Publications by authors named "Eva Ardanaz"

385 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.

Nutrition and Metabolism Branch, International Agency For Research On Cancer.

Background: Evidence is accumulating that immune cells play a prominent role in pancreatic cancer aetiology 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 sub-lineages: total CD3+, CD8+, CD4+, and FOXP3+ regulatory T cells (Tregs) relative to nucleated cells, (white blood cells) were measured by qRT-PCR. Odds ratios with 95% Confidence Intervals were estimated using logistic regressions, modelling 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 sub-group 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

Prognostic biomarkers of Parkinson's disease in the Spanish EPIC cohort: a multiplatform metabolomics approach.

NPJ Parkinsons Dis 2021 Aug 16;7(1):73. Epub 2021 Aug 16.

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

The lack of knowledge about the onset and progression of Parkinson's disease (PD) hampers its early diagnosis and treatment. Metabolomics might shed light on the PD imprint seeking a broader view of the biochemical remodeling induced by this disease in an early and pre-symptomatic stage and unveiling potential biomarkers. To achieve this goal, we took advantage of the great potential of the European Prospective Study on Nutrition and Cancer (EPIC) cohort to apply metabolomics searching for early diagnostic PD markers. This cohort consisted of healthy volunteers that were followed for around 15 years until June 2011 to ascertain incident PD. For this untargeted metabolomics-based study, baseline preclinical plasma samples of 39 randomly selected individuals that developed PD (Pre-PD group) and the corresponding control group were analyzed using a multiplatform approach. Data were statistically analyzed and exposed alterations in 33 metabolites levels, including significantly lower levels of free fatty acids (FFAs) in the preclinical samples from PD subjects. These results were then validated by adopting a targeted HPLC-QqQ-MS approach. After integrating all the metabolites affected, our finding revealed alterations in FFAs metabolism, mitochondrial dysfunction, oxidative stress, and gut-brain axis dysregulation long before the development of PD hallmarks. Although the biological purpose of these events is still unknown, the remodeled metabolic pathways highlighted in this work might be considered worthy prognostic biomarkers of early prodromal PD. The findings revealed by this work are of inestimable value since this is the first study conducted with samples collected many years before the disease development.
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http://dx.doi.org/10.1038/s41531-021-00216-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8368017PMC
August 2021

Association of Cycling With All-Cause and Cardiovascular Disease Mortality Among Persons With Diabetes: The European Prospective Investigation Into Cancer and Nutrition (EPIC) Study.

JAMA Intern Med 2021 Sep;181(9):1196-1205

University of Southern Denmark, Odense, Denmark.

Importance: Premature death from all causes and cardiovascular disease (CVD) causes is higher among persons with diabetes.

Objective: To investigate the association between time spent cycling and all-cause and CVD mortality among persons with diabetes, as well as to evaluate the association between change in time spent cycling and risk of all-cause and CVD mortality.

Design, Setting, And Participants: This prospective cohort study included 7459 adults with diabetes from the European Prospective Investigation into Cancer and Nutrition study. Questionnaires regarding medical history, sociodemographic, and lifestyle information were administered in 10 Western European countries from 1992 through 2000 (baseline examination) and at a second examination 5 years after baseline. A total of 5423 participants with diabetes completed both examinations. The final updated primary analysis was conducted on November 13, 2020.

Exposures: The primary exposure was self-reported time spent cycling per week at the baseline examination. The secondary exposure was change in cycling status from baseline to the second examination.

Main Outcomes And Measures: The primary and secondary outcomes were all-cause and CVD mortality, respectively, adjusted for other physical activity modalities, diabetes duration, and sociodemographic and lifestyle factors.

Results: Of the 7459 adults with diabetes included in the analysis, the mean (SD) age was 55.9 (7.7) years, and 3924 (52.6%) were female. During 110 944 person-years of follow-up, 1673 deaths from all causes were registered. Compared with the reference group of people who reported no cycling at baseline (0 min/wk), the multivariable-adjusted hazard ratios for all-cause mortality were 0.78 (95% CI, 0.61-0.99), 0.76 (95% CI, 0.65-0.88), 0.68 (95% CI, 0.57-0.82), and 0.76 (95% CI, 0.63-0.91) for cycling 1 to 59, 60 to 149, 150 to 299, and 300 or more min/wk, respectively. In an analysis of change in time spent cycling with 57 802 person-years of follow-up, a total of 975 deaths from all causes were recorded. Compared with people who reported no cycling at both examinations, the multivariable-adjusted hazard ratios for all-cause mortality were 0.90 (95% CI, 0.71-1.14) in those who cycled and then stopped, 0.65 (95% CI, 0.46-0.92) in initial noncyclists who started cycling, and 0.65 (95% CI, 0.53-0.80) for people who reported cycling at both examinations. Similar results were observed for CVD mortality.

Conclusion And Relevance: In this cohort study, cycling was associated with lower all-cause and CVD mortality risk among people with diabetes independent of practicing other types of physical activity. Participants who took up cycling between the baseline and second examination had a considerably lower risk of both all-cause and CVD mortality compared with consistent noncyclists.
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http://dx.doi.org/10.1001/jamainternmed.2021.3836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290339PMC
September 2021

[Family history of first degree as a risk factor for colorectal cancer].

Gac Sanit 2021 Jul 13. Epub 2021 Jul 13.

CIBER de Epidemiología y Salud Pública (CIBERESP), España; Programa de Recerca en Epidemiologia del Càncer, Institut Català d'Oncologia (IDIBELL), L'Hospitalet de Llobregat, Barcelona, España.

Objective: To evaluate the association between first-degree family history and colorectal cancer (CRC).

Method: We analyzed data from 2857 controls and 1360 CRC cases, collected in the MCC-Spain project. The adjusted odds ratio (OR) and 95% confidence interval (95% CI) of association with the family history of CRC was estimated by non-conditional logistic regression.

Results: First-degree relatives doubled the risk of CRC (OR: 2.19; 95% CI: 1.80-2.66), increasing in those with two or more (OR: 4.22; 95% CI: 2.29-7.78) and in those whose relatives were diagnosed before 50 years (OR: 3.24; 95% CI: 1.52-6.91). Regarding the association of the family history with the location, no significant differences were observed between colon and rectum, but there were in the relation of these with the age of diagnosis, having more relatives those diagnosed before 50 years (OR: 4.79; 95% CI: 2.65-8.65).

Conclusions: First-degree relatives of CRC increase the chances of developing this tumor, they also increase when the relative is diagnosed at an early age. Therefore, it must be a target population on which to carry out prevention measures.
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http://dx.doi.org/10.1016/j.gaceta.2021.04.006DOI Listing
July 2021

Plasma concentrations of persistent organic pollutants and pancreatic cancer risk.

Int J Epidemiol 2021 Jul 14. Epub 2021 Jul 14.

Cancer Registry and Histopathology Department, "Civic-M.P. Arezzo" Hospital, ASP Ragusa, Ragusa, Italy.

Background: Findings and limitations of previous studies on persistent organic pollutants (POPs) and pancreatic cancer risk support conducting further research in prospective cohorts.

Methods: We conducted a prospective case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Participants were 513 pancreatic cancer cases and 1020 matched controls. Concentrations of 22 POPs were measured in plasma collected at baseline.

Results: Some associations were observed at higher concentrations of p, p'-DDT, trans-nonachlor, β-hexachlorocyclohexane and the sum of six organochlorine pesticides and of 16 POPs. The odds ratio (OR) for the upper quartile of trans-nonachlor was 1.55 (95% confidence interval 1.06-2.26; P for trend = 0.025). Associations were stronger in the groups predefined as most valid (participants having fasted >6 h, with microscopic diagnostic confirmation, normal weight, and never smokers), and as most relevant (follow-up ≥10 years). Among participants having fasted >6 h, the ORs were relevant for 10 of 11 exposures. Higher ORs were also observed among cases with microscopic confirmation than in cases with a clinical diagnosis, and among normal-weight participants than in the rest of participants. Among participants with a follow-up ≥10 years, estimates were higher than in participants with a shorter follow-up (for trans-nonachlor: OR = 2.14, 1.01 to 4.53, P for trend = 0.035). Overall, trans-nonachlor, three PCBs and the two sums of POPs were the exposures most clearly associated with pancreatic cancer risk.

Conclusions: Individually or in combination, most of the 22 POPs analysed did not or only moderately increased the risk of pancreatic cancer.
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http://dx.doi.org/10.1093/ije/dyab115DOI Listing
July 2021

Hepcidin-regulating iron metabolism genes and pancreatic ductal adenocarcinoma: a pathway analysis of genome-wide association studies.

Am J Clin Nutr 2021 Jul 13. Epub 2021 Jul 13.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

Background: Epidemiological studies have suggested positive associations for iron and red meat intake with risk of pancreatic ductal adenocarcinoma (PDAC). Inherited pathogenic variants in genes involved in the hepcidin-regulating iron metabolism pathway are known to cause iron overload and hemochromatosis.

Objectives: The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC.

Methods: We conducted a pathway analysis of the hepcidin-regulating genes using single nucleotide polymorphism (SNP) summary statistics generated from 4 genome-wide association studies in 2 large consortium studies using the summary data-based adaptive rank truncated product method. Our population consisted of 9253 PDAC cases and 12,525 controls of European descent. Our analysis included 11 hepcidin-regulating genes [bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 6 (BMP6), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), hepcidin (HAMP), homeostatic iron regulator (HFE), hemojuvelin (HJV), nuclear factor erythroid 2-related factor 2 (NRF2), ferroportin 1 (SLC40A1), transferrin receptor 1 (TFR1), and transferrin receptor 2 (TFR2)] and their surrounding genomic regions (±20 kb) for a total of 412 SNPs.

Results: The hepcidin-regulating gene pathway was significantly associated with PDAC (P = 0.002), with the HJV, TFR2, TFR1, BMP6, and HAMP genes contributing the most to the association.

Conclusions: Our results support that genetic susceptibility related to the hepcidin-regulating gene pathway is associated with PDAC risk and suggest a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate effect modification by intake of iron-rich foods on this association.
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http://dx.doi.org/10.1093/ajcn/nqab217DOI Listing
July 2021

Factors associated with serum ferritin levels and iron excess: results from the EPIC-EurGast study.

Eur J Nutr 2021 Jul 2. Epub 2021 Jul 2.

Unit of Nutrition and Cancer, Catalan Institute of Oncology - ICO, Nutrition and Cancer Group, Bellvitge Biomedical Research Institute -(IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.

Purpose: Excess iron is involved in the development of non-communicable diseases such as cancer, type 2 diabetes and cardiovascular conditions. We aimed to describe the prevalence of excess iron and its determinants in healthy European adults.

Methods: Sociodemographic, lifestyle, iron status, dietary information, and HFE genotyping were obtained from controls from the nested case-control study EPIC-EurGast study. High sensitivity C-reactive protein (hsCRP) was measured to address possible systemic inflammation. Descriptive and multivariate analyses were used to assess iron status and its determinants.

Results: Out of the 828 participants (median age: 58.7 years), 43% were females. Median serum ferritin and prevalence of excess iron were 143.7 µg/L and 35.2% in males, respectively, and 77 µg/L and 20% in females, both increasing with latitude across Europe. Prevalence of HFE C282Y mutation was significantly higher in Northern and Central Europe (~ 11%) than in the South (5%). Overweight/obesity, age, and daily alcohol and heme iron intake were independent determinants for iron status, with sex differences even after excluding participants with hsCRP > 5 mg/L. Obese males showed a greater consumption of alcohol, total and red meat, and heme iron, compared with those normal weight.

Conclusion: Obesity, higher alcohol and heme iron consumption were the main risk factors for excess iron in males while only age was associated with iron overload in females. Weight control and promoting healthy lifestyle may help prevent iron overload, especially in obese people. Further research is needed to clarify determinants of excess iron in the healthy adult population, helping to reduce the associated comorbidities.
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http://dx.doi.org/10.1007/s00394-021-02625-wDOI Listing
July 2021

Inflammatory Potential of the Diet and Incidence of Crohn's Disease and Ulcerative Colitis in the EPIC-Spain Cohort.

Nutrients 2021 Jun 26;13(7). Epub 2021 Jun 26.

Instituto de Salud Pública de Navarra, 31003 Pamplona, Spain.

Diet may influence the development of inflammatory bowel disease through the modulation of inflammation. We investigated whether the inflammatory potential of the diet is associated with the risk of Crohn's disease (CD) and ulcerative colitis (UC) in the Spanish cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Spain). The study included 32,633 participants aged 29-69 years. The inflammatory potential of the diet was measured by using an inflammatory score of the diet (ISD) based on a baseline dietary history questionnaire. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During 21 years (674,547 person-years) of follow-up, 32 and 57 participants developed CD and UC, respectively. In multivariable analysis, a one-standard deviation (SD) increment in the ISD (two-unit increase) was associated with a higher risk of CD (HR of 1.71; 95% CI: 1.05-2.80; = 0.031). By contrast, ISD was not associated with UC (HR for one-SD increment of 0.89; 95% CI: 0.66-1.19; = 0.436). Our results suggest that consuming a more pro-inflammatory diet may contribute to the risk of CD, supporting that a healthy diet might be beneficial in its prevention. Further, larger studies are needed to verify these findings.
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http://dx.doi.org/10.3390/nu13072201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8308349PMC
June 2021

Circulating tryptophan metabolites and risk of colon cancer: Results from case-control and prospective cohort studies.

Int J Cancer 2021 Nov 12;149(9):1659-1669. Epub 2021 Jul 12.

International Agency for Research on Cancer, Lyon, France.

Dysregulation of tryptophan metabolism has been linked to colorectal tumorigenesis; however, epidemiological studies investigating tryptophan metabolites in relation to colorectal cancer risk are limited. We studied associations of plasma tryptophan, serotonin and kynurenine with colon cancer risk in two studies with cancer patients and controls, and in one prospective cohort: ColoCare Study (110 patients/153 controls), the Colorectal Cancer Study of Austria (CORSA; 46 patients/390 controls) and the European Prospective Investigation into Cancer and Nutrition (EPIC; 456 matched case-control pairs). Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for colon cancer risk. Tryptophan was inversely associated with colon cancer risk in ColoCare (OR per 1-SD = 0.44; 95% CI, 0.31-0.64) and EPIC (OR per 1-SD = 0.86; 95% CI, 0.74-0.99). Comparing detectable vs nondetectable levels, serotonin was positively associated with colon cancer in CORSA (OR = 6.39; 95% CI, 3.61-11.3) and EPIC (OR = 2.03; 95% CI, 1.20-3.40). Kynurenine was inversely associated with colon cancer in ColoCare (OR per 1-SD = 0.74; 95% CI, 0.55-0.98), positively associated in CORSA (OR per 1-SD = 1.79; 95% CI, 1.27-2.52), while no association was observed in EPIC. The kynurenine-to-tryptophan ratio was positively associated with colon cancer in ColoCare (OR per 1-SD = 1.38; 95% CI, 1.03-1.84) and CORSA (OR per 1-SD = 1.44; 95% CI, 1.06-1.96), but not in EPIC. These results suggest that higher plasma tryptophan may be associated with lower colon cancer risk, while increased serotonin may be associated with a higher risk of colon cancer. The kynurenine-to-tryptophan ratio may also reflect altered tryptophan catabolism during colon cancer development.
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http://dx.doi.org/10.1002/ijc.33725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429124PMC
November 2021

Inflammatory potential of the diet and risk of breast cancer in the European Investigation into Cancer and Nutrition (EPIC) study.

Eur J Epidemiol 2021 Jun 20. Epub 2021 Jun 20.

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

The role of chronic inflammation on breast cancer (BC) risk remains unclear beyond as an underlying mechanism of obesity and physical activity. We aimed to evaluate the association between the inflammatory potential of the diet and risk of BC overall, according to menopausal status and tumour subtypes. Within the European Prospective Investigation into Cancer and Nutrition cohort, 318,686 women were followed for 14 years, among whom 13,246 incident BC cases were identified. The inflammatory potential of the diet was characterized by an inflammatory score of the diet (ISD). Multivariable Cox regression models were used to assess the potential effect of the ISD on BC risk by means of hazard ratios (HR) and 95% confidence intervals (CI). ISD was positively associated with BC risk. Each increase of one standard deviation (1-Sd) of the score increased by 4% the risk of BC (HR = 1.04; 95% CI 1.01-1.07). Women in the highest quintile of the ISD (indicating a most pro-inflammatory diet) had a 12% increase in risk compared with those in the lowest quintile (HR = 1.12; 95% CI 1.04-1.21) with a significant trend. The association was strongest among premenopausal women, with an 8% increased risk for 1-Sd increase in the score (HR = 1.08; 95% CI 1.01-1.14). The pattern of the association was quite homogeneous by BC subtypes based on hormone receptor status. There were no significant interactions between ISD and body mass index, physical activity, or alcohol consumption. Women consuming more pro-inflammatory diets as measured by ISD are at increased risk for BC, especially premenopausal women.
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http://dx.doi.org/10.1007/s10654-021-00772-2DOI Listing
June 2021

Concentrations of bisphenol-A in adults from the general population: A systematic review and meta-analysis.

Sci Total Environ 2021 Jun 11;775:145755. Epub 2021 Feb 11.

Department of Epidemiology, Murcia Regional Health Council, Murcia, Spain; CIBER Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Department of Health and Social Sciences, University of Murcia, Murcia, Spain; Murcia Biomedical Research Institute (IMIB-Arrixaca), Murcia, Spain.

Background: Human bisphenol-A (BPA) exposure has been linked to adverse health effects even at low doses, which may be of potential public health concern.

Objective: To summarize BPA concentrations in general human population and their variability according to sex, geographic area, and analytical method.

Methods: Systematic review and meta-analysis of studies reporting BPA concentrations in adult human populations. Separate meta-analyses of median values were carried out for BPA in serum, creatinine-adjusted urinary BPA, and unadjusted urinary BPA concentrations using a random-effects model. Cochran's Q-statistic, I index, 95% prediction intervals (PIs), between-studies standard deviation (τ), and forest plots were applied to verify study heterogeneity. Sensitivity and subgroup analyses and weighted ANOVAs and meta-regressions were conducted. Funnel plots and Egger's tests were used to examine publication bias.

Results: Fifteen studies were included in the meta-analysis, totaling 28,353 participants. BPA was detected in over 90% of participants. The pooled creatinine-adjusted urinary BPA concentration was 1.76 μg/g (95% PI: 0.79-2.73), with individual estimates ranging between 1.20 and 2.41. The pooled estimate for unadjusted urinary BPA was 1.91 μg/l (95% PI: 0-3.97), ranging between 0.81 and 3.50, while the pooled estimate for serum BPA was 1.75 μg/l (95% PI: 0-10.58), ranging between 0.34 and 3.76. No differences were found by sex, geographic area or analytical technique. Larger sample sizes were associated with lower BPA concentrations. There was large heterogeneity across studies, whereas data for urinary BPA levels suggested a publication bias affecting research in low exposed populations.

Conclusion: This first meta-analysis of human BPA concentrations highlights a widespread population exposure to BPA. Although there was high heterogeneity across studies, the expected range of estimated human BPA concentrations suggests that potential health risks are unlikely. Further studies are warranted to better characterize the epidemiology of human BPA exposure, accounting for ethnic, geographic, individual and environmental variability.
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http://dx.doi.org/10.1016/j.scitotenv.2021.145755DOI Listing
June 2021

Sleep duration and napping in relation to colorectal and gastric cancer in the MCC-Spain study.

Sci Rep 2021 Jun 3;11(1):11822. Epub 2021 Jun 3.

Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain.

Sleep duration is a novel and potentially modifiable risk factor for cancer. We evaluated the association of self-reported sleep duration and daytime napping with odds of colorectal and gastric cancer. We included 2008 incident colorectal cancer cases, 542 gastric cancer cases and 3622 frequency-matched population controls, recruited in the MCC-Spain case-control study (2008-2013). Sleep information, socio-demographic and lifestyle characteristics were obtained through personal interviews. Multivariable adjusted logistic regression models were used to estimate odds ratios (OR) with 95% confidence intervals (CI) for cancer, across categories of sleep duration (≤ 5, 6, 7, 8, ≥ 9 hours/day), daytime napping frequency (naps/week) and duration (minutes/nap). Compared to 7 hours of sleep, long sleep was associated with increased odds of colorectal (OR: 1.59; 95%CI 1.30-1.94) and gastric cancer (OR: 1.95; 1.37-2.76); short sleep was associated with increased odds of gastric cancer (OR: 1.32; 0.93-1.88). Frequent and long daytime naps increased the odds of colorectal (OR: 1.32; 1.14-1.54) and gastric cancer (OR: 1.56; 1.21-2.02). Effects of short sleep and frequent long naps were stronger among participants with night shift-work history. Sleep and circadian disruption may jointly play a role in the etiology of colorectal and gastric cancer.
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http://dx.doi.org/10.1038/s41598-021-91275-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175745PMC
June 2021

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

Nutrients 2021 May 28;13(6). Epub 2021 May 28.

Office of the Director, International Agency for Research on Cancer, CEDEX 08, 69372 Lyon, France.

(1) Background: Methyl-group donors (MGDs), including folate, choline, betaine, and methionine, may influence breast cancer (BC) risk through their role in one-carbon metabolism; (2) Methods: We studied the relationship between dietary intakes of MGDs and BC risk, adopting data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort; (3) Results: 318,686 pre- and postmenopausal women were followed between enrolment in 1992-2000 and December 2013-December 2015. Dietary MGD intakes were estimated at baseline through food-frequency questionnaires. Multivariable Cox proportional hazards regression models were used to quantify the association between dietary intake of MGDs, measured both as a calculated score based on their sum and individually, and BC risk. Subgroup analyses were performed by hormone receptor status, menopausal status, and level of alcohol intake. During a mean follow-up time of 14.1 years, 13,320 women with malignant BC were identified. No associations were found between dietary intakes of the MGD score or individual MGDs and BC risk. However, a potential U-shaped relationship was observed between dietary folate intake and overall BC risk, suggesting an inverse association for intakes up to 350 µg/day compared to a reference intake of 205 µg/day. No statistically significant differences in the associations were observed by hormone receptor status, menopausal status, or level of alcohol intake; (4) Conclusions: There was no strong evidence for an association between MGDs involved in one-carbon metabolism and BC risk. However, a potential U-shaped trend was suggested for dietary folate intake and BC risk. Further research is needed to clarify this association.
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http://dx.doi.org/10.3390/nu13061843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228096PMC
May 2021

Novel Biomarkers of Habitual Alcohol Intake and Associations with Risk of Pancreatic and Liver Cancers and Liver Disease Mortality.

J Natl Cancer Inst 2021 May 19. Epub 2021 May 19.

Institute for Risk Assessment Sciences, Division of Environmental Epidemiology, Utrecht University, Utrecht, The Netherlands.

Background: Alcohol is an established risk factor for several cancers, but modest alcohol-cancer associations may be missed due to measurement error in self-reported assessments. Biomarkers of habitual alcohol intake may provide novel insight into the relationship between alcohol and cancer risk.

Methods: Untargeted metabolomics was used to identify metabolites correlated with self-reported habitual alcohol intake in a discovery dataset from the European Prospective Investigation into Cancer and Nutrition (EPIC; n = 454). Statistically significant correlations were tested in independent datasets of controls from case-control studies nested within EPIC (n = 280) and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC; n = 438) study. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations of alcohol-associated metabolites and self-reported alcohol intake with risk of pancreatic cancer, hepatocellular carcinoma (HCC), liver cancer, and liver disease mortality in the contributing studies.

Results: Two metabolites displayed a dose-response association with self-reported alcohol intake 2-hydroxy-3-methylbutyric acid and an unidentified compound. A 1-SD (log2) increase in levels of 2-hydroxy-3-methylbutyric acid was associated with risk of HCC (OR = 2.54; 95% CI = 1.51-4.27) and pancreatic cancer (OR = 1.43; 95% CI = 1.03-1.99) in EPIC and liver cancer (OR = 2.00; 95% CI = 1.44-2.77) and liver disease mortality (OR = 2.16; 95% CI = 1.63-2.86) in ATBC. Conversely, a 1-SD (log2) increase in questionnaire-derived alcohol intake was not associated with HCC or pancreatic cancer in EPIC or liver cancer in ATBC but was associated with liver disease mortality (OR = 2.19; 95% CI = 1.60-2.98) in ATBC.

Conclusions: 2-Hydroxy-3-methylbutyric acid is a candidate biomarker of habitual alcohol intake that may advance the study of alcohol and cancer risk in population-based studies.
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http://dx.doi.org/10.1093/jnci/djab078DOI Listing
May 2021

A Prospective Diet-Wide Association Study for Risk of Colorectal Cancer in EPIC.

Clin Gastroenterol Hepatol 2021 Apr 24. Epub 2021 Apr 24.

Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background & Aims: Evidence regarding the association of dietary exposures with colorectal cancer (CRC) risk is not consistent with a few exceptions. Therefore, we conducted a diet-wide association study (DWAS) in the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate the associations between several dietary exposures with CRC risk.

Methods: The association of 92 food and nutrient intakes with CRC risk was assessed in 386,792 participants, 5069 of whom developed incident CRC. Correction for multiple comparisons was performed using the false discovery rate, and emerging associations were examined in the Netherlands Cohort Study (NLCS). Multiplicative gene-nutrient interactions were also tested in EPIC based on known CRC-associated loci.

Results: In EPIC, alcohol, liquor/spirits, wine, beer/cider, soft drinks, and pork were positively associated with CRC, whereas milk, cheese, calcium, phosphorus, magnesium, potassium, riboflavin, vitamin B6, beta carotene, fruit, fiber, nonwhite bread, banana, and total protein intakes were inversely associated. Of these 20 associations, 13 were replicated in the NLCS, for which a meta-analysis was performed, namely alcohol (summary hazard ratio [HR] per 1-SD increment in intake: 1.07; 95% confidence interval [CI], 1.04-1.09), liquor/spirits (HR per 1-SD increment in intake, 1.04; 95% CI, 1.02-1.06), wine (HR per 1-SD increment in intake, 1.04; 95% CI, 1.02-1.07), beer/cider (HR per 1-SD increment in intake, 1.06; 95% CI, 1.04-1.08), milk (HR per 1-SD increment in intake, 0.95; 95% CI, 0.93-0.98), cheese (HR per 1-SD increment in intake, 0.96; 95% CI, 0.94-0.99), calcium (HR per 1-SD increment in intake, 0.93; 95% CI, 0.90-0.95), phosphorus (HR per 1-SD increment in intake, 0.92; 95% CI, 0.90-0.95), magnesium (HR per 1-SD increment in intake, 0.95; 95% CI, 0.92-0.98), potassium (HR per 1-SD increment in intake, 0.96; 95% CI, 0.94-0.99), riboflavin (HR per 1-SD increment in intake, 0.94; 95% CI, 0.92-0.97), beta carotene (HR per 1-SD increment in intake, 0.96; 95% CI, 0.93-0.98), and total protein (HR per 1-SD increment in intake, 0.94; 95% CI, 0.92-0.97). None of the gene-nutrient interactions were significant after adjustment for multiple comparisons.

Conclusions: Our findings confirm a positive association for alcohol and an inverse association for dairy products and calcium with CRC risk, and also suggest a lower risk at higher dietary intakes of phosphorus, magnesium, potassium, riboflavin, beta carotene, and total protein.
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http://dx.doi.org/10.1016/j.cgh.2021.04.028DOI Listing
April 2021

Association of Pre-diagnostic Antibody Responses to Escherichia coli and Bacteroides fragilis Toxin Proteins with Colorectal Cancer in a European Cohort.

Gut Microbes 2021 Jan-Dec;13(1):1-14

Department of Medical Biosciences, Pathology, Umeå University, Ireland.

Experimental evidence has implicated genotoxic () and enterotoxigenic (ETBF) in the development of colorectal cancer (CRC). However, evidence from epidemiological studies is sparse. We therefore assessed the association of serological markers of and ETBF exposure with odds of developing CRC in the European Prospective Investigation into Nutrition and Cancer (EPIC) study.Serum samples of incident CRC cases and matched controls (n = 442 pairs) were analyzed for immunoglobulin (Ig) A and G antibody responses to seven proteins and two isoforms of the ETBF toxin via multiplex serology. Multivariable-adjusted conditional logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of sero-positivity to and ETBF with CRC.The IgA-positivity of any of the tested antigens was associated with higher odds of developing CRC (OR: 1.42; 95% CI: 1.05-1.91). Dual-positivity for both IgA and IgG to and ETBF was associated with >1.7-fold higher odds of developing CRC, with a significant association only for IgG (OR: 1.75; 95% CI: 1.04, 2.94). This association was more pronounced when restricted to the proximal colon cancers (OR: 2.62; 95% CI: 1.09, 6.29) compared to those of the distal colon (OR: 1.24; 95% CI: 0.51, 3.00) (= 0.095). Sero-positivity to and ETBF was associated with CRC development, suggesting that co-infection of these bacterial species may contribute to colorectal carcinogenesis. These findings warrant further exploration in larger prospective studies and within different population groups.
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http://dx.doi.org/10.1080/19490976.2021.1903825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078709PMC
April 2021

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

Am J Clin Nutr 2021 07;114(1):338-347

Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.

Background: Vitamin B6 insufficiency has been linked to increased risk of cancer and other chronic diseases. The circulating concentration of pyridoxal 5'-phosphate (PLP) is a commonly used measure of vitamin B6 status. Ratios of substrates indicating PLP coenzymatic function and metabolism may be useful complementary measures to further explore the role of vitamin B6 in health.

Objectives: We explored the sensitivity of 5 outcomes, namely PLP concentration, homocysteine:cysteine (Hcy:Cys), cystathionine:cysteine (Cysta:Cys), the 3´-hydroxykynurenine ratio (HKr), and the 4-pyridoxic acid ratio (PAr) to vitamin B6 intake as well as personal and lifestyle characteristics.

Medthods: Dietary intake and biomarker data were collected from participants from 3 nested case-control studies within the European Prospective Investigation into Cancer and Nutrition (EPIC). Bayesian regression models assessed the associations of the 5 biomarker outcomes with vitamin B6 intake and personal and lifestyle covariates. Analogous models examined the relations of Hcy:Cys, Cysta:Cys, and HKr with PLP.

Results: In total, 4608 participants were included in the analyses. Vitamin B6 intake was most strongly associated with PLP, moderately associated with Hcy:Cys, Cysta:Cys, and HKr, and not associated with PAr (fold change in marker given a doubling of vitamin B6 intake: PLP 1.60 [95% credible interval (CrI): 1.50, 1.71]; Hcy:Cys 0.87 [95% CrI: 0.84, 0.90]; Cysta:Cys 0.89 [95% CrI: 0.84, 0.94]; HKr 0.88 [95% CrI: 0.85, 0.91]; PAr 1.00 [95% CrI: 0.95, 1.05]). PAr was most sensitive to age, and HKr was least sensitive to BMI and alcohol intake. Sex and menopause status were strongly associated with all 5 markers.

Conclusions: We found that 5 different markers, capturing different aspects of vitamin B6-related biological processes, varied in their associations with vitamin B6 intake and personal and lifestyle predictors.
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http://dx.doi.org/10.1093/ajcn/nqab045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246608PMC
July 2021

Dietary intake of trans fatty acids and breast cancer risk in 9 European countries.

BMC Med 2021 03 30;19(1):81. Epub 2021 Mar 30.

Clinical Sciences Lund, Oncology, Lund University and Skåne University Hospital, Lund, Sweden.

Background: Trans fatty acids (TFAs) have been hypothesised to influence breast cancer risk. However, relatively few prospective studies have examined this relationship, and well-powered analyses according to hormone receptor-defined molecular subtypes, menopausal status, and body size have rarely been conducted.

Methods: In the European Prospective Investigation into Cancer and Nutrition (EPIC), we investigated the associations between dietary intakes of TFAs (industrial trans fatty acids [ITFAs] and ruminant trans fatty acids [RTFAs]) and breast cancer risk among 318,607 women. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models, adjusted for other breast cancer risk factors.

Results: After a median follow-up of 8.1 years, 13,241 breast cancer cases occurred. In the multivariable-adjusted model, higher total ITFA intake was associated with elevated breast cancer risk (HR for highest vs lowest quintile, 1.14, 95% CI 1.06-1.23; P trend = 0.001). A similar positive association was found between intake of elaidic acid, the predominant ITFA, and breast cancer risk (HR for highest vs lowest quintile, 1.14, 95% CI 1.06-1.23; P trend = 0.001). Intake of total RTFAs was also associated with higher breast cancer risk (HR for highest vs lowest quintile, 1.09, 95% CI 1.01-1.17; P trend = 0.015). For individual RTFAs, we found positive associations with breast cancer risk for dietary intakes of two strongly correlated fatty acids (Spearman correlation r = 0.77), conjugated linoleic acid (HR for highest vs lowest quintile, 1.11, 95% CI 1.03-1.20; P trend = 0.001) and palmitelaidic acid (HR for highest vs lowest quintile, 1.08, 95% CI 1.01-1.16; P trend = 0.028). Similar associations were found for total ITFAs and RTFAs with breast cancer risk according to menopausal status, body mass index, and breast cancer subtypes.

Conclusions: These results support the hypothesis that higher dietary intakes of ITFAs, in particular elaidic acid, are associated with elevated breast cancer risk. Due to the high correlation between conjugated linoleic acid and palmitelaidic acid, we were unable to disentangle the positive associations found for these fatty acids with breast cancer risk. Further mechanistic studies are needed to identify biological pathways that may underlie these associations.
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http://dx.doi.org/10.1186/s12916-021-01952-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008592PMC
March 2021

Mediterranean Diet and Risk of Dementia and Alzheimer's Disease in the EPIC-Spain Dementia Cohort Study.

Nutrients 2021 Feb 22;13(2). Epub 2021 Feb 22.

Murcia Biomedical Research Institute (IMIB-Arrixaca), 30120 Murcia, Spain.

The Mediterranean diet (MD) has shown to reduce the occurrence of several chronic diseases. To evaluate its potential protective role on dementia incidence we studied 16,160 healthy participants from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Spain Dementia Cohort study recruited between 1992-1996 and followed up for a mean (±SD) of 21.6 (±3.4) years. A total of 459 incident cases of dementia were ascertained through expert revision of medical records. Data on habitual diet was collected through a validated diet history method to assess adherence to the relative Mediterranean Diet (rMED) score. Hazard ratios (HR) of dementia by rMED levels (low, medium and high adherence levels: ≤6, 7-10 and ≥11 points, respectively) were estimated using multivariable Cox models, whereas time-dependent effects were evaluated using flexible parametric Royston-Parmar (RP) models. Results of the fully adjusted model showed that high versus low adherence to the categorical rMED score was associated with a 20% (HR = 0.80, 95%CI: 0.60-1.06) lower risk of dementia overall and HR of dementia was 8% (HR = 0.92, 0.85-0.99, = 0.021) lower for each 2-point increment of the continuous rMED score. By sub-types, a favorable association was also found in women for non-AD (HR per 2-points = 0.74, 95%CI: 0.62-0.89), while not statistically significant in men for AD (HR per 2-points = 0.88, 0.76-1.01). The association was stronger in participants with lower education. In conclusion, in this large prospective cohort study MD was inversely associated with dementia incidence after accounting for major cardiovascular risk factors. The results differed by dementia sub-type, sex, and education but there was no significant evidence of effect modification.
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http://dx.doi.org/10.3390/nu13020700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927039PMC
February 2021

Red Blood Cell Fatty Acids and Risk of Colorectal Cancer in The European Prospective Investigation into Cancer and Nutrition (EPIC).

Cancer Epidemiol Biomarkers Prev 2021 05 22;30(5):874-885. Epub 2021 Feb 22.

Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.

Background: A growing body of evidence suggests that alterations of dietary fatty acid (FA) profiles are associated with colorectal cancer risk. However, data from large-scale epidemiologic studies using circulating FA measurements to objectively assess individual FA and FA categories are scarce.

Methods: We investigate the association between red blood cell (RBC) membrane FAs and risk of colorectal cancer in a case-control study nested within a large prospective cohort. After a median follow-up of 6.4 years, 1,069 incident colorectal cancer cases were identified and matched to 1,069 controls among participants of the European Prospective Investigation into Cancer and Nutrition (EPIC). The FA composition of RBC phospholipids (in mol%) was analyzed by gas chromatography, and their association with risk of colorectal cancer was estimated by multivariable adjusted conditional logistic regression models.

Results: After correction for multiple testing, subjects with higher concentrations of RBC stearic acid were at higher risk for colorectal cancer (OR = 1.23; 95% CI = 1.07-1.42, per 1 mol%). Conversely, colorectal cancer incidence decreased with increasing proportions of RBC n-3 PUFA, particularly eicosapentaenoic acid (0.75; 0.62-0.92, per 1 mol%). The findings for the n-6 PUFA arachidonic acid were inconsistent.

Conclusions: The positive association between prediagnostic RBC stearic acid and colorectal cancer reflects putative differences in FA intake and metabolism between cancer cases and matched controls, which deserve further investigation. The inverse relationship between EPA and colorectal cancer is in line with the repeatedly reported protective effect of fish consumption on colorectal cancer risk.

Impact: These findings add to the evidence on colorectal cancer prevention.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1426DOI Listing
May 2021

Validation of diagnostic codes and epidemiologic trends of Huntington disease: a population-based study in Navarre, Spain.

Orphanet J Rare Dis 2021 02 10;16(1):77. Epub 2021 Feb 10.

Department of Health Sciences, Universidad Pública de Navarra, IdiSNA, Pamplona, Spain.

Background: There is great heterogeneity on geographic and temporary Huntington disease (HD) epidemiological estimates. Most research studies of rare diseases, including HD, use health information systems (HIS) as data sources. This study investigates the validity and accuracy of national and international diagnostic codes for HD in multiple HIS and analyses the epidemiologic trends of HD in the Autonomous Community of Navarre (Spain).

Methods: HD cases were ascertained by the Rare Diseases Registry and the reference Medical Genetics Centre of Navarre. Positive predictive values (PPV) and sensitivity with 95% confidence intervals (95% CI) were estimated. Overall and 9-year periods (1991-2017) HD prevalence, incidence and mortality rates were calculated, and trends were assessed by Joinpoint regression.

Results: Overall PPV and sensitivity of combined HIS were 71.8% (95% CI: 59.7, 81.6) and 82.2% (95% CI: 70.1, 90.4), respectively. Primary care data was a more valuable resource for HD ascertainment than hospital discharge records, with 66% versus 50% sensitivity, respectively. It also had the highest number of "unique to source" cases. Thirty-five per cent of HD patients were identified by a single database and only 4% by all explored sources. Point prevalence was 4.94 (95% CI: 3.23, 6.65) per 100,000 in December 2017, and showed an annual 6.1% increase from 1991 to 1999. Incidence and mortality trends remained stable since 1995-96, with mean annual rates per 100,000 of 0.36 (95% CI: 0.27, 0.47) and 0.23 (95% CI: 0.16, 0.32), respectively. Late-onset HD patients (23.1%), mean age at onset (49.6 years), age at death (66.6 years) and duration of disease (16.7 years) were slightly higher than previously reported.

Conclusion: HD did not experience true temporary variations in prevalence, incidence or mortality over 23 years of post-molecular testing in our population. Ascertainment bias may largely explain the worldwide heterogeneity in results of HD epidemiological estimates. Population-based rare diseases registries are valuable instruments for epidemiological studies on low prevalence genetic diseases, like HD, as long as they include validated data from multiple HIS and genetic/family information.
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http://dx.doi.org/10.1186/s13023-021-01699-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877055PMC
February 2021

Lifetime alcohol intake, drinking patterns over time and risk of stomach cancer: A pooled analysis of data from two prospective cohort studies.

Int J Cancer 2021 06 22;148(11):2759-2773. Epub 2021 Feb 22.

Hellenic Health Foundation, Athens, Greece.

Alcohol consumption is causally linked to several cancers but the evidence for stomach cancer is inconclusive. In our study, the association between long-term alcohol intake and risk of stomach cancer and its subtypes was evaluated. We performed a pooled analysis of data collected at baseline from 491 714 participants in the European Prospective Investigation into Cancer and Nutrition and the Melbourne Collaborative Cohort Study. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for incident stomach cancer in relation to lifetime alcohol intake and group-based life course intake trajectories, adjusted for potential confounders including Helicobacter pylori infection. In all, 1225 incident stomach cancers (78% noncardia) were diagnosed over 7 094 637 person-years; 984 in 382 957 study participants with lifetime alcohol intake data (5 455 507 person-years). Although lifetime alcohol intake was not associated with overall stomach cancer risk, we observed a weak positive association with noncardia cancer (HR = 1.03, 95% CI: 1.00-1.06 per 10 g/d increment), with a HR of 1.50 (95% CI: 1.08-2.09) for ≥60 g/d compared to 0.1 to 4.9 g/d. A weak inverse association with cardia cancer (HR = 0.93, 95% CI: 0.87-1.00) was also observed. HRs of 1.48 (95% CI: 1.10-1.99) for noncardia and 0.51 (95% CI: 0.26-1.03) for cardia cancer were observed for a life course trajectory characterized by heavy decreasing intake compared to light stable intake (P = .02). These associations did not differ appreciably by smoking or H pylori infection status. Limiting alcohol use during lifetime, particularly avoiding heavy use during early adulthood, might help prevent noncardia stomach cancer. Heterogeneous associations observed for cardia and noncardia cancers may indicate etiologic differences.
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http://dx.doi.org/10.1002/ijc.33504DOI Listing
June 2021

Occupational Heat Exposure and Breast Cancer Risk in the MCC-Spain Study.

Cancer Epidemiol Biomarkers Prev 2021 02 2;30(2):364-372. Epub 2020 Dec 2.

Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain.

Background: Mechanisms linking occupational heat exposure with chronic diseases have been proposed. However, evidence on occupational heat exposure and cancer risk is limited.

Methods: We evaluated occupational heat exposure and female breast cancer risk in a large Spanish case-control study. We enrolled 1,738 breast cancer cases and 1,910 frequency-matched population controls. A Spanish job-exposure matrix, MatEmEsp, was used to assign estimates of the proportion of workers exposed ( ≥ 25% for at least 1 year) and work time with heat stress (wet bulb globe temperature ISO 7243) for each occupation. We used three exposure indices: ever versus never exposed, lifetime cumulative exposure, and duration of exposure (years). We estimated ORs and 95% confidence intervals (CI), applying a lag period of 5 years and adjusting for potential confounders.

Results: Ever occupational heat exposure was associated with a moderate but statistically significant higher risk of breast cancer (OR 1.22; 95% CI, 1.01-1.46), with significant trends across categories of lifetime cumulative exposure and duration ( = 0.01 and 0.03, respectively). Stronger associations were found for hormone receptor-positive disease (OR ever exposure = 1.38; 95% CI, 1.12-1.67). We found no confounding effects from multiple other common occupational exposures; however, results attenuated with adjustment for occupational detergent exposure.

Conclusions: This study provides some evidence of an association between occupational heat exposure and female breast cancer risk.

Impact: Our results contribute substantially to the scientific literature. Further investigations are needed considering multiple occupational exposures.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0732DOI Listing
February 2021

Regarding the estimations of people affected by rare diseases.

Eur J Hum Genet 2021 Jun 1;29(6):1032-1033. Epub 2020 Dec 1.

Community Health Observatory Section, Instituto de Salud Pública y Laboral de Navarra, IdiSNA (Navarra Institute for Health Research), Pamplona, Spain.

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http://dx.doi.org/10.1038/s41431-020-00763-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187376PMC
June 2021

Plasma Vitamin C and Type 2 Diabetes: Genome-Wide Association Study and Mendelian Randomization Analysis in European Populations.

Diabetes Care 2021 01 17;44(1):98-106. Epub 2020 Nov 17.

Unit of Nutrition and Cancer, Cancer Epidemiology Research Program and Translational Research Laboratory; Catalan Institute of Oncology - ICO, Group of Research on Nutrition and Cancer, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet of Llobregat, Barcelona, Spain.

Objective: Higher plasma vitamin C levels are associated with lower type 2 diabetes risk, but whether this association is causal is uncertain. To investigate this, we studied the association of genetically predicted plasma vitamin C with type 2 diabetes.

Research Design And Methods: We conducted genome-wide association studies of plasma vitamin C among 52,018 individuals of European ancestry to discover novel genetic variants. We performed Mendelian randomization analyses to estimate the association of genetically predicted differences in plasma vitamin C with type 2 diabetes in up to 80,983 case participants and 842,909 noncase participants. We compared this estimate with the observational association between plasma vitamin C and incident type 2 diabetes, including 8,133 case participants and 11,073 noncase participants.

Results: We identified 11 genomic regions associated with plasma vitamin C ( < 5 × 10), with the strongest signal at , and 10 novel genetic loci including , , , , , , , , , and . Plasma vitamin C was inversely associated with type 2 diabetes (hazard ratio per SD 0.88; 95% CI 0.82, 0.94), but there was no association between genetically predicted plasma vitamin C (excluding variant due to its apparent pleiotropic effect) and type 2 diabetes (1.03; 95% CI 0.96, 1.10).

Conclusions: These findings indicate discordance between biochemically measured and genetically predicted plasma vitamin C levels in the association with type 2 diabetes among European populations. The null Mendelian randomization findings provide no strong evidence to suggest the use of vitamin C supplementation for type 2 diabetes prevention.
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http://dx.doi.org/10.2337/dc20-1328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783939PMC
January 2021

Quality of Life in a Cohort of 1078 Women Diagnosed with Breast Cancer in Spain: 7-Year Follow-Up Results in the MCC-Spain Study.

Int J Environ Res Public Health 2020 11 13;17(22). Epub 2020 Nov 13.

CIBER Epidemiologia y Salud Pública (CIBERESP), 28029 Madrid, Spain.

Breast cancer is the most frequent cause of tumors and net survival is increasing. Achieving a higher survival probability reinforces the importance of studying health-related quality of life (HR-QoL). The main aim of this work is to test the relationship between different sociodemographic, clinical and tumor-intrinsic characteristics, and treatment received with HR-QoL measured using SF-12 and the FACT/NCCN (National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy) Breast Symptom Index (FBSI). Women with breast cancer recruited between 2008 and 2013 and followed-up until 2017-2018 in a prospective cohort answered two HR-QoL surveys: the SF-12 and FBSI. The scores obtained were related to woman and tumor characteristics using linear regression models. The telephone survey was answered by 1078 women out of 1685 with medical record follow-up (64%). Increases in all three HR-QoL scores were associated with higher educational level. The score differences between women with university qualifications and women with no schooling were 5.43 for PCS-12, 6.13 for MCS-12 and 4.29 for FBSI. Histological grade at diagnosis and recurrence in the follow-up displayed a significant association with mental and physical HR-QoL, respectively. First-line treatment received was not associated with HR-QoL scores. On the other hand, most tumor characteristics were not associated with HR-QoL. As breast cancer survival is improving, further studies are needed to ascertain if these differences still hold in the long run.
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http://dx.doi.org/10.3390/ijerph17228411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696097PMC
November 2020

Genome-wide association analysis of type 2 diabetes in the EPIC-InterAct study.

Sci Data 2020 11 13;7(1):393. Epub 2020 Nov 13.

Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

Type 2 diabetes (T2D) is a global public health challenge. Whilst the advent of genome-wide association studies has identified >400 genetic variants associated with T2D, our understanding of its biological mechanisms and translational insights is still limited. The EPIC-InterAct project, centred in 8 countries in the European Prospective Investigations into Cancer and Nutrition study, is one of the largest prospective studies of T2D. Established as a nested case-cohort study to investigate the interplay between genetic and lifestyle behavioural factors on the risk of T2D, a total of 12,403 individuals were identified as incident T2D cases, and a representative sub-cohort of 16,154 individuals was selected from a larger cohort of 340,234 participants with a follow-up time of 3.99 million person-years. We describe the results from a genome-wide association analysis between more than 8.9 million SNPs and T2D risk among 22,326 individuals (9,978 cases and 12,348 non-cases) from the EPIC-InterAct study. The summary statistics to be shared provide a valuable resource to facilitate further investigations into the genetics of T2D.
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http://dx.doi.org/10.1038/s41597-020-00716-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666191PMC
November 2020

Soluble Receptor for Advanced Glycation End-products (sRAGE) and Colorectal Cancer Risk: A Case-Control Study Nested within a European Prospective Cohort.

Cancer Epidemiol Biomarkers Prev 2021 01 20;30(1):182-192. Epub 2020 Oct 20.

Public Health Directorate, Oviedo, Spain.

Background: Overexpression of the receptor for advanced glycation end-product (RAGE) has been associated with chronic inflammation, which in turn has been associated with increased colorectal cancer risk. Soluble RAGE (sRAGE) competes with RAGE to bind its ligands, thus potentially preventing RAGE-induced inflammation.

Methods: To investigate whether sRAGE and related genetic variants are associated with colorectal cancer risk, we conducted a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC). Plasma sRAGE concentrations were measured by ELISA in 1,361 colorectal cancer matched case-control sets. Twenty-four SNPs encoded in the genes associated with sRAGE concentrations were available for 1,985 colorectal cancer cases and 2,220 controls. Multivariable adjusted ORs and 95% confidence intervals (CIs) were computed using conditional and unconditional logistic regression for colorectal cancer risk and circulating sRAGE and SNPs, respectively.

Results: Higher sRAGE concentrations were inversely associated with colorectal cancer (OR, 0.77; 95% CI, 0.59-1.00). Sex-specific analyses revealed that the observed inverse risk association was restricted to men (OR, 0.63; 95% CI, 0.42-0.94), whereas no association was observed in women (OR, 1.00; 95% CI, 0.68-1.48; for sex = 0.006). Participants carrying minor allele of rs653765 (promoter region of ) had lower colorectal cancer risk (C vs. T, OR, 0.90; 95% CI, 0.82-0.99).

Conclusions: Prediagnostic sRAGE concentrations were inversely associated with colorectal cancer risk in men, but not in women. An SNP located within gene, pertaining to RAGE shedding, was associated with colorectal cancer risk.

Impact: Further studies are needed to confirm our observed sex difference in the association and better explore the potential involvement of genetic variants of sRAGE in colorectal cancer development.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0855DOI Listing
January 2021

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

PLoS Med 2020 10 16;17(10):e1003394. Epub 2020 Oct 16.

Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.

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.
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http://dx.doi.org/10.1371/journal.pmed.1003394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567390PMC
October 2020

Weight change in middle adulthood and risk of cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

Int J Cancer 2021 04 9;148(7):1637-1651. Epub 2020 Nov 9.

Unit of Cancer Epidemiology, Città della Salute e della Scienza University-Hospital and Center for Cancer Prevention (CPO), Turin, Italy.

Obesity is a risk factor for several major cancers. Associations of weight change in middle adulthood with cancer risk, however, are less clear. We examined the association of change in weight and body mass index (BMI) category during middle adulthood with 42 cancers, using multivariable Cox proportional hazards models in the European Prospective Investigation into Cancer and Nutrition cohort. Of 241 323 participants (31% men), 20% lost and 32% gained weight (>0.4 to 5.0 kg/year) during 6.9 years (average). During 8.0 years of follow-up after the second weight assessment, 20 960 incident cancers were ascertained. Independent of baseline BMI, weight gain (per one kg/year increment) was positively associated with cancer of the corpus uteri (hazard ratio [HR] = 1.14; 95% confidence interval: 1.05-1.23). Compared to stable weight (±0.4 kg/year), weight gain (>0.4 to 5.0 kg/year) was positively associated with cancers of the gallbladder and bile ducts (HR = 1.41; 1.01-1.96), postmenopausal breast (HR = 1.08; 1.00-1.16) and thyroid (HR = 1.40; 1.04-1.90). Compared to maintaining normal weight, maintaining overweight or obese BMI (World Health Organisation categories) was positively associated with most obesity-related cancers. Compared to maintaining the baseline BMI category, weight gain to a higher BMI category was positively associated with cancers of the postmenopausal breast (HR = 1.19; 1.06-1.33), ovary (HR = 1.40; 1.04-1.91), corpus uteri (HR = 1.42; 1.06-1.91), kidney (HR = 1.80; 1.20-2.68) and pancreas in men (HR = 1.81; 1.11-2.95). Losing weight to a lower BMI category, however, was inversely associated with cancers of the corpus uteri (HR = 0.40; 0.23-0.69) and colon (HR = 0.69; 0.52-0.92). Our findings support avoiding weight gain and encouraging weight loss in middle adulthood.
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April 2021
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