Number Variation and Pancreatic Cancer Risk in the Prospective EPIC Cohort.

Cancer Epidemiol Biomarkers Prev 2020 03 13;29(3):681-686. Epub 2020 Jan 13.

University of Cambridge, School of Clinical Medicine Addenbrooke's Hospital, Cambridge, United Kingdom.

Background: Mitochondrial DNA (mtDNA) copy number in peripheral blood has been found to be associated with risk of developing several cancers. However, data on pancreatic ductal adenocarcinoma (PDAC) are very limited.

Methods: To further our knowledge on this topic, we measured relative mtDNA copy number by a quantitative real-time PCR assay in peripheral leukocyte samples of 476 PDAC cases and 357 controls nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

Results: We observed lower mtDNA copy number with advancing age ( = 6.54 × 10) and with a high body mass index (BMI) level ( = 0.004) and no association with sex, smoking behavior, and alcohol consumption. We found an association between increased mtDNA copy number and decreased risk of developing PDAC with an odds ratios (OR) of 0.35 [95% confidence interval (CI), 0.16-0.79; = 0.01] when comparing the fifth quintile with the first using an unconditional logistic regression and an OR of 0.19 (95% CI, 0.07-0.52; = 0.001) with a conditional analysis. Analyses stratified by BMI showed an association between high mtDNA copy number and decreased risk in the stratum of normal weight, consistent with the main analyses.

Conclusions: Our results suggest a protective effect of a higher number of mitochondria, measured in peripheral blood leukocytes, on PDAC risk.

Impact: Our findings highlight the importance of understanding the mitochondrial biology in pancreatic cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611119PMC
March 2020

Thrombomodulin and Thrombopoietin, Two Biomarkers of Hemostasis, Are Positively Associated with Adherence to the World Cancer Research Fund/American Institute for Cancer Research Recommendations for Cancer Prevention in a Population-Based Cross-Sectional Study.

Nutrients 2019 Sep 3;11(9). Epub 2019 Sep 3.

Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany.

A pro-coagulative state is related to increased risk of cardiovascular diseases but also certain cancers. Since experimental and smaller human studies suggest that diet, physical activity, and body weight may all affect coagulation, we evaluated associations between these lifestyle factors and hemostatic biomarkers in a population-based study. Cross-sectional baseline data from 2267 randomly selected participants of EPIC-Heidelberg (age range 35-65 years) was used. Fibrinogen, glycoprotein IIb/IIIa, P-selectin, thrombomodulin (TM), and thrombopoietin (TPO) were measured in baseline plasma samples. A score reflecting adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) recommendations for cancer prevention was created. Associations between the WCRF/AICR score as well as its individual components and hemostatic biomarkers were analyzed by linear regression models. Multivariable-adjusted geometric means (95% confidence intervals) of TM and TPO were higher with greater adherence to the WCRF/AICR recommendations (TM, lowest vs. highest score category: 2.90 (2.7,3.1) vs. 3.10 (2.9,3.3) ng/mL, = 0.0001; TPO: 328 (302,356) vs. 348 (321,378) pg/mL, = 0.0007). These associations were driven by lower alcohol and meat consumption among persons with higher WCRF/AICR scores. Our results indicate that lifestyle factors favorably affect TM and TPO, two hemostatic factors implicated in chronic disease development.
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http://dx.doi.org/10.3390/nu11092067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770787PMC
September 2019

Socioeconomic Effect of Education on Pancreatic Cancer Risk in Western Europe: An Update on the EPIC Cohorts Study.

Cancer Epidemiol Biomarkers Prev 2019 06;28(6):1089-1092

Department of Public Health, Aarhus University, Aarhus, Denmark.

Background: To analyze the potential effect of social inequality on pancreatic cancer risk in Western Europe, by reassessing the association within the European Prospective Investigation into Cancer and Nutrition (EPIC) Study, including a larger number of cases and an extended follow-up.

Methods: Data on highest education attained were gathered for 459,170 participants (70% women) from 10 European countries. A relative index of inequality (RII) based on adult education was calculated for comparability across countries and generations. Cox regression models were applied to estimate relative inequality in pancreatic cancer risk, stratifying by age, gender, and center, and adjusting for known pancreatic cancer risk factors.

Results: A total of 1,223 incident pancreatic cancer cases were included after a mean follow-up of 13.9 (±4.0) years. An inverse social trend was found in models adjusted for age, sex, and center for both sexes [HR of RII, 1.27; 95% confidence interval (CI), 1.02-1.59], which was also significant among women (HR, 1.42; 95% CI, 1.05-1.92). Further adjusting by smoking intensity, alcohol consumption, body mass index, prevalent diabetes, and physical activity led to an attenuation of the RII risk and loss of statistical significance.

Conclusions: The present reanalysis does not sustain the existence of an independent social inequality influence on pancreatic cancer risk in Western European women and men, using an index based on adult education, the most relevant social indicator linked to individual lifestyles, in a context of very low pancreatic cancer survival from (quasi) universal public health systems.

Impact: The results do not support an association between education and risk of pancreatic cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-1153DOI Listing
June 2019

Plasma Fibrinogen and sP-Selectin are Associated with the Risk of Lung Cancer in a Prospective Study.

Cancer Epidemiol Biomarkers Prev 2019 07 23;28(7):1221-1227. Epub 2019 Apr 23.

Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: While enhanced platelet activation and a procoagulant state may drive lung cancer progression and metastases, less is known about their role in earlier phases of cancer development. Thus, we evaluated whether prediagnostic biomarkers of platelet activation and coagulation are related to the risk of lung cancer in the prospective EPIC-Heidelberg Study using a case-cohort design.

Methods: Levels of fibrinogen, soluble glycoprotein (sGP) IIb/IIIa, soluble P-selectin (sP-selectin), soluble thrombomodulin (sTM), and thrombopoietin (TPO) were measured in baseline plasma samples of a random subcohort ( = 2,480) and incident cases of lung cancer ( = 190). Multivariable-adjusted Cox proportional hazards regression analyses were used to obtain HRs of lung cancer across quartiles of biomarker levels.

Results: Fibrinogen [HR highest vs. lowest quartile: 1.91 (95% confidence interval: 1.09-3.34)] and sP-Selectin [HR: 2.51 (1.39-4.52)] were significantly associated with lung cancer risk in multivariable adjusted Cox regression models. Adding both biomarkers to the established PLCO algorithm, which alone showed a C-statistic of 0.788, led to a slight increment in lung cancer risk prediction, with a C-statistic of 0.814.

Conclusion: Our findings indicate that enhanced platelet activation and a procoagulative state contribute to lung carcinogenesis.

Impact: The current prospective study supports the hypothesis of increased coagulation being a possible driver of lung carcinogenesis, as strong positive associations were found between two procoagulative markers, sP-Selectin and fibrinogen, with lung cancer risk. Both biomarkers could improve lung cancer risk prediction, but external validation of the results is needed.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-1285DOI Listing
July 2019

General and abdominal adiposity and the risk of Parkinson's disease: A prospective cohort study.

Parkinsonism Relat Disord 2019 05 8;62:98-104. Epub 2019 Feb 8.

Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Germany. Electronic address:

Introduction: Due to demographic change, an increase in the frequency of Parkinson's disease (PD) patients is expected in the future and, thus, the identification of modifiable risk factors is urgently needed. We aimed to examine the associations of body mass index (BMI) and waist circumference (WC) with incident PD.

Methods: In 13 of the 23 centers of the European Prospective Investigation into Cancer and Nutrition (EPIC) study, a total of 734 incident cases of PD were identified between 1992 and 2012 with a mean follow-up of 12 years. Cox proportional hazards regression was used to calculate hazard ratios (HR) with 95% confidence intervals (CI). We modelled anthropometric variables as continuous and categorical exposures and performed subgroup analyses by potential effect modifiers including sex and smoking.

Results: We found no association between BMI, WC and incident PD, neither among men nor among women. Among never and former smokers, BMI and waist circumference were also not associated with PD risk. For male smokers, however, we observed a statistically significant inverse association between BMI and PD risk (HR 0.51, 95%CI: 0.30, 0.84) and the opposite for women, i.e. a significant direct association of BMI (HR 1.79, 95%CI: 1.04, 3.08) and waist circumference (HR 1.64, 95%CI: 1.03, 2.61) with risk of PD.

Conclusion: Our data revealed no association between excess weight and PD risk but a possible interaction between anthropometry, sex and smoking.
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http://dx.doi.org/10.1016/j.parkreldis.2019.01.019DOI Listing
May 2019

Exploring causality of the association between smoking and Parkinson's disease.

Int J Epidemiol 2019 06;48(3):912-925

School of Public Health, Imperial College London, London, UK.

Background: The aim of this paper is to investigate the causality of the inverse association between cigarette smoking and Parkinson's disease (PD). The main suggested alternatives include a delaying effect of smoking, reverse causality or an unmeasured confounding related to a low-risk-taking personality trait.

Methods: A total of 715 incident PD cases were ascertained in a cohort of 220 494 individuals from NeuroEPIC4PD, a prospective European population-based cohort study including 13 centres in eight countries. Smoking habits were recorded at recruitment. We analysed smoking status, duration, and intensity and exposure to passive smoking in relation to PD onset.

Results: Former smokers had a 20% decreased risk and current smokers a halved risk of developing PD compared with never smokers. Strong dose-response relationships with smoking intensity and duration were found. Hazard ratios (HRs) for smoking <20 years were 0.84 [95% confidence interval (CI) 0.67-1.07], 20-29 years 0.73 (95% CI 0.56-0.96) and >30 years 0.54 (95% CI 0.43-0.36) compared with never smokers. The proportional hazard assumption was verified, showing no change of risk over time, arguing against a delaying effect. Reverse causality was disproved by the consistency of dose-response relationships among former and current smokers. The inverse association between passive smoking and PD, HR 0.70 (95% CI 0.49-0.99) ruled out the effect of unmeasured confounding.

Conclusions: These results are highly suggestive of a true causal link between smoking and PD, although it is not clear which is the chemical compound in cigarette smoking responsible for the biological effect.
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http://dx.doi.org/10.1093/ije/dyy230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6659366PMC
June 2019

CA19-9 and apolipoprotein-A2 isoforms as detection markers for pancreatic cancer: a prospective evaluation.

Int J Cancer 2019 04 4;144(8):1877-1887. Epub 2018 Dec 4.

Escuela Andaluza de Salud Pública. Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain.

Recently, we identified unique processing patterns of apolipoprotein A2 (ApoA2) in patients with pancreatic cancer. Our study provides a first prospective evaluation of an ApoA2 isoform ("ApoA2-ATQ/AT"), alone and in combination with carbohydrate antigen 19-9 (CA19-9), as an early detection biomarker for pancreatic cancer. We performed ELISA measurements of CA19-9 and ApoA2-ATQ/AT in 156 patients with pancreatic cancer and 217 matched controls within the European EPIC cohort, using plasma samples collected up to 60 months prior to diagnosis. The detection discrimination statistics were calculated for risk scores by strata of lag-time. For CA19-9, in univariate marker analyses, C-statistics to distinguish future pancreatic cancer patients from cancer-free individuals were 0.80 for plasma taken ≤6 months before diagnosis, and 0.71 for >6-18 months; for ApoA2-ATQ/AT, C-statistics were 0.62, and 0.65, respectively. Joint models based on ApoA2-ATQ/AT plus CA19-9 significantly improved discrimination within >6-18 months (C = 0.74 vs. 0.71 for CA19-9 alone, p = 0.022) and ≤ 18 months (C = 0.75 vs. 0.74, p = 0.022). At 98% specificity, and for lag times of ≤6, >6-18 or ≤ 18 months, sensitivities were 57%, 36% and 43% for CA19-9 combined with ApoA2-ATQ/AT, respectively, vs. 50%, 29% and 36% for CA19-9 alone. Compared to CA19-9 alone, the combination of CA19-9 and ApoA2-ATQ/AT may improve detection of pancreatic cancer up to 18 months prior to diagnosis under usual care, and may provide a useful first measure for pancreatic cancer detection prior to imaging.
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http://dx.doi.org/10.1002/ijc.31900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760974PMC
April 2019

Lifestyle and Progression of Lower Urinary Tract Symptoms in German Men-Results From the EPIC-Heidelberg Cohort.

Urology 2018 Oct 27;120:192-196. Epub 2018 Jun 27.

Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.

Objective: To examine if lower urinary tract symptom (LUTS) progression was related to anthropometric and lifestyle factors.

Material And Methods: The analysis included 5495 men who participated in the EPIC-Heidelberg cohort (recruited 1994-1998) and who reported an International Prostate Symptom Score < 8 at follow-up 4 (FUP4, 2007-2009), had not reported taking α-adrenoreceptor antagonists or 5-α reductase inhibitors or prostate surgery for benign prostatic hyperplasia/LUTS treatment. LUTS progression was defined as an International Prostate Symptom Score ≥ 8 at FUP5 (2010-2012). Using logistic regression analysis, education, marital status, satisfaction with life, satisfaction with health, history of diabetes and of hypertension, smoking, alcohol consumption, body mass index (BMI), waist circumference, and physical activity were examined as potential LUTS risk factors adjusting for age.

Results: Increase in BMI between baseline and FUP4 of ≥ 2 BMI units was related to LUTS progression (odds ratio 1.30, 95% confidence interval 1.08-1.57) compared with stable BMI. Compared to men who were very satisfied with life at baseline, those who were satisfied (1.28, 1.11-1.47), unsatisfied (1.80, 1.31-2.46) or very unsatisfied with life (1.43, 0.62-3.34) were more likely to report LUTS progression. Men with longer education had higher odds of LUTS progression than men with primary education only (1.25, 1.06-1.48). Adjusting for BMI or lifestyle factors did not attenuate these associations. Smoking habits, alcohol consumption, physical activity, self-reported history of diabetes or hypertension, and marital status were not related with LUTS progression.

Conclusion: Our results confirm some, but not all previously observed risk factors for LUTS progression.
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http://dx.doi.org/10.1016/j.urology.2018.06.013DOI Listing
October 2018

Iron status in relation to cancer risk and mortality: Findings from a population-based prospective study.

Int J Cancer 2018 08 1;143(3):561-569. Epub 2018 Apr 1.

Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, Heidelberg, 69120, Germany.

While experimental evidence suggests potential carcinogenic effects of increased iron load, there is a lack of data on iron status and cancer risk from epidemiological studies. Here, we evaluated prediagnostic serum concentrations of ferritin, iron and transferrin as well as transferrin saturation (TSAT) in relation to cancer risk and mortality in a prospective study by multivariable Cox regression analyses. A case-cohort sample of the population-based EPIC-Heidelberg Study including a random subcohort (n = 2738) and incident cases of breast cancer (n = 627), prostate cancer (n = 554), lung cancer (n = 195), colorectal cancer (n = 256) and cancer death (n = 759) was used. Ferritin levels were inversely associated with breast cancer risk in the multivariable Cox regression model, with a hazard ratio (HR) of 0.67 [95% confidence interval: 0.49, 0.92] for women in the highest quartile compared to those in the lowest quartile. Neither ferritin nor the other markers of iron status were significantly associated with colorectal, prostate or lung cancer risk. An inverse association was observed between ferritin and total cancer mortality (HR: 0.70 [0.53, 0.92]). There were no significant overall associations between serum iron, transferrin or TSAT and cancer mortality. The present findings do not support the notion of increased iron load constituting a cancer risk factor in the general population. By contrast, our analyses revealed inverse associations between ferritin levels and breast cancer risk as well as cancer mortality.
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http://dx.doi.org/10.1002/ijc.31384DOI Listing
August 2018

[Assessing incident cardiovascular and metabolic diseases in epidemiological cohort studies in Germany].

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2018 Apr;61(4):420-431

Forschergruppe Molekulare Epidemiologie, Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft (MDC), Robert-Rössle-Straße 10, 13125, Berlin, Deutschland.

Background: Cardiovascular and metabolic diseases are a major cause of mortality and loss of quality of life in Germany. Research into risk factors of these diseases requires large population-based cohort studies. Complete and accurate assessment of the incidence of cardiovascular and metabolic diseases is a key element for valid interpretation of the results from such studies.

Objective: Our aim was to identify population-based cohort studies with incidence of cardiovascular and metabolic diseases in Germany and to summarize their methods for assessment and classification of disease endpoints, including myocardial infarction, type 2 diabetes, stroke, heart failure, and arterial hypertension.

Methods: Within the framework of a workshop, representatives of the ascertained population-based cohort studies in Germany with incidence of cardiovascular or metabolic diseases were invited to present and to systematically provide information on their methods of endpoint identification.

Results: We identified eight studies from different regions in Germany with a total of 100,571 participants, aged 18-83 years at baseline. Self-reporting by study participants is the major source for further inquiries to assess disease endpoints in these studies. Most studies use additional data sources to verify the incidence of diseases, such as documents provided by the treating physician or hospital.

Conclusions: Our results highlight the central role of self-reporting and the efforts associated with identification and verification of disease endpoints in cohort studies. They also provide a basis for future population-based studies that aim for standardized assessment of the incidence of cardiovascular and metabolic diseases.
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http://dx.doi.org/10.1007/s00103-018-2712-4DOI Listing
April 2018

Interaction of Dietary and Genetic Factors Influencing Body Iron Status and Risk of Type 2 Diabetes Within the EPIC-InterAct Study.

Diabetes Care 2018 02 22;41(2):277-285. Epub 2017 Nov 22.

Public Health Directorate, Asturias, Spain.

Objective: Meat intake has been consistently shown to be positively associated with incident type 2 diabetes. Part of that association may be mediated by body iron status, which is influenced by genetic factors. We aimed to test for interactions of genetic and dietary factors influencing body iron status in relation to the risk of incident type 2 diabetes.

Research Design And Methods: The case-cohort comprised 9,347 case subjects and 12,301 subcohort participants from eight European countries. Single nucleotide polymorphisms (SNPs) were selected from genome-wide association studies on iron status biomarkers and candidate gene studies. A ferritin-related gene score was constructed. Multiplicative and additive interactions of heme iron and SNPs as well as the gene score were evaluated using Cox proportional hazards regression.

Results: Higher heme iron intake (per 1 SD) was associated with higher ferritin levels (β = 0.113 [95% CI 0.082; 0.144]), but not with transferrin (-0.019 [-0.043; 0.006]) or transferrin saturation (0.016 [-0.006; 0.037]). Five SNPs located in four genes (rs1799945 [ H63D], rs1800562 [ C282Y], rs236918 [], rs744653 [], and rs855791 [ V736A]) were associated with ferritin. We did not detect an interaction of heme iron and the gene score on the risk of diabetes in the overall study population ( = 0.16, = 0.21) but did detect a trend toward a negative interaction in men ( = 0.04, = 0.03).

Conclusions: We found no convincing evidence that the interplay of dietary and genetic factors related to body iron status associates with type 2 diabetes risk above the level expected from the sum or product of the two individual exposures.
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http://dx.doi.org/10.2337/dc17-1080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130703PMC
February 2018

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

Int J Cancer 2018 03 22;142(6):1189-1201. Epub 2017 Nov 22.

Dipartimento di medicina clinica e chirurgia, Federico II university, Naples, Italy.

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)D and 25(OH)D 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.
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http://dx.doi.org/10.1002/ijc.31146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5813219PMC
March 2018

Reproducibility of serum oxysterols and lanosterol among postmenopausal women: Results from EPIC-Heidelberg.

Clin Biochem 2018 Feb 22;52:117-122. Epub 2017 Nov 22.

Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address:

Background: Circulating oxysterols have been proposed as biological markers of disease risk. However, within-person reproducibility of circulating oxysterols over time is not well established.

Methods: We evaluated the one-year reproducibility of 11 oxysterols and lanosterol among 30 postmenopausal women with repeat blood samples in the European Prospective Investigation into Cancer and Nutrition (EPIC) - Heidelberg, Germany cohort. Liquid chromatography-mass spectrometry (LC/MS) was performed to quantify serum concentrations of 22R-hydroxycholesterol, 25-hydroxycholesterol, 24S-hydroxycholesterol, 27-hydroxycholesterol, 22S-hydroxycholeterol, 24,25-epoxycholesterol, 5α,6β-dihydroxycholestanol, 7α-hydroxycholesterol, 5β,6β-epoxycholesterol, 5α,6α-epoxycholesterol, 24-dihydrolanosterol, and lanosterol. We evaluated Spearman correlations and intraclass correlation coefficients (ICCs) between quantifiable concentrations measured in repeat samples taken one-year apart to estimate within-person reproducibility.

Results: Spearman correlations (ICCs) over one year ranged from 0 (ICC=0.10) for 5β,6β-epoxycholesterol and 0.10 (ICC=0.20) for 5α,6α-epoxycholesterol, representing low within-person stability, to 0.81 (ICC=0.75) for 27-hydroxycholesterol and 0.86 (ICC=0.91) for 24S-hydroxycholesterol, representing relatively high within-person stability. Correlations between oxysterols and lanosterol ranged from 0.01 between 24S-hydroxycholesterol and lanosterol to 0.70 between 5α,6α-epoxycholesterol and 5β,6β-epoxycholesterol.

Conclusions: Our results demonstrate that for 27-hydroxycholesterol, 24S-hydroxycholesterol, 25-hydroxycholesterol, 7α-hydroxycholesterol and lanosterol, a single serum measurement can reliably estimate average levels over a one-year period. Circulating oxysterols are of increasing interest in epidemiologic studies of chronic disease risk including cancer and cardiovascular disease. Our data suggest that within-person stability of oxysterols differs depending on the individual oxysterol evaluated. We identified four oxysterols and lanosterol as stable over time to inform the use of circulating oxysterols in epidemiologic studies.
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http://dx.doi.org/10.1016/j.clinbiochem.2017.11.001DOI Listing
February 2018

Nut intake and 5-year changes in body weight and obesity risk in adults: results from the EPIC-PANACEA study.

Eur J Nutr 2018 Oct 21;57(7):2399-2408. Epub 2017 Jul 21.

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.

Purpose: There is inconsistent evidence regarding the relationship between higher intake of nuts, being an energy-dense food, and weight gain. We investigated the relationship between nut intake and changes in weight over 5 years.

Methods: This study includes 373,293 men and women, 25-70 years old, recruited between 1992 and 2000 from 10 European countries in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Habitual intake of nuts including peanuts, together defined as nut intake, was estimated from country-specific validated dietary questionnaires. Body weight was measured at recruitment and self-reported 5 years later. The association between nut intake and body weight change was estimated using multilevel mixed linear regression models with center/country as random effect and nut intake and relevant confounders as fixed effects. The relative risk (RR) of becoming overweight or obese after 5 years was investigated using multivariate Poisson regressions stratified according to baseline body mass index (BMI).

Results: On average, study participants gained 2.1 kg (SD 5.0 kg) over 5 years. Compared to non-consumers, subjects in the highest quartile of nut intake had less weight gain over 5 years (-0.07 kg; 95% CI -0.12 to -0.02) (P trend = 0.025) and had 5% lower risk of becoming overweight (RR 0.95; 95% CI 0.92-0.98) or obese (RR 0.95; 95% CI 0.90-0.99) (both P trend <0.008).

Conclusions: Higher intake of nuts is associated with reduced weight gain and a lower risk of becoming overweight or obese.
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http://dx.doi.org/10.1007/s00394-017-1513-0DOI Listing
October 2018

Interaction between genes and macronutrient intake on the risk of developing type 2 diabetes: systematic review and findings from European Prospective Investigation into Cancer (EPIC)-InterAct.

Am J Clin Nutr 2017 Jul 7;106(1):263-275. Epub 2017 Jun 7.

University Medical Center Utrecht, Utrecht, Netherlands.

Gene-diet interactions have been reported to contribute to the development of type 2 diabetes (T2D). However, to our knowledge, few examples have been consistently replicated to date. We aimed to identify existing evidence for gene-macronutrient interactions and T2D and to examine the reported interactions in a large-scale study. We systematically reviewed studies reporting gene-macronutrient interactions and T2D. We searched the MEDLINE, Human Genome Epidemiology Network, and WHO International Clinical Trials Registry Platform electronic databases to identify studies published up to October 2015. Eligibility criteria included assessment of macronutrient quantity (e.g., total carbohydrate) or indicators of quality (e.g., dietary fiber) by use of self-report or objective biomarkers of intake. Interactions identified in the review were subsequently examined in the EPIC (European Prospective Investigation into Cancer)-InterAct case-cohort study ( = 21,148, with 9403 T2D cases; 8 European countries). Prentice-weighted Cox regression was used to estimate country-specific HRs, 95% CIs, and -interaction values, which were then pooled by random-effects meta-analysis. A primary model was fitted by using the same covariates as reported in the published studies, and a second model adjusted for additional covariates and estimated the effects of isocaloric macronutrient substitution. Thirteen observational studies met the eligibility criteria ( < 1700 cases). Eight unique interactions were reported to be significant between macronutrients [carbohydrate, fat, saturated fat, dietary fiber, and glycemic load derived from self-report of dietary intake and circulating n-3 (ω-3) polyunsaturated fatty acids] and genetic variants in or near transcription factor 7-like 2 (), gastric inhibitory polypeptide receptor (), caveolin 2 (), and peptidase D () (-interaction < 0.05). We found no evidence of interaction when we tried to replicate previously reported interactions. In addition, no interactions were detected in models with additional covariates. Eight gene-macronutrient interactions were identified for the risk of T2D from the literature. These interactions were not replicated in the EPIC-InterAct study, which mirrored the analyses undertaken in the original reports. Our findings highlight the importance of independent replication of reported interactions.
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http://dx.doi.org/10.3945/ajcn.116.150094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486199PMC
July 2017

Plasma microRNAs as biomarkers of pancreatic cancer risk in a prospective cohort study.

Int J Cancer 2017 09 12;141(5):905-915. Epub 2017 Jun 12.

MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.

Noninvasive biomarkers for early pancreatic ductal adenocarcinoma (PDAC) diagnosis and disease risk stratification are greatly needed. We conducted a nested case-control study within the Prospective Investigation into Cancer and Nutrition (EPIC) cohort to evaluate prediagnostic microRNAs (miRs) as biomarkers of subsequent PDAC risk. A panel of eight miRs (miR-10a, -10b, -21-3p, -21-5p, -30c, -106b, -155 and -212) based on previous evidence from our group was evaluated in 225 microscopically confirmed PDAC cases and 225 controls matched on center, sex, fasting status and age/date/time of blood collection. MiR levels in prediagnostic plasma samples were determined by quantitative RT-PCR. Logistic regression was used to model levels and PDAC risk, adjusting for covariates and to estimate area under the receiver operating characteristic curves (AUC). Plasma miR-10b, -21-5p, -30c and -106b levels were significantly higher in cases diagnosed within 2 years of blood collection compared to matched controls (all p-values <0.04). Based on adjusted logistic regression models, levels for six miRs (miR-10a, -10b, -21-5p, -30c, -155 and -212) overall, and for four miRs (-10a, -10b, -21-5p and -30c) at shorter follow-up time between blood collection and diagnosis (≤5 yr, ≤2 yr), were statistically significantly associated with risk. A score based on the panel showed a linear dose-response trend with risk (p-value = 0.0006). For shorter follow-up (≤5 yr), AUC for the score was 0.73, and for individual miRs ranged from 0.73 (miR-212) to 0.79 (miR-21-5p).
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http://dx.doi.org/10.1002/ijc.30790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5536971PMC
September 2017

Helicobacter pylori infection, chronic corpus atrophic gastritis and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort: A nested case-control study.

Int J Cancer 2017 04;140(8):1727-1735

Andalusian School of Public Health, Instituto De Investigación Biosanitaria Ibs, Granada, Spain.

The association between H. pylori infection and pancreatic cancer risk remains controversial. We conducted a nested case-control study with 448 pancreatic cancer cases and their individually matched control subjects, based on the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, to determine whether there was an altered pancreatic cancer risk associated with H. pylori infection and chronic corpus atrophic gastritis. Conditional logistic regression models were applied to calculate odds ratios (ORs) and corresponding 95% confidence intervals (CIs), adjusted for matching factors and other potential confounders. Our results showed that pancreatic cancer risk was neither associated with H. pylori seropositivity (OR = 0.96; 95% CI: 0.70, 1.31) nor CagA seropositivity (OR = 1.07; 95% CI: 0.77, 1.48). We also did not find any excess risk among individuals seropositive for H. pylori but seronegative for CagA, compared with the group seronegative for both antibodies (OR = 0.94; 95% CI: 0.63, 1.38). However, we found that chronic corpus atrophic gastritis was non-significantly associated with an increased pancreatic cancer risk (OR = 1.35; 95% CI: 0.77, 2.37), and although based on small numbers, the excess risk was particularly marked among individuals seronegative for both H. pylori and CagA (OR = 5.66; 95% CI: 1.59, 20.19, p value for interaction < 0.01). Our findings provided evidence supporting the null association between H. pylori infection and pancreatic cancer risk in western European populations. However, the suggested association between chronic corpus atrophic gastritis and pancreatic cancer risk warrants independent verification in future studies, and, if confirmed, further studies on the underlying mechanisms.
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http://dx.doi.org/10.1002/ijc.30590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5930360PMC
April 2017

Sweet-beverage consumption and risk of pancreatic cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC).

Am J Clin Nutr 2016 Sep 10;104(3):760-8. Epub 2016 Aug 10.

Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute, Catalan Institute of Oncology, Barcelona, Spain;

Background: The consumption of sweet beverages has been associated with greater risk of type 2 diabetes and obesity, which may be involved in the development of pancreatic cancer. Therefore, it has been hypothesized that sweet beverages may increase pancreatic cancer risk as well.

Objective: We examined the association between sweet-beverage consumption (including total, sugar-sweetened, and artificially sweetened soft drink and juice and nectar consumption) and pancreatic cancer risk.

Design: The study was conducted within the European Prospective Investigation into Cancer and Nutrition cohort. A total of 477,199 participants (70.2% women) with a mean age of 51 y at baseline were included, and 865 exocrine pancreatic cancers were diagnosed after a median follow-up of 11.60 y (IQR: 10.10-12.60 y). Sweet-beverage consumption was assessed with the use of validated dietary questionnaires at baseline. HRs and 95% CIs were obtained with the use of multivariable Cox regression models that were stratified by age, sex, and center and adjusted for educational level, physical activity, smoking status, and alcohol consumption. Associations with total soft-drink consumption were adjusted for juice and nectar consumption and vice versa.

Results: Total soft-drink consumption (HR per 100 g/d: 1.03; 95% CI: 0.99, 1.07), sugar-sweetened soft-drink consumption (HR per 100 g/d: 1.02; 95% CI: 0.97, 1.08), and artificially sweetened soft-drink consumption (HR per 100 g/d: 1.04; 95% CI: 0.98, 1.10) were not associated with pancreatic cancer risk. Juice and nectar consumption was inversely associated with pancreatic cancer risk (HR per 100 g/d: 0.91; 95% CI: 0.84, 0.99); this association remained statistically significant after adjustment for body size, type 2 diabetes, and energy intake.

Conclusions: Soft-drink consumption does not seem to be associated with pancreatic cancer risk. Juice and nectar consumption might be associated with a modest decreased pancreatic cancer risk. Additional studies with specific information on juice and nectar subtypes are warranted to clarify these results.
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http://dx.doi.org/10.3945/ajcn.116.130963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6241849PMC
September 2016

Diet Quality Scores and Prediction of All-Cause, Cardiovascular and Cancer Mortality in a Pan-European Cohort Study.

PLoS One 2016 13;11(7):e0159025. Epub 2016 Jul 13.

Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece.

Scores of overall diet quality have received increasing attention in relation to disease aetiology; however, their value in risk prediction has been little examined. The objective was to assess and compare the association and predictive performance of 10 diet quality scores on 10-year risk of all-cause, CVD and cancer mortality in 451,256 healthy participants to the European Prospective Investigation into Cancer and Nutrition, followed-up for a median of 12.8y. All dietary scores studied showed significant inverse associations with all outcomes. The range of HRs (95% CI) in the top vs. lowest quartile of dietary scores in a composite model including non-invasive factors (age, sex, smoking, body mass index, education, physical activity and study centre) was 0.75 (0.72-0.79) to 0.88 (0.84-0.92) for all-cause, 0.76 (0.69-0.83) to 0.84 (0.76-0.92) for CVD and 0.78 (0.73-0.83) to 0.91 (0.85-0.97) for cancer mortality. Models with dietary scores alone showed low discrimination, but composite models also including age, sex and other non-invasive factors showed good discrimination and calibration, which varied little between different diet scores examined. Mean C-statistic of full models was 0.73, 0.80 and 0.71 for all-cause, CVD and cancer mortality. Dietary scores have poor predictive performance for 10-year mortality risk when used in isolation but display good predictive ability in combination with other non-invasive common risk factors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0159025PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4943719PMC
July 2017

Comparison of abdominal adiposity and overall obesity in relation to risk of small intestinal cancer in a European Prospective Cohort.

Cancer Causes Control 2016 07 13;27(7):919-27. Epub 2016 Jun 13.

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Norfolk Place, London, W2 1PG, UK.

Background: The etiology of small intestinal cancer (SIC) is largely unknown, and there are very few epidemiological studies published to date. No studies have investigated abdominal adiposity in relation to SIC.

Methods: We investigated overall obesity and abdominal adiposity in relation to SIC in the European Prospective Investigation into Cancer and Nutrition (EPIC), a large prospective cohort of approximately half a million men and women from ten European countries. Overall obesity and abdominal obesity were assessed by body mass index (BMI), waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR). Multivariate Cox proportional hazards regression modeling was performed to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs). Stratified analyses were conducted by sex, BMI, and smoking status.

Results: During an average of 13.9 years of follow-up, 131 incident cases of SIC (including 41 adenocarcinomas, 44 malignant carcinoid tumors, 15 sarcomas and 10 lymphomas, and 21 unknown histology) were identified. WC was positively associated with SIC in a crude model that also included BMI (HR per 5-cm increase = 1.20, 95 % CI 1.04, 1.39), but this association attenuated in the multivariable model (HR 1.18, 95 % CI 0.98, 1.42). However, the association between WC and SIC was strengthened when the analysis was restricted to adenocarcinoma of the small intestine (multivariable HR adjusted for BMI = 1.56, 95 % CI 1.11, 2.17). There were no other significant associations.

Conclusion: WC, rather than BMI, may be positively associated with adenocarcinomas but not carcinoid tumors of the small intestine.

Impact: Abdominal obesity is a potential risk factor for adenocarcinoma in the small intestine.
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http://dx.doi.org/10.1007/s10552-016-0772-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4923177PMC
July 2016

Dairy Products, Dietary Calcium, and Risk of Inflammatory Bowel Disease: Results From a European Prospective Cohort Investigation.

Inflamm Bowel Dis 2016 06;22(6):1403-11

1Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands; 2Department of Medicine, Norwich Medical School, University of East Anglia, Norwich, United Kingdom; 3Department of Gastroenterology, Norfolk and Norwich University Hospital NHS Trust, Norwich, United Kingdom; 4Strangeways Research Laboratory, Institute of Public Health, University of Cambridge, Cambridge, United Kingdom; 5Department of Public Health and Clinical Medicine, Nutritional Research, Umeå University, Umeå, Sweden; 6Department of Public Health and Clinical Medicine, GI Unit, Umeå University, Umeå, Sweden; 7Department of Clinical Sciences, Lund University, Lund, Sweden; 8Gastroenterology-Hepatology Division, University Hospital Skane, Malmö, Sweden; 9Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom; 10Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Potsdam, Germany; 11Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark; 12Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), Florence, Italy; 13French Institute of Health and Medical Research (INSERM), Centre for Research in Epidemiology and Population Health, Institut Gustave Roussy, Villejuif, France; 14Université Paris Sud, Paris, France; 15Department of Gastroenterology, Bicêtre University Hospital, Assistance Publique des Hôpitaux de Paris, Paris, France; 16Diet, Genes and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark; 17Institute of Regional Research, Center Sønderjylland, University of Southern Denmark, Odense, Denmark; 18Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; 19Cancer Registry and Histopathology Unit, "Civic-M.P. Arezzo" Hospital, Ragusa, Italy; 20Department of Hygiene and Epidemiology, WHO Collaborating Center for Food and Nu

Background: Dairy products may be involved in the etiology of inflammatory bowel disease by modulating gut microbiota and immune responses, but data from epidemiological studies examining this relationship are limited. We investigated the association between prediagnostic intake of these foods and dietary calcium, and the subsequent development of Crohn's disease (CD) and ulcerative colitis (UC).

Methods: In total, 401,326 participants were enrolled in the European Prospective Investigation into Cancer and Nutrition cohort. At recruitment, consumption of total and specific dairy products (milk, yogurt, and cheese) and dietary calcium was measured using validated food frequency questionnaires. Cases developing incident CD (n = 110) or UC (n = 244) during follow-up were matched with 4 controls. Conditional logistic regression analyses were used to calculate odds ratios (ORs) with 95% confidence intervals (CIs), adjusted for total energy intake and smoking.

Results: Compared with the lowest quartile, the ORs for the highest quartile of total dairy products and dietary calcium intake were 0.61 (95% CI, 0.32-1.19, p trend = 0.19) and 0.63 (95% CI, 0.28-1.42, p trend = 0.23) for CD, and 0.80 (95% CI, 0.50-1.30, p trend = 0.40) and 0.81 (95% CI, 0.49-1.34, p trend = 0.60) for UC, respectively. Compared with nonconsumers, individuals consuming milk had significantly reduced odds of CD (OR 0.30, 95% CI, 0.13-0.65) and nonsignificantly reduced odds of UC (OR 0.85, 95% CI, 0.49-1.47).

Conclusions: Milk consumption may be associated with a decreased risk of developing CD, although a clear dose-response relationship was not established. Further studies are warranted to confirm this possible protective effect.
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http://dx.doi.org/10.1097/MIB.0000000000000798DOI Listing
June 2016

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).

PLoS Med 2016 Apr 5;13(4):e1001988. Epub 2016 Apr 5.

Dipartimento di Medicina Clinica e Sperimentale, Federico II University, Naples, Italy.

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 <0.05 was considered statistically significant. In multivariable-adjusted conditional logistic regression models with BMI used to define adiposity, compared with metabolically healthy/normal weight individuals, we observed a higher colorectal cancer risk among metabolically unhealthy/normal weight (odds ratio [OR] = 1.59, 95% CI 1.10-2.28) and metabolically unhealthy/overweight (OR = 1.40, 95% CI 1.01-1.94) participants, but not among metabolically healthy/overweight individuals (OR = 0.96, 95% CI 0.65-1.42). Among the overweight individuals, lower colorectal cancer risk was observed for metabolically healthy/overweight individuals compared with metabolically unhealthy/overweight individuals (OR = 0.69, 95% CI 0.49-0.96). These associations were generally consistent when waist circumference was used as the measure of adiposity. To our knowledge, there is no universally accepted clinical definition for using C-peptide level as an indication of hyperinsulinaemia. Therefore, a possible limitation of our analysis was that the classification of individuals as being hyperinsulinaemic-based on their C-peptide level-was arbitrary. However, when we used quartiles or the median of C-peptide, instead of tertiles, as the cut-point of hyperinsulinaemia, a similar pattern of associations was observed.

Conclusions: These results support the idea that individuals with the metabolically healthy/overweight phenotype (with normal insulin levels) are at lower colorectal cancer risk than those with hyperinsulinaemia. The combination of anthropometric measures with metabolic parameters, such as C-peptide, may be useful for defining strata of the population at greater risk of colorectal cancer.
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http://dx.doi.org/10.1371/journal.pmed.1001988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4821615PMC
April 2016

Dietary Patterns and Risk of Inflammatory Bowel Disease in Europe: Results from the EPIC Study.

Inflamm Bowel Dis 2016 Feb;22(2):345-54

1INSERM, Centre for Research in Epidemiology and Population, Health, UMR1018, Institut Gustave Roussy, Université Paris Sud, Villejuif, France; 2Department of Gastroenterology, University Hospital of Bicêtre, Assistance Publique Hôpitaux de Paris, Université Paris-Sud, Le Kremlin Bicêtre, France; 3Department of Medicine, Norwich Medical School, University of East Anglia, Norwich, United Kingdom; 4Department of Gastroenterology, Norfolk and Norwich University Hospital NHS Trust, Norwich, United Kingdom; 5Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands; 6Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, the Netherlands; 7Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, United Kingdom; 8Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; 9Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark; 10Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark; 11Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom; 12Strangeways Research Laboratory, Institute of Public Health, University of Cambridge, Cambridge, United Kingdom; 13Division of Epidemiology, Imperial College London, London, United Kingdom; 14Department of Gastroenterology and Hepatology, University Hospital Malmö, Malmö, Sweden; 15Department of Public Health and Clinical Medicine, Nutritional Research, Umea University, Umea, Sweden; 16Department of Public Health and Clinical Medicine, GI unit, Umea University, Umea, Sweden; 17Department of Epidemiology, German Institute of Human Nutrition, Potsdam, Germany; 18Division of Clinical Epidemiology, DKFZ-German Cancer Research Centre Heidelberg, Heidelberg, Germany; 19Molecular and Nutritional Epidemio

Background: Specific nutrients or foods have been inconsistently associated with ulcerative colitis (UC) or Crohn's disease (CD) risks. Thus, we investigated associations between diet as a whole, as dietary patterns, and UC and CD risks.

Methods: Within the prospective EPIC (European Prospective Investigation into Cancer) study, we set up a nested matched case-control study among 366,351 participants with inflammatory bowel disease data, including 256 incident cases of UC and 117 of CD, and 4 matched controls per case. Dietary intake was recorded at baseline from validated food frequency questionnaires. Incidence rate ratios of developing UC and CD were calculated for quintiles of the Mediterranean diet score and a posteriori dietary patterns produced by factor analysis.

Results: No dietary pattern was associated with either UC or CD risks. However, when excluding cases occurring within the first 2 years after dietary assessment, there was a positive association between a "high sugar and soft drinks" pattern and UC risk (incidence rate ratios for the fifth versus first quintile, 1.68 [1.00-2.82]; Ptrend = 0.02). When considering the foods most associated with the pattern, high consumers of sugar and soft drinks were at higher UC risk only if they had low vegetables intakes.

Conclusions: A diet imbalance with high consumption of sugar and soft drinks and low consumption of vegetables was associated with UC risk. Further studies are needed to investigate whether microbiota alterations or other mechanisms mediate this association.
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http://dx.doi.org/10.1097/MIB.0000000000000638DOI Listing
February 2016

Reproductive factors and risk of mortality in the European Prospective Investigation into Cancer and Nutrition; a cohort study.

BMC Med 2015 Oct 30;13:252. Epub 2015 Oct 30.

CIBER de Epidemiología y Salud Pública (CIBERESP), Melchor Fernández Almagro, 3-5, 28029, Madrid, Spain.

Background: Reproductive events are associated with important physiologic changes, yet little is known about how reproductive factors influence long-term health in women. Our objective was to assess the relation of reproductive characteristics with all-cause and cause-specific mortality risk.

Methods: The analysis was performed within the European Investigation into Cancer and Nutrition prospective cohort study, which enrolled >500,000 women and men from 1992 to 2000, who were residing in a given town/geographic area in 10 European countries. The current analysis included 322,972 eligible women aged 25-70 years with 99 % complete follow-up for vital status. We assessed reproductive characteristics reported at the study baseline including parity, age at the first birth, breastfeeding, infertility, oral contraceptive use, age at menarche and menopause, total ovulatory years, and history of oophorectomy/hysterectomy. Hazard ratios (HRs) and 95 % confidence intervals (CIs) for mortality were determined using Cox proportional hazards regression models adjusted for menopausal status, body mass index, physical activity, education level, and smoking status/intensity and duration.

Results: During a mean follow-up of 12.9 years, 14,383 deaths occurred. The HR (95 % CI) for risk of all-cause mortality was lower in parous versus nulliparous women (0.80; 0.76-0.84), in women who had ever versus never breastfed (0.92; 0.87-0.97), in ever versus never users of oral contraceptives (among non-smokers; 0.90; 0.86-0.95), and in women reporting a later age at menarche (≥15 years versus <12; 0.90; 0.85-0.96; P for trend = 0.038).

Conclusions: Childbirth, breastfeeding, oral contraceptive use, and a later age at menarche were associated with better health outcomes. These findings may contribute to the development of improved strategies to promote better long-term health in women.
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http://dx.doi.org/10.1186/s12916-015-0484-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627614PMC
October 2015
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