Publications by authors named "Sandra Colorado-Yohar"

35 Publications

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

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

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

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

Prospective analysis of circulating metabolites and endometrial cancer risk.

Gynecol Oncol 2021 Aug 5;162(2):475-481. Epub 2021 Jun 5.

Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands.

Background: Endometrial cancer is strongly associated with obesity and dysregulation of metabolic factors such as estrogen and insulin signaling are causal risk factors for this malignancy. To identify additional novel metabolic pathways associated with endometrial cancer we performed metabolomic analyses on pre-diagnostic plasma samples from 853 case-control pairs from the European Prospective Investigation into Cancer and Nutrition (EPIC).

Methods: A total of 129 metabolites (acylcarnitines, amino acids, biogenic amines, glycerophospholipids, hexoses, and sphingolipids) were measured by liquid chromatography-mass spectrometry. Conditional logistic regression estimated the associations of metabolites with endometrial cancer risk. An analysis focusing on clusters of metabolites using the bootstrap lasso method was also employed.

Results: After adjustment for body mass index, sphingomyelin [SM] C18:0 was positively (OR: 1.18, 95% CI: 1.05-1.33), and glycine, serine, and free carnitine (C0) were inversely (OR: 0.89, 95% CI: 0.80-0.99; OR: 0.89, 95% CI: 0.79-1.00 and OR: 0.91, 95% CI: 0.81-1.00, respectively) associated with endometrial cancer risk. Serine, C0 and two sphingomyelins were selected by the lasso method in >90% of the bootstrap samples. The ratio of esterified to free carnitine (OR: 1.14, 95% CI: 1.02-1.28) and that of short chain to free acylcarnitines (OR: 1.12, 95% CI: 1.00-1.25) were positively associated with endometrial cancer risk. Further adjustment for C-peptide or other endometrial cancer risk factors only minimally altered the results.

Conclusion: These findings suggest that variation in levels of glycine, serine, SM C18:0 and free carnitine may represent specific pathways linked to endometrial cancer development. If causal, these pathways may offer novel targets for endometrial cancer prevention.
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http://dx.doi.org/10.1016/j.ygyno.2021.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336647PMC
August 2021

Circulating Levels of Testosterone, Sex Hormone Binding Globulin and Colorectal Cancer Risk: Observational and Mendelian Randomization Analyses.

Cancer Epidemiol Biomarkers Prev 2021 Jul 20;30(7):1336-1348. Epub 2021 Apr 20.

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

Background: Epidemiologic studies evaluating associations between sex steroid hormones and colorectal cancer risk have yielded inconsistent results. To elucidate the role of circulating levels of testosterone, and sex hormone-binding globulin (SHBG) in colorectal cancer risk, we conducted observational and Mendelian randomization (MR) analyses.

Methods: The observational analyses included 333,530 participants enrolled in the UK Biobank with testosterone and SHBG measured. HRs and 95% confidence intervals (CI) were estimated using multivariable Cox proportional hazards models. For MR analyses, genetic variants robustly associated with hormone levels were identified and their association with colorectal cancer (42,866 cases/42,752 controls) was examined using two-sample MR.

Results: In the observational analysis, there was little evidence that circulating levels of total testosterone were associated with colorectal cancer risk; the MR analyses showed a greater risk for women (OR per 1-SD = 1.09; 95% CI, 1.01-1.17), although pleiotropy may have biased this result. Higher SHBG concentrations were associated with greater colorectal cancer risk for women (HR per 1-SD = 1.16; 95% CI, 1.05-1.29), but was unsupported by the MR analysis. There was little evidence of associations between free testosterone and colorectal cancer in observational and MR analyses.

Conclusions: Circulating concentrations of sex hormones are unlikely to be causally associated with colorectal cancer. Additional experimental studies are required to better understand the possible role of androgens in colorectal cancer development.

Impact: Our results from large-scale analyses provide little evidence for sex hormone pathways playing a causal role in colorectal cancer development..
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1690DOI Listing
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

Plasma concentrations of advanced glycation end-products and colorectal cancer risk in the EPIC study.

Carcinogenesis 2021 05;42(5):705-713

Office of the Director, International Agency for Research on Cancer (IARC), Lyon, France.

Advanced glycation end-products (AGEs) are a heterogeneous group of compounds formed by the non-enzymatic reaction between amino acids and reducing sugars, or dicarbonyls as intermediate compounds. Experimental studies suggest that AGEs may promote colorectal cancer, but prospective epidemiologic studies are inconclusive. We conducted a case-control study nested within a large European cohort. Plasma concentrations of three protein-bound AGEs-Nε-(carboxy-methyl)lysine (CML), Nε-(carboxy-ethyl)lysine (CEL) and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1)-were measured by ultra-performance liquid chromatography-tandem mass spectrometry in baseline samples collected from 1378 incident primary colorectal cancer cases and 1378 matched controls. Multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed using conditional logistic regression for colorectal cancer risk associated with CML, CEL, MG-H1, total AGEs, and [CEL+MG-H1: CML] and [CEL:MG-H1] ratios. Inverse colorectal cancer risk associations were observed for CML (OR comparing highest to lowest quintile, ORQ5 versus Q1 = 0.40, 95% CI: 0.27-0.59), MG-H1 (ORQ5 versus Q1 = 0.73, 95% CI: 0.53-1.00) and total AGEs (OR Q5 versus Q1 = 0.52, 95% CI: 0.37-0.73), whereas no association was observed for CEL. A higher [CEL+MG-H1: CML] ratio was associated with colorectal cancer risk (ORQ5 versus Q1 = 1.91, 95% CI: 1.31-2.79). The associations observed did not differ by sex, or by tumour anatomical sub-site. Although individual AGEs concentrations appear to be inversely associated with colorectal cancer risk, a higher ratio of methylglyoxal-derived AGEs versus those derived from glyoxal (calculated by [CEL+MG-H1: CML] ratio) showed a strong positive risk association. Further insight on the metabolism of AGEs and their dicarbonyls precursors, and their roles in colorectal cancer development is needed.
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http://dx.doi.org/10.1093/carcin/bgab026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162627PMC
May 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

Metabolic Signatures of Healthy Lifestyle Patterns and Colorectal Cancer Risk in a European Cohort.

Clin Gastroenterol Hepatol 2020 Dec 29. Epub 2020 Dec 29.

CIBER Epidemiología y Salud Pública, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain; Department of Preventive Medicine and Public Health, University of Granada, Granada, Spain.

Background & Aims: Colorectal cancer risk can be lowered by adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) guidelines. We derived metabolic signatures of adherence to these guidelines and tested their associations with colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort.

Methods: Scores reflecting adherence to the WCRF/AICR recommendations (scale, 1-5) were calculated from participant data on weight maintenance, physical activity, diet, and alcohol among a discovery set of 5738 cancer-free European Prospective Investigation into Cancer and Nutrition participants with metabolomics data. Partial least-squares regression was used to derive fatty acid and endogenous metabolite signatures of the WCRF/AICR score in this group. In an independent set of 1608 colorectal cancer cases and matched controls, odds ratios (ORs) and 95% CIs were calculated for colorectal cancer risk per unit increase in WCRF/AICR score and per the corresponding change in metabolic signatures using multivariable conditional logistic regression.

Results: Higher WCRF/AICR scores were characterized by metabolic signatures of increased odd-chain fatty acids, serine, glycine, and specific phosphatidylcholines. Signatures were inversely associated more strongly with colorectal cancer risk (fatty acids: OR, 0.51 per unit increase; 95% CI, 0.29-0.90; endogenous metabolites: OR, 0.62 per unit change; 95% CI, 0.50-0.78) than the WCRF/AICR score (OR, 0.93 per unit change; 95% CI, 0.86-1.00) overall. Signature associations were stronger in male compared with female participants.

Conclusions: Metabolite profiles reflecting adherence to WCRF/AICR guidelines and additional lifestyle or biological risk factors were associated with colorectal cancer. Measuring a specific panel of metabolites representative of a healthy or unhealthy lifestyle may identify strata of the population at higher risk of colorectal cancer.
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http://dx.doi.org/10.1016/j.cgh.2020.11.045DOI Listing
December 2020

Incidence of Dementia and Associated Factors in the EPIC-Spain Dementia Cohort.

J Alzheimers Dis 2020 ;78(2):543-555

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

Background: Dementia has become a public health priority as the number of cases continues to grow worldwide.

Objective: To assess dementia incidence and determinants in the EPIC-Spain Dementia Cohort.

Methods: 25,015 participants (57% women) were recruited from three Spanish regions between 1992-1996 and followed-up for over 20 years. Incident cases were ascertained through individual revision of medical records of potential cases. Crude and age-adjusted incidence rates (IR) of dementia and sub-types (Alzheimer's disease (AD), and non-AD) were calculated by sex. Neelson-Aalen cumulative incidence estimates at 10, 15, and 20 years were obtained for each sex and age group. Multivariate Royston-Parmar models were used to assess independent determinants.

Results: Global IR were higher in women for dementia and AD, and similar by sex for non-AD. IR ranged from 0.09 cases of dementia (95% confidence interval: 0.06-0.13) and 0.05 (0.03-0.09) of AD per 1000 person-years (py) in participants below 60 years, to 23.2 (15.9-33.8) cases of dementia and 14.6 (9.1-33.5) of AD (per 1000 py) in those ≥85 years. Adjusted IR were consistently higher in women than men for overall dementia and AD. Up to 12.5% of women and 9.1% of men 60-65 years-old developed dementia within 20 years. Low education, diabetes, and hyperlipidemia were the main independent predictors of dementia risk, whereas alcohol showed an inverse association.

Conclusion: Dementia incidence increased with age and was higher among women, but showed no geographical pattern. Dementia risk was higher among subjects with lower education, not drinking alcohol, and presenting cardiovascular risk factors.
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http://dx.doi.org/10.3233/JAD-200774DOI Listing
May 2021

Adiposity and Endometrial Cancer Risk in Postmenopausal Women: A Sequential Causal Mediation Analysis.

Cancer Epidemiol Biomarkers Prev 2021 01 2;30(1):104-113. Epub 2020 Oct 2.

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

Background: Adiposity increases endometrial cancer risk, possibly through inflammation, hyperinsulinemia, and increasing estrogens. We aimed to quantify the mediating effects of adiponectin (anti-inflammatory adipocytokine); IL6, IL1-receptor antagonist, TNF receptor 1 and 2, and C-reactive protein (inflammatory status biomarkers); C-peptide (hyperinsulinemia biomarker); and free estradiol and estrone (estrogen biomarkers) in the adiposity-endometrial cancer link in postmenopausal women.

Methods: We used data from a case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC). Eligible women did not have cancer, hysterectomy, and diabetes; did not use oral contraceptives or hormone therapy; and were postmenopausal at recruitment. Mediating pathways from adiposity to endometrial cancer were investigated by estimating natural indirect (NIE) and direct (NDE) effects using sequential mediation analysis.

Results: The study included 163 cases and 306 controls. The adjusted OR for endometrial cancer for body mass index (BMI) ≥30 versus ≥18.5-<25 kg/m was 2.51 (95% confidence interval, 1.26-5.02). The ORs were 1.95 (1.01-3.74) through all biomarkers [72% proportion mediated (PM)] decomposed as: 1.35 (1.06-1.73) through pathways originating with adiponectin (33% PM); 1.13 (0.71-1.80) through inflammation beyond (the potential influence of) adiponectin (13% PM); 1.05 (0.88-1.24) through C-peptide beyond adiponectin and inflammation (5% PM); and 1.22 (0.89-1.67) through estrogens beyond preceding biomarkers (21% PM). The OR not through biomarkers was 1.29 (0.54-3.09). Waist circumference gave similar results.

Conclusions: Reduced adiponectin and increased inflammatory biomarkers, C-peptide, and estrogens mediated approximately 70% of increased odds of endometrial cancer in women with obesity versus normal weight.

Impact: If replicated, these results could have implications for identifying targets for intervention to reduce endometrial cancer risk in women with obesity.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0965DOI Listing
January 2021

Fried-Food Consumption Does Not Increase the Risk of Stroke in the Spanish Cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC) Study.

J Nutr 2020 12;150(12):3241-3248

CIBERESP (CIBER of Epidemiology and Public Health), Madrid, Spain.

Background: The nutritional determinants of stroke and, more specifically, the association of frying with the risk of incident stroke have rarely been studied.

Objectives: Our aim was to evaluate prospectively the association between the consumption of fried food and the risk of incident stroke in the European Prospective Investigation into Cancer and Nutrition study using the Spanish cohort.

Methods: Participants included 40,328 healthy adults (62% women) aged 29-69 y at study entry who were enrolled between 1992 and 1996. Participants were followed up until 31 December, 2017, at which time incident stroke (the main outcome) was measured. The main exposure measure was the percentage of energy obtained from fried-food consumption. Sex-specific quintiles were calculated.

Results: During a follow-up period of 23.5 y, 975 cases of stroke occurred (750 ischemic, 185 hemorrhagic, and 40 undetermined). Compared with those in the first (lowest) quintile of fried-food consumption, the multivariate HRs (95% CIs) of incident stroke in the consecutive quintiles were 1.05 (0.86, 1.30), 1.11 (0.90, 1.36), 1.05 (0.84, 1.31), and 0.91 (0.72, 1.15; P-trend = 0.45). There were no differences identified when subtypes of stroke were considered.

Conclusions: In this Spanish cohort, whose participants mainly used olive oil or sunflower oil when frying, the consumption of fried food was not associated with an increased risk of incident stroke.
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http://dx.doi.org/10.1093/jn/nxaa272DOI Listing
December 2020

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

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

AOU Federico II, Naples, Italy.

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

Design: Population based cohort study.

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

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

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

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

Conclusions: In this large multinational European cohort, consuming foods with a higher FSAm-NPS score (lower nutritional quality) was associated with a higher mortality for all causes and for cancer and diseases of the circulatory, respiratory, and digestive systems, supporting the relevance of FSAm-NPS to characterise healthier food choices in the context of public health policies (eg, the Nutri-Score) for European populations. This is important considering ongoing discussions about the potential implementation of a unique nutrition labelling system at the European Union level.
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http://dx.doi.org/10.1136/bmj.m3173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491938PMC
September 2020

Bisphenol A exposure and risk of ischemic heart disease in the Spanish European Prospective Investigation into cancer and nutrition study.

Chemosphere 2020 Dec 20;261:127697. Epub 2020 Jul 20.

Andalusian School of Public Health (EASP), Granada, Spain; Instituto de Investigación Biosanitaria Ibs.GRANADA, Granada, Spain; CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Department of Preventive Medicine and Public Health, University of Granada, Granada, Spain.

Background: Cardiovascular disease, particularly ischemic heart disease (IHD), is the leading cause of mortality worldwide. Bisphenol A (BPA) is considered an endocrine disruptor and obesogen, present in numerous products of daily use. The aim of this study was to assess the potential association of serum BPA concentrations and the risk of incident IHD in a sub-cohort of the Spanish European Prospective Investigation into Cancer and Nutrition (EPIC).

Methods: We designed a case-cohort study within the EPIC-Spain cohort. The population consisted of 4636 participants from 4 EPIC-Spain centers (946 IHD cases and 3690 sub-cohort participants). BPA exposure was assessed by means of chemical analyses of serum samples collected at recruitment. Follow-up was performed by linking with national and regional databases and reviewing patients' clinical records. Cox Proportional Hazards Models were used for the statistical analyses.

Results: Median follow-up time was 16 years and 70% of the participants showed detectable BPA values (>0.2 ng/ml). Geometric mean (GM) values of cases and sub-cohort were 1.22 ng/ml vs 1.19 ng/ml respectively (p = 0.90). Cox regression models showed no significant association of BPA serum levels and IHD, acute myocardial infarction or angina pectoris risk.

Conclusions: We evidenced a similar percentage of detection of BPA among cases and sub-cohort participants from our population, and no clear association with IHD risk was observed. However, further investigation is needed to understand the influence of BPA on IHD risk.
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http://dx.doi.org/10.1016/j.chemosphere.2020.127697DOI Listing
December 2020

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

Association of prediagnostic vitamin D status with mortality among colorectal cancer patients differs by common, inherited vitamin D-binding protein isoforms.

Int J Cancer 2020 11 25;147(10):2725-2734. Epub 2020 May 25.

Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.

Lower prediagnostic circulating 25-hydroxyvitamin D (25[OH]D)-considered the best marker of total vitamin D exposure-is associated with higher mortality risk among colorectal cancer (CRC) patients. However, it is unknown whether this association differs by the vitamin D-binding protein (GC) isoform Gc2 (encoded by GC rs4588*C>A, Thr436Lys), which may substantially affect vitamin D metabolism and modify associations of 25(OH)D with colorectal neoplasm risk. Prediagnostic 25(OH)D-mortality associations according to Gc2 isoform were estimated using multivariable Cox proportional hazards regression among 1281 CRC cases (635 deaths, 483 from CRC) from two large prospective cohorts conducted in the United States (Cancer Prevention Study-II) and Europe (European Prospective Investigation into Cancer and Nutrition). 25(OH)D measurements were calibrated to a single assay, season standardized, and categorized using Institute of Medicine recommendations (deficient [<30], insufficient [30 - <50], sufficient [≥50 nmol/L]). In the pooled analysis, multivariable-adjusted hazard ratios (HRs) for CRC-specific mortality associated with deficient relative to sufficient 25(OH)D concentrations were 2.24 (95% CI 1.44-3.49) among cases with the Gc2 isoform, and 0.94 (95% CI 0.68-1.22) among cases without Gc2 (P = .0002). The corresponding HRs for all-cause mortality were 1.80 (95% CI 1.24-2.60) among those with Gc2, and 1.12 (95% CI 0.84-1.51) among those without Gc2 (P = .004). Our findings suggest that the association of prediagnostic vitamin D status with mortality among CRC patients may differ by functional GC isoforms, and patients who inherit the Gc2 isoform (GC rs4588*A) may particularly benefit from higher circulating 25(OH)D for improved CRC prognosis.
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http://dx.doi.org/10.1002/ijc.33043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529852PMC
November 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

Bisphenol-A in the European Prospective Investigation into Cancer and Nutrition cohort in Spain: Levels at recruitment and associated dietary factors.

Environ Res 2020 03 7;182:109012. Epub 2019 Dec 7.

Andalusian School of Public Health (EASP). Granada, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA. Granada, Spain; CIBER de Epidemiología y Salud Pública (CIBERESP). Madrid, Spain; Universidad de Granada. Granada, Spain.

Bisphenol A (BPA) is considered an endocrine disruptor and it is present in numerous products of daily use. The aim of this study was to analyze serum BPA concentrations in a subcohort of the Spanish European Prospective Investigation into Cancer and Nutrition (EPIC), as well as to identify potential predictors of the exposure. The population consisted on 3553 subjects from 4 EPIC-Spain centres and BPA levels were measured in serum samples by UHPLC-MS/MS. Almost 70% of the participants showed detectable BPA values (>0.2 ng/ml), with a geometric mean of 1.19 ng/ml (95% CI: 1.12-1.25). By sex, detectable percentages were similar (p = 0.56) but with higher serum levels in men (1.27 vs 1.11 ng/ml, p = 0.01). Based on the adjusted regression models, a 50 g/day increase in the consumption of added fats and oils were associated with 43% lower BPA serum levels, while sugar and confectionary was associated with 25% higher levels of serum BPA. We evidenced differential exposure levels by province, sex and age, but not by anthropometric or lifestyle characteristics. Further investigation is needed to understand the influence of diet in BPA exposure.
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http://dx.doi.org/10.1016/j.envres.2019.109012DOI Listing
March 2020

Development and validation of circulating CA125 prediction models in postmenopausal women.

J Ovarian Res 2019 Nov 26;12(1):116. Epub 2019 Nov 26.

CIBER of Epidemiology and Public Health (CIBERESP), Madrid, Spain.

Background: Cancer Antigen 125 (CA125) is currently the best available ovarian cancer screening biomarker. However, CA125 has been limited by low sensitivity and specificity in part due to normal variation between individuals. Personal characteristics that influence CA125 could be used to improve its performance as screening biomarker.

Methods: We developed and validated linear and dichotomous (≥35 U/mL) circulating CA125 prediction models in postmenopausal women without ovarian cancer who participated in one of five large population-based studies: Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO, n = 26,981), European Prospective Investigation into Cancer and Nutrition (EPIC, n = 861), the Nurses' Health Studies (NHS/NHSII, n = 81), and the New England Case Control Study (NEC, n = 923). The prediction models were developed using stepwise regression in PLCO and validated in EPIC, NHS/NHSII and NEC.

Result: The linear CA125 prediction model, which included age, race, body mass index (BMI), smoking status and duration, parity, hysterectomy, age at menopause, and duration of hormone therapy (HT), explained 5% of the total variance of CA125. The correlation between measured and predicted CA125 was comparable in PLCO testing dataset (r = 0.18) and external validation datasets (r = 0.14). The dichotomous CA125 prediction model included age, race, BMI, smoking status and duration, hysterectomy, time since menopause, and duration of HT with AUC of 0.64 in PLCO and 0.80 in validation dataset.

Conclusions: The linear prediction model explained a small portion of the total variability of CA125, suggesting the need to identify novel predictors of CA125. The dichotomous prediction model showed moderate discriminatory performance which validated well in independent dataset. Our dichotomous model could be valuable in identifying healthy women who may have elevated CA125 levels, which may contribute to reducing false positive tests using CA125 as screening biomarker.
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http://dx.doi.org/10.1186/s13048-019-0591-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878636PMC
November 2019

Exogenous hormone use and cutaneous melanoma risk in women: The European Prospective Investigation into Cancer and Nutrition.

Int J Cancer 2020 06 10;146(12):3267-3280. Epub 2019 Oct 10.

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

Evidence suggests an influence of sex hormones on cutaneous melanoma risk, but epidemiologic findings are conflicting. We examined the associations between use of oral contraceptives (OCs) and menopausal hormone therapy (MHT) and melanoma risk in women participating in the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC is a prospective cohort study initiated in 1992 in 10 European countries. Information on exogenous hormone use at baseline was derived from country-specific self-administered questionnaires. We used Cox proportional hazards regression models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Over 1992-2015, 1,696 melanoma cases were identified among 334,483 women, whereof 770 cases among 134,758 postmenopausal women. There was a positive, borderline-significant association between OC use and melanoma risk (HR = 1.12, 95% CI = 1.00-1.26), with no detected heterogeneity across countries (p = 0.42). This risk increased linearly with duration of use (p = 0.01). Among postmenopausal women, ever use of MHT was associated with a nonsignificant increase in melanoma risk overall (HR = 1.14, 95% CI = 0.97-1.43), which was heterogeneous across countries (p = 0.05). Our findings do not support a strong and direct association between exogenous hormone use and melanoma risk. In order to better understand these relations, further research should be performed using prospectively collected data including detailed information on types of hormone, and on sun exposure, which may act as an important confounder or effect modifier on these relations.
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http://dx.doi.org/10.1002/ijc.32674DOI Listing
June 2020

Prediagnostic Plasma Bile Acid Levels and Colon Cancer Risk: A Prospective Study.

J Natl Cancer Inst 2020 05;112(5):516-524

Hellenic Health Foundation, Athens, Greece.

Background: Bile acids have been proposed to promote colon carcinogenesis. However, there are limited prospective data on circulating bile acid levels and colon cancer risk in humans.

Methods: Associations between prediagnostic plasma levels of 17 primary, secondary, and tertiary bile acid metabolites (conjugated and unconjugated) and colon cancer risk were evaluated in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Bile acid levels were quantified by tandem mass spectrometry in samples from 569 incident colon cancer cases and 569 matched controls. Multivariable logistic regression analyses were used to estimate odds ratios (ORs) for colon cancer risk across quartiles of bile acid concentrations.

Results: Positive associations were observed between colon cancer risk and plasma levels of seven conjugated bile acid metabolites: the primary bile acids glycocholic acid (ORquartile 4 vs quartile 1= 2.22, 95% confidence interval [CI] = 1.52 to 3.26), taurocholic acid (OR = 1.78, 95% CI = 1.23 to 2.58), glycochenodeoxycholic acid (OR = 1.68, 95% CI = 1.13 to 2.48), taurochenodeoxycholic acid (OR = 1.62, 95% CI = 1.11 to 2.36), and glycohyocholic acid (OR = 1.65, 95% CI = 1.13 to 2.40), and the secondary bile acids glycodeoxycholic acid (OR = 1.68, 95% CI = 1.12 to 2.54) and taurodeoxycholic acid (OR = 1.54, 95% CI = 1.02 to 2.31). By contrast, unconjugated bile acids and tertiary bile acids were not associated with risk.

Conclusions: This prospective study showed that prediagnostic levels of certain conjugated primary and secondary bile acids were positively associated with risk of colon cancer. Our findings support experimental data to suggest that a high bile acid load is colon cancer promotive.
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http://dx.doi.org/10.1093/jnci/djz166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225675PMC
May 2020

Vitamin D-Related Genes, Blood Vitamin D Levels and Colorectal Cancer Risk in Western European Populations.

Nutrients 2019 08 20;11(8). Epub 2019 Aug 20.

CIBER Epidemiology and Public Healh (CIBERESP), Madrid 28029, Spain.

Higher circulating 25-hydroxyvitamin D levels (25(OH)D) have been found to be associated with lower risk for colorectal cancer (CRC) in prospective studies. Whether this association is modified by genetic variation in genes related to vitamin D metabolism and action has not been well studied in humans. We investigated 1307 functional and tagging single-nucleotide polymorphisms (SNPs; individually, and by gene/pathway) in 86 vitamin D-related genes in 1420 incident CRC cases matched to controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We also evaluated the association between these SNPs and circulating 25(OH)D in a subset of controls. We confirmed previously reported CRC risk associations between SNPs in the , , and genes. We also identified additional associations with 25(OH)D, as well as CRC risk, and several potentially novel SNPs in genes related to vitamin D transport and action (, and ). However, none of these SNPs were statistically significant after Benjamini-Hochberg (BH) multiple testing correction. When assessed by a priori defined functional pathways, tumor growth factor β (TGFβ) signaling was associated with CRC risk ( ≤ 0.001), with most statistically significant genes being = 0.008) and = 0.008), and 18 SNPs in the vitamin D receptor (VDR) binding sites ( = 0.036). The 25(OH)D-gene pathway analysis suggested that genetic variants in the genes related to VDR complex formation and transcriptional activity are associated with CRC depending on 25(OH)D levels (interaction = 0.041). Additional studies in large populations and consortia, especially with measured circulating 25(OH)D, are needed to confirm our findings.
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http://dx.doi.org/10.3390/nu11081954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722852PMC
August 2019

Polyphenol intake and differentiated thyroid cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

Int J Cancer 2020 04 7;146(7):1841-1850. Epub 2019 Aug 7.

Department of Surgery, Skåne University Hospital Malmö, Lund University, Lund, Sweden.

Polyphenols are bioactive compounds with several anticarcinogenic activities; however, human data regarding associations with thyroid cancer (TC) is still negligible. Our aim was to evaluate the association between intakes of total, classes and subclasses of polyphenols and risk of differentiated TC and its main subtypes, papillary and follicular, in a European population. The European Prospective Investigation into Cancer and Nutrition cohort included 476,108 men and women from 10 European countries. During a mean follow-up of 14 years, there were 748 incident differentiated TC cases, including 601 papillary and 109 follicular tumors. Polyphenol intake was estimated at baseline using validated center/country-specific dietary questionnaires and the Phenol-Explorer database. In multivariable-adjusted Cox regression models, no association between total polyphenol and the risks of overall differentiated TC (HR = 0.99, 95% confidence interval [CI] 0.77-1.29), papillary (HR = 1.06, 95% CI 0.80-1.41) or follicular TC (HR = 1.10, 95% CI 0.55-2.22) were found. No associations were observed either for flavonoids, phenolic acids or the rest of classes and subclasses of polyphenols. After stratification by body mass index (BMI), an inverse association between the intake of polyphenols (p-trend = 0.019) and phenolic acids (p-trend = 0.007) and differentiated TC risk in subjects with BMI ≥ 25 was observed. In conclusion, our study showed no associations between dietary polyphenol intake and differentiated TC risk; although further studies are warranted to investigate the potential protective associations in overweight and obese individuals.
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http://dx.doi.org/10.1002/ijc.32589DOI Listing
April 2020

Blood pressure and risk of cancer in the European Prospective Investigation into Cancer and Nutrition.

Int J Cancer 2020 05 20;146(10):2680-2693. Epub 2019 Aug 20.

Public Health Division of Gipuzkoa, BioDonostia Research Institute, San Sebastian, Spain.

Several studies have reported associations of hypertension with cancer, but not all results were conclusive. We examined the association of systolic (SBP) and diastolic (DBP) blood pressure with the development of incident cancer at all anatomical sites in the European Prospective Investigation into Cancer and Nutrition (EPIC). Hazard ratios (HRs) (95% confidence intervals) were estimated using multivariable Cox proportional hazards models, stratified by EPIC-participating center and age at recruitment, and adjusted for sex, education, smoking, body mass index, physical activity, diabetes and dietary (in women also reproductive) factors. The study included 307,318 men and women, with an average follow-up of 13.7 (standard deviation 4.4) years and 39,298 incident cancers. We confirmed the expected positive association with renal cell carcinoma: HR = 1.12 (1.08-1.17) per 10 mm Hg higher SBP and HR = 1.23 (1.14-1.32) for DBP. We additionally found positive associations for esophageal squamous cell carcinoma (SCC): HR = 1.16 (1.07-1.26) (SBP), HR = 1.31 (1.13-1.51) (DBP), weaker for head and neck cancers: HR = 1.08 (1.04-1.12) (SBP), HR = 1.09 (1.01-1.17) (DBP) and, similarly, for skin SCC, colon cancer, postmenopausal breast cancer and uterine adenocarcinoma (AC), but not for esophageal AC, lung SCC, lung AC or uterine endometroid cancer. We observed weak inverse associations of SBP with cervical SCC: HR = 0.91 (0.82-1.00) and lymphomas: HR = 0.97 (0.93-1.00). There were no consistent associations with cancers in other locations. Our results are largely compatible with published studies and support weak associations of blood pressure with cancers in specific locations and morphologies.
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http://dx.doi.org/10.1002/ijc.32576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115826PMC
May 2020

Generalizability of a Diabetes-Associated Country-Specific Exploratory Dietary Pattern Is Feasible Across European Populations.

J Nutr 2019 06;149(6):1047-1055

German Cancer Research Center [DKFZ], Heidelberg, Germany.

Background: Population-specificity of exploratory dietary patterns limits their generalizability in investigations with type 2 diabetes incidence.

Objective: The aim of this study was to derive country-specific exploratory dietary patterns, investigate their association with type 2 diabetes incidence, and replicate diabetes-associated dietary patterns in other countries.

Methods: Dietary intake data were used, assessed by country-specific questionnaires at baseline of 11,183 incident diabetes cases and 14,694 subcohort members (mean age 52.9 y) from 8 countries, nested within the European Prospective Investigation into Cancer and Nutrition study (mean follow-up time 6.9 y). Exploratory dietary patterns were derived by principal component analysis. HRs for incident type 2 diabetes were calculated by Prentice-weighted Cox proportional hazard regression models. Diabetes-associated dietary patterns were simplified or replicated to be applicable in other countries. A meta-analysis across all countries evaluated the generalizability of the diabetes-association.

Results: Two dietary patterns per country/UK-center, of which overall 3 dietary patterns were diabetes-associated, were identified. A risk-lowering French dietary pattern was not confirmed across other countries: pooled HRFrance per 1 SD: 1.00; 95% CI: 0.90, 1.10. Risk-increasing dietary patterns, derived in Spain and UK-Norfolk, were confirmed, but only the latter statistically significantly: HRSpain: 1.09; 95% CI: 0.97, 1.22 and HRUK-Norfolk: 1.12; 95% CI: 1.04, 1.20. Respectively, this dietary pattern was characterized by relatively high intakes of potatoes, processed meat, vegetable oils, sugar, cake and cookies, and tea.

Conclusions: Only few country/center-specific dietary patterns (3 of 18) were statistically significantly associated with diabetes incidence in this multicountry European study population. One pattern, whose association with diabetes was confirmed across other countries, showed overlaps in the food groups potatoes and processed meat with identified diabetes-associated dietary patterns from other studies. The study demonstrates that replication of associations of exploratory patterns with health outcomes is feasible and a necessary step to overcome population-specificity in associations from such analyses.
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http://dx.doi.org/10.1093/jn/nxz031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543295PMC
June 2019

Predicting Circulating CA125 Levels among Healthy Premenopausal Women.

Cancer Epidemiol Biomarkers Prev 2019 06 4;28(6):1076-1085. Epub 2019 Apr 4.

Public Health Direction and Biodonostia Research Institute and Ciberesp, Basque Regional Health Department, San Sebastian, Spain.

Background: Cancer antigen 125 (CA125) is the most promising ovarian cancer screening biomarker to date. Multiple studies reported CA125 levels vary by personal characteristics, which could inform personalized CA125 thresholds. However, this has not been well described in premenopausal women.

Methods: We evaluated predictors of CA125 levels among 815 premenopausal women from the New England Case Control Study (NEC). We developed linear and dichotomous (≥35 U/mL) CA125 prediction models and externally validated an abridged model restricting to available predictors among 473 premenopausal women in the European Prospective Investigation into Cancer and Nutrition Study (EPIC).

Results: The final linear CA125 prediction model included age, race, tubal ligation, endometriosis, menstrual phase at blood draw, and fibroids, which explained 7% of the total variance of CA125. The correlation between observed and predicted CA125 levels based on the abridged model (including age, race, and menstrual phase at blood draw) had similar correlation coefficients in NEC ( = 0.22) and in EPIC ( = 0.22). The dichotomous CA125 prediction model included age, tubal ligation, endometriosis, prior personal cancer diagnosis, family history of ovarian cancer, number of miscarriages, menstrual phase at blood draw, and smoking status with AUC of 0.83. The abridged dichotomous model (including age, number of miscarriages, menstrual phase at blood draw, and smoking status) showed similar AUCs in NEC (0.73) and in EPIC (0.78).

Conclusions: We identified a combination of factors associated with CA125 levels in premenopausal women.

Impact: Our model could be valuable in identifying healthy women likely to have elevated CA125 and consequently improve its specificity for ovarian cancer screening.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-1120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548604PMC
June 2019

Association of menopausal characteristics and risk of coronary heart disease: a pan-European case-cohort analysis.

Int J Epidemiol 2019 08;48(4):1275-1285

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

Background: Earlier age at menopause has been associated with increased risk of coronary heart disease (CHD), but the shape of association and role of established cardiovascular risk factors remain unclear. Therefore, we examined the associations between menopausal characteristics and CHD risk; the shape of the association between age at menopause and CHD risk; and the extent to which these associations are explained by established cardiovascular risk factors.

Methods: We used data from EPIC-CVD, a case-cohort study, which includes data from 23 centres from 10 European countries. We included only women, of whom 10 880 comprise the randomly selected sub-cohort, supplemented with 4522 cases outside the sub-cohort. We conducted Prentice-weighted Cox proportional hazards regressions with age as the underlying time scale, stratified by country and adjusted for relevant confounders.

Results: After confounder and intermediate adjustment, post-menopausal women were not at higher CHD risk compared with pre-menopausal women. Among post-menopausal women, earlier menopause was linearly associated with higher CHD risk [HRconfounder and intermediate adjusted per-year decrease = 1.02, 95% confidence interval (CI) = 1.01-1.03, p = 0.001]. Women with a surgical menopause were at higher risk of CHD compared with those with natural menopause (HRconfounder-adjusted = 1.25, 95% CI = 1.10-1.42, p < 0.001), but this attenuated after additional adjustment for age at menopause and intermediates (HR = 1.12, 95% CI = 0.96-1.29, p = 0.15). A proportion of the association was explained by cardiovascular risk factors.

Conclusions: Earlier and surgical menopause were associated with higher CHD risk. These associations could partially be explained by differences in conventional cardiovascular risk factors. These women might benefit from close monitoring of cardiovascular risk factors and disease.
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http://dx.doi.org/10.1093/ije/dyz016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693816PMC
August 2019

Ascertainment of Dementia Cases in the Spanish European Prospective Investigation into Cancer and Nutrition-Murcia Cohort.

Neuroepidemiology 2019 26;52(1-2):63-73. Epub 2018 Nov 26.

Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain.

Background: Cohort studies generally focus on a particular disease, although they offer the possibility of evaluating different outcomes with minimal additional investment. The objective of this study was to describe the methodology used to assess dementia in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Murcia study.

Methods: The EPIC-Murcia cohort consists of 8,515 healthy participants (68% women, aged 30-70 years), recruited between 1992 and 1996 and followed up for over 20 years. Incident cases were ascertained by a 2-step protocol: a record linkage with health databases to identify potential events and a review of medical records of potential cases to validate incident cases.

Results: Overall, 1,202 potential cases were identified, and 275 dementia cases were validated. Medical reports were the source of information in 243 cases, with complete neurological information in 227, and a high degree of certainty of the diagnosis in 229 cases. P70 (dementia code) and/or antidementia drugs and/or ICD codes identified 259 cases (sensitivity: 94.2%, 95% CI 90.7-96.6; specificity: 98.1%, 95% CI 97.8-98.4).

Conclusion: Ascertainment of incident dementia in the EPIC-Murcia cohort study was feasible using information from medical records. This systematic 2-step validation protocol is proposed as a feasible way to ascertain dementia in cohort studies originally designed for other endpoints.
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December 2019

The influence of lifestyle, diet, and reproductive history on age at natural menopause in Spain: Analysis from the EPIC-Spain sub-cohort.

Am J Hum Biol 2018 11 24;30(6):e23181. Epub 2018 Sep 24.

Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain.

Objective: To determinate the role of lifestyle factors, recent diet, menstrual factors, and reproductive history in age at natural menopause in adult Spanish women.

Methods: In total, 12 562 pre-menopausal women were available for analysis from the EPIC-Spain sub-cohort. Women were recruited between 1992 and 1996 in five regions of Spain (Asturias, Granada, Murcia, Navarra, and San Sebastian) and, for these analyses, were followed for 3 years. Questionnaires on diet, lifestyle, anthropometric measurements, and reproductive and exogenous hormones history were collected at baseline. Menopause status was updated at a median of 3 years of follow-up.

Results: After a median of 3 years of follow-up 1166 women became postmenopausal. An earlier age at menopause was observed in current smokers (HR: 1.29; 95%CI 1.08-1.55) and in non-users of oral contraceptives (HR: 1.32; 95%CI 1.01-1.57). A later age at menopause was observed in women with irregular menses (HR: 0.71; 95%CI 0.56-0.91) and in women with a higher number of pregnancies (HR: 0.74; 95%CI 0.56-0.94).

Conclusions: Our results confirm that women who smoked had an earlier age at natural menopause, while use of oral contraceptives, higher number of pregnancies, and irregularity of menses were associated with a prolonged reproductive lifespan. No associations were observed for dietary habits assessed after the age of 40 years.
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November 2018
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