Publications
1312 results found
Wu L, Wang J, Cai Q, et al., 2019, Identification of Novel Susceptibility Loci and Genes for Prostate Cancer Risk: A Transcriptome-Wide Association Study in over 140,000 European Descendants, CANCER RESEARCH, Vol: 79, Pages: 3192-3204, ISSN: 0008-5472
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- Citations: 34
Solans M, Benavente Y, Saez M, et al., 2019, Adherence to the mediterranean diet and lymphoma risk in the european prospective investigation into cancer and nutrition., International Journal of Cancer, Vol: 145, Pages: 122-131, ISSN: 0020-7136
There is a growing evidence of the protective role of the Mediterranean diet (MD) on cancer. However, no prospective study has yet investigated its influence on lymphoma. We evaluated the association between adherence to the MD and risk of lymphoma and its subtypes in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The analysis included 476,160 participants, recruited from 10 European countries between 1991 and 2001. Adherence to the MD was estimated through the adapted relative MD (arMED) score excluding alcohol. Cox proportional hazards regression models were used while adjusting for potential confounders. During an average follow-up of 13.9 years, 3,136 lymphomas (135 Hodgkin lymphoma [HL], 2,606 non-HL and 395 lymphoma not otherwise specified) were identified. Overall, a 1-unit increase in the arMED score was associated with a 2% lower risk of lymphoma (95% CI: 0.97; 1.00, p-trend = 0.03) while a statistically nonsignificant inverse association between a high versus low arMED score and risk of lymphoma was observed (hazard ratio [HR]: 0.91 [95% CI 0.80; 1.03], p-trend = 0.12). Analyses by lymphoma subtype did not reveal any statistically significant associations. Albeit with small numbers of cases (N = 135), a suggestive inverse association was found for HL (HR 1-unit increase = 0.93 [95% CI: 0.86; 1.01], p-trend = 0.07). However, the study may have lacked statistical power to detect small effect sizes for lymphoma subtype. Our findings suggest that an increasing arMED score was inversely related to the risk of overall lymphoma in EPIC but not by subtypes. Further large prospective studies are warranted to confirm these findings.
Mandle H, Jenab M, Hughes D, et al., 2019, Gut barrier function-related genes and colorectal cancer risk in Western European populations, AACR Annual Meeting on Bioinformatics, Convergence Science, and Systems Biology, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Bien SA, Su Y-R, Conti DV, et al., 2019, Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer (vol 138, pg 307, 2019), HUMAN GENETICS, Vol: 138, Pages: 789-791, ISSN: 0340-6717
Laskar RS, Muller DC, Li P, et al., 2019, Sex specific associations in genome wide association analysis of renal cell carcinoma, European Journal of Human Genetics, Vol: 27, Pages: 1589-1598, ISSN: 1018-4813
Renal cell carcinoma (RCC) has an undisputed genetic component and a stable 2:1 male to female sex ratio in its incidence across populations, suggesting possible sexual dimorphism in its genetic susceptibility. We conducted the first sex-specific genome-wide association analysis of RCC for men (3227 cases, 4916 controls) and women (1992 cases, 3095 controls) of European ancestry from two RCC genome-wide scans and replicated the top findings using an additional series of men (2261 cases, 5852 controls) and women (1399 cases, 1575 controls) from two independent cohorts of European origin. Our study confirmed sex-specific associations for two known RCC risk loci at 14q24.2 (DPF3) and 2p21(EPAS1). We also identified two additional suggestive male-specific loci at 6q24.3 (SAMD5, male odds ratio (ORmale) = 0.83 [95% CI = 0.78-0.89], Pmale = 1.71 × 10-8 compared with female odds ratio (ORfemale) = 0.98 [95% CI = 0.90-1.07], Pfemale = 0.68) and 12q23.3 (intergenic, ORmale = 0.75 [95% CI = 0.68-0.83], Pmale = 1.59 × 10-8 compared with ORfemale = 0.93 [95% CI = 0.82-1.06], Pfemale = 0.21) that attained genome-wide significance in the joint meta-analysis. Herein, we provide evidence of sex-specific associations in RCC genetic susceptibility and advocate the necessity of larger genetic and genomic studies to unravel the endogenous causes of sex bias in sexually dimorphic traits and diseases like RCC.
Key TJ, Appleby PN, Bradbury KE, et al., 2019, Consumption of Meat, Fish, Dairy Products, and Eggs and Risk of Ischemic Heart Disease:A Prospective Study of 7198 Incident Cases Among 409885 Participants in the Pan-European EPIC Cohort, Circulation, Vol: 139, Pages: 2835-2845, ISSN: 0009-7322
BACKGROUND: There is uncertainty about the relevance of animal foods to the etiology of ischemic heart disease (IHD). We examined meat, fish, dairy products and eggs and risk for IHD in the pan-European EPIC cohort. METHODS: A prospective study of 409,885 men and women in nine European countries. Diet was assessed using validated questionnaires, calibrated using 24-hour recalls. Lipids and blood pressure were measured in a subsample. During 12.6 years mean follow up, 7198 participants had a myocardial infarction or died from IHD. The relationships of animal foods with risk were examined using Cox regression with adjustment for other animal foods and relevant covariates. RESULTS: The hazard ratio (HR) for IHD was 1.19 (95% CI 1.06-1.33) for a 100 g/d increment in intake of red and processed meat, and this remained significant after excluding the first 4 years of follow-up (HR 1.25 [1.09-1.42]). Risk was inversely associated with intakes of yogurt (HR 0.93 [0.89-0.98] per 100 g/d increment), cheese (HR 0.92 [0.86-0.98] per 30 g/d increment) and eggs (HR 0.93 [0.88-0.99] per 20 g/d increment); the associations with yogurt and eggs were attenuated and non-significant after excluding the first 4 years of follow-up. Risk was not significantly associated with intakes of poultry, fish or milk. In analyses modelling dietary substitutions, replacement of 100 kcal/d from red and processed meat with 100 kcal/d from fatty fish, yogurt, cheese or eggs was associated with approximately 20% lower risk of IHD. Consumption of red and processed meat was positively associated with serum non-HDL cholesterol concentration and systolic blood pressure, and consumption of cheese was inversely associated with serum non-HDL cholesterol. CONCLUSIONS: Risk for IHD was positively associated with consumption of red and processed meat, and inversely associated with consumption of yogurt, cheese and eggs, although the associations with yogurt and eggs may be influenced by reverse causation bias. It
Cirera L, Maria Huerta J, Dolores Chirlaque M, et al., 2019, Socioeconomic effect of education on pancreatic cancer risk in Western Europe: an update on the EPIC cohorts study, Cancer Epidemiology, Biomarkers and Prevention, Vol: 28, Pages: 1089-1092, ISSN: 1055-9965
Background: To analyze the potential effect of social inequality on pancreatic cancer risk in Western Europe, by reassessing the association within the European Prospective Investigation into Cancer and Nutrition (EPIC) Study, including a larger number of cases and an extended follow-up.Methods: Data on highest education attained were gathered for 459,170 participants (70% women) from 10 European countries. A relative index of inequality (RII) based on adult education was calculated for comparability across countries and generations. Cox regression models were applied to estimate relative inequality in pancreatic cancer risk, stratifying by age, gender, and center, and adjusting for known pancreatic cancer risk factors.Results: A total of 1,223 incident pancreatic cancer cases were included after a mean follow-up of 13.9 (±4.0) years. An inverse social trend was found in models adjusted for age, sex, and center for both sexes [HR of RII, 1.27; 95% confidence interval (CI), 1.02–1.59], which was also significant among women (HR, 1.42; 95% CI, 1.05–1.92). Further adjusting by smoking intensity, alcohol consumption, body mass index, prevalent diabetes, and physical activity led to an attenuation of the RII risk and loss of statistical significance.Conclusions: The present reanalysis does not sustain the existence of an independent social inequality influence on pancreatic cancer risk in Western European women and men, using an index based on adult education, the most relevant social indicator linked to individual lifestyles, in a context of very low pancreatic cancer survival from (quasi) universal public health systems.Impact: The results do not support an association between education and risk of pancreatic cancer.
Sasamoto N, Babic A, Rosner BA, et al., 2019, Predicting circulating CA125 levels among healthy premenopausal women, Cancer Epidemiology, Biomarkers and Prevention, Vol: 28, Pages: 1076-1085, ISSN: 1055-9965
Background: 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(r=0.22) and in EPIC(r=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.
Smith Byrne K, Appleby PN, Key TJ, et al., 2019, The role of plasma microseminoprotein-beta in prostate cancer: an observational nested case-control and Mendelian randomization study in the European prospective investigation into cancer and nutrition., Annals of Oncology, Vol: 30, Pages: 983-989, ISSN: 0923-7534
BACKGROUND: Microseminoprotein-beta (MSP), a protein secreted by the prostate epithelium, may have a protective role in the development of prostate cancer. The only previous prospective study found a 2% reduced prostate cancer risk per unit increase in MSP. This work investigates the association of MSP with prostate cancer risk using observational and Mendelian randomization (MR) methods. PATIENTS AND METHODS: A nested case-control study was conducted with the European Prospective Investigation into Cancer and Nutrition (EPIC) with 1871 cases and 1871 matched controls. Conditional logistic regression analysis was used to investigate the association of pre-diagnostic circulating MSP with risk of incident prostate cancer overall and by tumour subtype. EPIC-derived estimates were combined with published data to calculate an MR estimate using two-sample inverse-variance method. RESULTS: Plasma MSP concentrations were inversely associated with prostate cancer risk after adjusting for total prostate-specific antigen concentration [odds ratio (OR) highest versus lowest fourth of MSP = 0.65, 95% confidence interval (CI) 0.51-0.84, Ptrend = 0.001]. No heterogeneity in this association was observed by tumour stage or histological grade. Plasma MSP concentrations were 66% lower in rs10993994 TT compared with CC homozygotes (per allele difference in MSP: 6.09 ng/ml, 95% CI 5.56-6.61, r2=0.42). MR analyses supported a potentially causal protective association of MSP with prostate cancer risk (OR per 1 ng/ml increase in MSP for MR: 0.96, 95% CI 0.95-0.97 versus EPIC observational: 0.98, 95% CI 0.97-0.99). Limitations include lack of complete tumour subtype information and more complete information on the biological function of MSP. CONCLUSIONS: In this large prospective European study and using MR analyses, men with high circulating MSP concentration have a lower risk of prostate cancer. MSP may play a causally protective role in prostate c
Gallo V, Vineis P, Cancellieri M, et al., 2019, Exploring causality of the association between smoking and Parkinson's disease, International Journal of Epidemiology, Vol: 48, Pages: 912-925, ISSN: 1464-3685
Background: The aim of this paper is to investigate the causality of the inverse association between cigarette smoking and Parkinson's disease (PD). The main suggested alternatives include a delaying effect of smoking, reverse causality or an unmeasured confounding related to a low-risk-taking personality trait. Methods: A total of 715 incident PD cases were ascertained in a cohort of 220 494 individuals from NeuroEPIC4PD, a prospective European population-based cohort study including 13 centres in eight countries. Smoking habits were recorded at recruitment. We analysed smoking status, duration, and intensity and exposure to passive smoking in relation to PD onset. Results: Former smokers had a 20% decreased risk and current smokers a halved risk of developing PD compared with never smokers. Strong dose-response relationships with smoking intensity and duration were found. Hazard ratios (HRs) for smoking <20 years were 0.84 [95% confidence interval (CI) 0.67-1.07], 20-29 years 0.73 (95% CI 0.56-0.96) and >30 years 0.54 (95% CI 0.43-0.36) compared with never smokers. The proportional hazard assumption was verified, showing no change of risk over time, arguing against a delaying effect. Reverse causality was disproved by the consistency of dose-response relationships among former and current smokers. The inverse association between passive smoking and PD, HR 0.70 (95% CI 0.49-0.99) ruled out the effect of unmeasured confounding. Conclusions: These results are highly suggestive of a true causal link between smoking and PD, although it is not clear which is the chemical compound in cigarette smoking responsible for the biological effect.
Murphy N, Ward HA, Jenab M, et al., 2019, Heterogeneity of colorectal cancer risk factors by anatomical subsite in 10 European countries: a multinational cohort study, Clinical Gastroenterology and Hepatology, Vol: 17, Pages: 1323-1331.e6, ISSN: 1542-3565
Background and AimsColorectal cancer located at different anatomical subsites may have distinct etiologies and risk factors. Previous studies that have examined this hypothesis have yielded inconsistent results, possibly because most have been of insufficient size to identify heterogeneous associations with precision.MethodsIn the European Prospective Investigation into Cancer and Nutrition study, we used multivariable joint Cox proportional hazards models, which accounted for tumors at different anatomical sites (proximal colon, distal colon, and rectum) as competing risks, to examine the relationships between 14 established/suspected lifestyle, anthropometric, and reproductive/menstrual risk factors with colorectal cancer risk. Heterogeneity across sites was tested using Wald tests.ResultsAfter 14.9 years (median) follow-up of 521,330 men and women, 6,291 colorectal cancer cases occurred. Physical activity was inversely related to proximal colon and distal colon cancer, but not to rectal cancer (P-heterogeneity=0.03). Height was positively associated with proximal and distal colon cancer only, but not rectal cancer (P-heterogeneity=0.0001). For men, but not women, heterogeneous relationships were observed for body mass index (P-heterogeneity=0.008) and waist circumference (P-heterogeneity=0.03), with weaker positive associations found for rectal cancer, compared to proximal and distal colon cancer. Current smoking was associated with a greater risk of rectal and proximal colon cancer, but not distal colon cancer (P-heterogeneity=0.05). No heterogeneity by anatomical site was found for alcohol consumption, diabetes, nonsteroidal anti-inflammatory drug use, and reproductive/menstrual factors.ConclusionsThe physical activity, anthropometry, and smoking relationships with colorectal cancer risk differed by subsite, supporting the hypothesis that tumors in different anatomical regions may have distinct etiologies.
Jannasch F, Kroeger J, Agnoli C, et al., 2019, Generalizability of a Diabetes-Associated Country-Specific Exploratory Dietary Pattern Is Feasible Across European Populations, JOURNAL OF NUTRITION, Vol: 149, Pages: 1047-1055, ISSN: 0022-3166
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- Citations: 4
Bixby H, Bentham J, Zhou B, et al., 2019, Rising rural body-mass index is the main driver of the global obesity epidemic, Nature, Vol: 569, Pages: 260-264, ISSN: 0028-0836
Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities1,2. This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity3,4,5,6. Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017—and more than 80% in some low- and middle-income regions—was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing—and in some countries reversal—of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.
Baumeister SE, Schlesinger S, Aleksandrova K, et al., 2019, Association of physical activity and risk of hepatobiliary cancers: a multinational cohort study, Journal of Hepatology, Vol: 70, Pages: 885-892, ISSN: 0168-8278
BACKGROUND & AIMS: Evidence on the association between physical activity and risk of hepatobiliary cancers is inconclusive. We examined this association in the European Prospective Investigation into Cancer and Nutrition cohort (EPIC). METHODS: We identified 275 hepatocellular carcinoma (HCC) cases, 93 intrahepatic bile duct cancers (IHBC), and 164 non-gallbladder extrahepatic bile duct cancers (NGBC) among 467,336 EPIC participants (median follow-up 14.9 years). We estimated cause-specific hazard ratios (HRs) for total physical activity and vigorous physical activity, performed mediation analysis, and secondary analyses to assess robustness to confounding (e.g., due to hepatitis virus infection). RESULTS: In the EPIC cohort, the multivariable-adjusted HR of HCC was 0.55 (95% confidence intervals (CI) 0.38-0.80) comparing active and inactive individuals. Regarding vigorous physical activity, for those reporting >2 hours/week compared to those with no vigorous activity, the HR for HCC was 0.50 (0.33-0.76). Estimates were similar in sensitivity analyses for confounding. Total and vigorous physical activity were unrelated to IHBC and NGBC. In mediation analysis, waist circumference explained about 40% and body mass index 30% of the overall association of total physical activity and HCC. CONCLUSIONS: Findings suggest an inverse association between physical activity and risk of HCC, which is potentially mediated by obesity. LAY SUMMARY: In a pan-European study of 467,336 men and women, we found that physical activity is associated with a reduced risk of developing liver cancers over the next decade. This risk was independent of other liver cancer risk factors, and did not vary by age, gender, smoking status, body weight, and alcohol consumption.
Riso L, Kaaks R, Kühn T, et al., 2019, General and abdominal adiposity and the risk of parkinson's disease.A prospective chort study, Parkinsonism and Related Disorders, Vol: 62, Pages: 98-104, ISSN: 1353-8020
IntroductionDue to demographic change, an increase in the frequency of Parkinson's disease (PD) patients is expected in the future and, thus, the identification of modifiable risk factors is urgently needed. We aimed to examine the associations of body mass index (BMI) and waist circumference (WC) with incident PD.MethodsIn 13 of the 23 centers of the European Prospective Investigation into Cancer and Nutrition (EPIC) study, a total of 734 incident cases of PD were identified between 1992 and 2012 with a mean follow-up of 12 years. Cox proportional hazards regression was used to calculate hazard ratios (HR) with 95% confidence intervals (CI). We modelled anthropometric variables as continuous and categorical exposures and performed subgroup analyses by potential effect modifiers including sex and smoking.ResultsWe found no association between BMI, WC and incident PD, neither among men nor among women. Among never and former smokers, BMI and waist circumference were also not associated with PD risk. For male smokers, however, we observed a statistically significant inverse association between BMI and PD risk (HR 0.51, 95%CI: 0.30, 0.84) and the opposite for women, i.e. a significant direct association of BMI (HR 1.79, 95%CI: 1.04, 3.08) and waist circumference (HR 1.64, 95%CI: 1.03, 2.61) with risk of PD.ConclusionOur data revealed no association between excess weight and PD risk but a possible interaction between anthropometry, sex and smoking.
Fedirko V, Jenab M, Meplan C, et al., 2019, Association of sSelenoprotein and selenium pathway genotypes with risk of colorectal cancer and interaction with selenium status, Nutrients, Vol: 11, Pages: 1-19, ISSN: 2072-6643
Selenoprotein genetic variations and suboptimal selenium (Se) levels may contribute to the risk of colorectal cancer (CRC) development. We examined the association between CRC risk and genotype for single nucleotide polymorphisms (SNPs) in selenoprotein and Se metabolic pathway genes. Illumina Goldengate assays were designed and resulted in the genotyping of 1040 variants in 154 genes from 1420 cases and 1421 controls within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Multivariable logistic regression revealed an association of 144 individual SNPs from 63 Se pathway genes with CRC risk. However, regarding the selenoprotein genes, only TXNRD1 rs11111979 retained borderline statistical significance after adjustment for correlated tests (PACT = 0.10; PACT significance threshold was P < 0.1). SNPs in Wingless/Integrated (Wnt) and Transforming growth factor (TGF) beta-signaling genes (FRZB, SMAD3, SMAD7) from pathways affected by Se intake were also associated with CRC risk after multiple testing adjustments. Interactions with Se status (using existing serum Se and Selenoprotein P data) were tested at the SNP, gene, and pathway levels. Pathway analyses using the modified Adaptive Rank Truncated Product method suggested that genes and gene x Se status interactions in antioxidant, apoptosis, and TGF-beta signaling pathways may be associated with CRC risk. This study suggests that SNPs in the Se pathway alone or in combination with suboptimal Se status may contribute to CRC development.
Perrier F, Viallon V, Ambatipudi S, et al., 2019, Association of leukocyte DNA methylation changes with dietary folate and alcohol intake in the EPIC study, Clinical Epigenetics, Vol: 11, ISSN: 1868-7083
BACKGROUND: There is increasing evidence that folate, an important component of one-carbon metabolism, modulates the epigenome. Alcohol, which can disrupt folate absorption, is also known to affect the epigenome. We investigated the association of dietary folate and alcohol intake on leukocyte DNA methylation levels in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Leukocyte genome-wide DNA methylation profiles on approximately 450,000 CpG sites were acquired with Illumina HumanMethylation 450K BeadChip measured among 450 women control participants of a case-control study on breast cancer nested within the EPIC cohort. After data preprocessing using surrogate variable analysis to reduce systematic variation, associations of DNA methylation with dietary folate and alcohol intake, assessed with dietary questionnaires, were investigated using CpG site-specific linear models. Specific regions of the methylome were explored using differentially methylated region (DMR) analysis and fused lasso (FL) regressions. The DMR analysis combined results from the feature-specific analysis for a specific chromosome and using distances between features as weights whereas FL regression combined two penalties to encourage sparsity of single features and the difference between two consecutive features. RESULTS: After correction for multiple testing, intake of dietary folate was not associated with methylation level at any DNA methylation site, while weak associations were observed between alcohol intake and methylation level at CpG sites cg03199996 and cg07382687, with qval = 0.029 and qval = 0.048, respectively. Interestingly, the DMR analysis revealed a total of 24 and 90 regions associated with dietary folate and alcohol, respectively. For alcohol intake, 6 of the 15 most significant DMRs were identified through FL. CONCLUSIONS: Alcohol intake was associated with methylation levels at two CpG sites. Evidence from DMR and FL analyses
Gunter MJ, Alhomoud S, Arnold M, et al., 2019, Meeting report from the joint IARC-NCI international cancer seminar series: a focus on colorectal cancer, Annals of Oncology, Vol: 30, Pages: 510-519, ISSN: 0923-7534
Despite significant progress in our understanding of the etiology, biology and genetics of colorectal cancer, as well as important clinical advances, it remains the third most frequently diagnosed cancer worldwide and is the second leading cause of cancer death. Based on demographic projections, the global burden of colorectal cancer would be expected to rise by 72% from 1.8 million new cases in 2018 to over 3 million in 2040 with substantial increases anticipated in low and middle income countries. In this meeting report, we summarize the content of a joint workshop led by the National Cancer Institute (NCI) and the International Agency for Research on Cancer (IARC) which was held to summarize the important achievements that have been made in our understanding of colorectal cancer etiology, genetics, early detection and treatment and to identify key research questions that remain to be addressed.
Zheng J-S, Imamura F, Sharp SJ, et al., 2019, Association of plasma vitamin D metabolites with incident type 2 diabetes: EPIC-InterAct case-cohort study, Journal of Clinical Endocrinology and Metabolism, Vol: 104, Pages: 1293-1303, ISSN: 0021-972X
Background: Existing evidence for the prospective association of vitamin D status with type 2 diabetes (T2D) is focused almost exclusively on circulating total 25-hydroxyvitamin D [25(OH)D] without distinction between its subtypes: non-epimeric and epimeric 25(OH)D3 stereoisomers; and 25(OH)D2, the minor component of 25(OH)D. We aimed to investigate the prospective associations of circulating levels of the sum and each of these three metabolites with incident T2D. Methods: This analysis in the EPIC-InterAct case-cohort study for T2D included 9671 incident T2D cases and 13562 subcohort members. Plasma vitamin D metabolites were quantified by liquid-chromatography mass-spectrometry. We used multivariable Prentice-weighted Cox regression to estimate hazard ratios (HRs) of T2D for each metabolite. Analyses were performed separately within country, and estimates combined across countries using random-effects meta-analysis. Results: The mean concentrations (standard deviation) of total 25(OH)D, non-epimeric 25(OH)D3, epimeric 25(OH)D3 and 25(OH)D2 were 41.1 (17.2), 40.7 (17.3), 2.13 (1.31), and 8.16 (6.52) nmol/L, respectively. Plasma total 25(OH)D and non-epimeric 25(OH)D3 were inversely associated with incident T2D [multivariable-adjusted HR per 1-SD=0.81 (95%CI: 0.77, 0.86) for both variables], while epimeric 25(OH)D3 was positively associated: per 1-SD HR=1.16 (1.09, 1.25). There was no statistically significant association with T2D for 25(OH)D2 [per 1-SD HR=0.94 (0.76, 1.18)]. Conclusions: Plasma non-epimeric 25(OH)D3 was inversely associated with incident T2D, consistent with it being the major metabolite contributing to total 25(OH)D. The positive association of the epimeric form of 25(OH)D3 with incident T2D provides novel information to assess the biological relevance of vitamin D epimerization and vitamin D subtypes in diabetes etiology.
Bien SA, Su Y-R, Conti DV, et al., 2019, Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer, Human Genetics, Vol: 138, Pages: 307-326, ISSN: 0340-6717
Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene expression. The computational method PrediXcan uses cis-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (n = 169) and whole blood (n = 922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Three novel associations were discovered from colon transverse models at FDR ≤ 0.2 and further evaluated in an independent replication including 32,825 cases and 39,933 controls. After adjusting for multiple comparisons, we found statistically significant associations using colon transcriptome models with TRIM4 (discovery P = 2.2 × 10- 4, replication P = 0.01), and PYGL (discovery P = 2.3 × 10- 4, replication P = 6.7 × 10- 4). Interestingly, both genes encode proteins that influence redox homeostasis and are related to cellular metabolic reprogramming in tumors, implicating a novel CRC pathway linked to cell growth and proliferation. Defining CRC risk regions as one megabase up- and downstream of one of the 56 independent risk variants, we defined 44 non-overlapping CRC-risk regions. Among these risk regions, we identified genes associated with CRC (P < 0.05) in 34/44 CRC-risk regions. Importantly, CRC association was found for two genes in the previously reported 2q25 locus, CXCR1 and CXCR2, which are potential cancer therapeutic targets. These findings provide strong candidate genes to prioritize for subsequent laboratory follow-up of GWAS loci. Thi
Solans M, Benavente Y, Saez M, et al., 2019, Inflammatory potential of diet and risk of lymphoma in the European Prospective Investigation into Cancer and Nutrition, European Journal of Nutrition, Vol: 59, Pages: 813-823, ISSN: 0044-264X
INTRODUCTION: Chronic inflammation plays a critical role in lymphomagenesis and several dietary factors seem to be involved its regulation. The aim of the current study was to assess the association between the inflammatory potential of the diet and the risk of lymphoma and its subtypes in the European Investigation into Cancer and Nutrition (EPIC) study. METHODS: The analysis included 476,160 subjects with an average follow-up of 13.9 years, during which 3,136 lymphomas (135 Hodgkin lymphoma (HL), 2606 non-Hodgkin lymphoma (NHL) and 395 NOS) were identified. The dietary inflammatory potential was assessed by means of an inflammatory score of the diet (ISD), calculated using 28 dietary components and their corresponding inflammatory weights. The association between the ISD and lymphoma risk was estimated by hazard ratios (HR) and 95% confidence intervals (CI) calculated by multivariable Cox regression models adjusted for potential confounders. RESULTS: The ISD was not associated with overall lymphoma risk. Among lymphoma subtypes, a positive association between the ISD and mature B-cell NHL (HR for a 1-SD increase: 1.07 (95% CI 1.01; 1.14), p trend = 0.03) was observed. No statistically significant association was found among other subtypes. However, albeit with smaller number of cases, a suggestive association was observed for HL (HR for a 1-SD increase = 1.22 (95% CI 0.94; 1.57), p trend 0.13). CONCLUSIONS: Our findings suggested that a high ISD score, reflecting a pro-inflammatory diet, was modestly positively associated with the risk of B-cell lymphoma subtypes. Further large prospective studies on low-grade inflammation induced by diet are warranted to confirm these findings.
Smith T, Muller D, Moons K, et al., 2019, Comparison of prognostic models to predict the occurrence of colorectal cancer in asymptomatic individuals: A systematic literature review and external validation in the EPIC and UK Biobank prospective cohort studies, Gut, Vol: 68, Pages: 672-683, ISSN: 0017-5749
ObjectiveTo systematically identify and validate published colorectal cancer risk prediction models that do not require invasive testing in two large population-based prospective cohorts.DesignModels were identified through an update of a published systematic review and validated in the European Prospective Investigation into Cancer and Nutrition (EPIC) and the UK Biobank. The performance of the models to predict the occurrence of colorectal cancer within 5 or 10 years after study enrolment was assessed by discrimination (C-statistic) and calibration (plots of observed versus predicted probability).ResultsThe systematic review and its update identified 16 models from 8 publications (8 colorectal, 5 colon and 3 rectal). The number of participants included in each model validation ranged from 41,587 to 396,515, and the number of cases from 115 to 1,781. Eligible and ineligible participants across the models were largely comparable. Calibration of the models, where assessable, was very good and further improved by recalibration. The C-statistics of the models were largely similar between validation cohorts with the highest values achieved being 0.70 (95%CI 0.68-0.72) in the UK Biobank and 0.71 (0.67-0.74) in EPIC. ConclusionSeveral of these non-invasive models exhibited good calibration and discrimination within both external validation populations and are therefore potentially suitable candidates for the facilitation of risk stratification in population-based colorectal screening programmes. Future work should both evaluate this potential, through modelling and impact studies, and ascertain if further enhancement in their performance can be obtained.
Vissers LET, Sluijs I, van der Schouw YT, et al., 2019, Dairy product intake and risk of type 2 diabetes in EPIC-InterAct: a mendelian randomization study, Diabetes Care, Vol: 42, ISSN: 0149-5992
OBJECTIVE To estimate the causal association between intake of dairy products and incident type 2 diabetes.RESEARCH DESIGN AND METHODS The analysis included 21,820 European individuals (9,686 diabetes cases) of the EPIC-InterAct case-cohort study. Participants were genotyped, and rs4988235 (LCT-12910C>T), a SNP for lactase persistence (LP) which enables digestion of dairy sugar, i.e., lactose, was imputed. Baseline dietary intakes were assessed with diet questionnaires. We investigated the associations between imputed SNP dosage for rs4988235 and intake of dairy products and other foods through linear regression. Mendelian randomization (MR) estimates for the milk-diabetes relationship were obtained through a two-stage least squares regression.RESULTS Each additional LP allele was associated with a higher intake of milk (β 17.1 g/day, 95% CI 10.6–23.6) and milk beverages (β 2.8 g/day, 95% CI 1.0–4.5) but not with intake of other dairy products. Other dietary intakes associated with rs4988235 included fruits (β −7.0 g/day, 95% CI −12.4 to −1.7 per additional LP allele), nonalcoholic beverages (β −18.0 g/day, 95% CI −34.4 to −1.6), and wine (β −4.8 g/day, 95% CI −9.1 to −0.6). In instrumental variable analysis, LP-associated milk intake was not associated with diabetes (hazard ratio 0.99per 15 g/day, 95% CI 0.93–1.05).CONCLUSIONS rs4988235 was associated with milk intake but not with intake of other dairy products. This MR study does not suggest that milk intake is associated with diabetes, which is consistent with previous observational and genetic associations. LP may be associated with intake of other foods as well, but owing to the modest associations we consider it unlikely that this has caused the observed null result.
Bradbury KE, Appleby PN, Tipper SJ, et al., 2019, Circulating insulin-like growth factor I in relation to melanoma risk in the European Prospective Investigation into Cancer and Nutrition, International Journal of Cancer, Vol: 144, Pages: 957-966, ISSN: 0020-7136
Insulin-like growth factor (IGF-I) regulates cell proliferation and apoptosis, and is thought to play a role in tumour development. Previous prospective studies have shown that higher circulating concentrations of IGF-I are associated with a higher risk of cancers at specific sites, including breast and prostate. No prospective study has examined the association between circulating IGF-I concentrations and melanoma risk. A nested case-control study of 1221 melanoma cases and 1221 controls was performed in the European Prospective Investigation into Cancer and Nutrition cohort, a prospective cohort of 520,000 participants recruited from 10 European countries. Conditional logistic regression was used to estimate odds ratios (ORs) for incident melanoma in relation to circulating IGF-I concentrations, measured by immunoassay. Analyses were conditioned on the matching factors and further adjusted for age at blood collection, education, height, BMI, smoking status, alcohol intake, marital status, physical activity, and in women only, use of menopausal hormone therapy. There was no significant association between circulating IGF-I concentration and melanoma risk (OR for highest vs lowest fifth=0.93 (95% confidence interval (CI): 0.71 to 1.22)). There was no significant heterogeneity in the association between IGF-I concentrations and melanoma risk when subdivided by sex, age at blood collection, BMI, height, age at diagnosis, time between blood collection and diagnosis, or by anatomical site or histological subtype of the tumour (Pheterogeneity≥0.078). We found no evidence for an association between circulating concentrations of IGF-I measured in adulthood and the risk of melanoma. This article is protected by copyright. All rights reserved.
Yang Y, Wu L, Shu X, et al., 2019, Genetic data from nearly 63,000 women of European descent predicts DNA methylation biomarkers and epithelial ovarian cancer risk, Cancer Research, Vol: 79, Pages: 505-517, ISSN: 1538-7445
DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N=1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P<7.94×10-7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27 and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression.
Aune D, Schlesinger S, Norat T, et al., 2019, Tobacco smoking and the risk of heart failure: a systematic review and meta-analysis of prospective studies, European Journal of Preventive Cardiology, Vol: 26, Pages: 279-288, ISSN: 2047-4873
Background We conducted a systematic review and meta-analysis to clarify the association between smoking and the risk of developing heart failure. Methods PubMed and Embase databases were searched up to 24 July 2018. Prospective studies were included if they reported adjusted relative risk (RR) estimates and 95% confidence intervals (CIs) of heart failure associated with smoking. Summary RRs and 95% CIs were estimated using a random effects model. Results Twenty-six studies were included. The summary RR was 1.75 (95% CI: 1.54-1.99, I2 = 81%, n = 10) for current smokers, 1.16 (95% CI: 1.08-1.24, I2 = 51%, n = 9) for former smokers, and 1.44 (1.34-1.55, I2 = 83%, n = 10) for ever smokers compared with never smokers. The summary RR was 1.41 (95% CI: 1.01-1.96, I2 = 82%, n = 2) per 10 cigarettes per day, 1.11 (95% CI: 1.04-1.18, I2 = 70%, n = 3) and 1.08 (95% CI: 1.02-1.14, I2 = 34%, n = 2) per 10 pack-years among ever smokers and former smokers, respectively, and 0.79 (95% CI: 0.63-1.00, I2 = 96%, n = 2) per 10 years since quitting smoking. The association between smoking cessation and heart failure reached significance at 15 years of smoking cessation, and at 30 years the summary RR was 0.72 (95% CI: 0.57-0.90), only slightly higher than the summary RR for never smokers (0.64 (95% CI: 0.57-0.72)) when compared with current smokers. Conclusion Smoking is associated with increased risk of heart failure, but the risk decreases with increasing duration since smoking cessation. Any further studies should investigate the association between number of cigarettes per day, duration, pack-years and time since quitting smoking and risk of heart failure.
Costas L, Lujan-Barroso L, Benavente Y, et al., 2019, Reproductive factors, exogenous hormone use, and risk of B-cell non-Hodgkin lymphoma in a cohort of women from the European prospective investigation into cancer and nutrition, American Journal of Epidemiology, Vol: 188, Pages: 274-281, ISSN: 1476-6256
The role of hormonal factors in the etiology of lymphoid neoplasms remains unclear. Previous studies have yielded conflicting results, have lacked sufficient statistical power to assess many lymphoma subtypes, or have lacked detailed information on relevant exposures. Within the European Prospective Investigation Into Cancer and Nutrition cohort, we analyzed comprehensive data on reproductive factors and exogenous hormone use collected at baseline (1992-2000) among 343,458 women, including data on 1,427 incident cases of B-cell non-Hodgkin lymphoma (NHL) and its major subtypes identified after a mean follow-up period of 14 years (through 2015). We estimated hazard ratios and 95% confidence intervals using multivariable proportional hazards modeling. Overall, we observed no statistically significant associations between parity, age at first birth, breastfeeding, oral contraceptive use, or ever use of postmenopausal hormone therapy and risk of B-cell NHL or its subtypes. Women who had undergone surgical menopause had a 51% higher risk of B-cell NHL (based on 67 cases) than women with natural menopause (hazard ratio = 1.51, 95% confidence interval: 1.17, 1.94). Given that this result may have been due to chance, our results provide little support for the hypothesis that sex hormones play a role in lymphomagenesis.
Gasull M, Pumarega J, Kiviranta H, et al., 2019, Methodological issues in a prospective study on plasma concentrations of persistent organic pollutants and pancreatic cancer risk within the EPIC cohort, Environmental Research, Vol: 169, Pages: 417-433, ISSN: 0013-9351
BACKGROUND: The use of biomarkers of environmental exposure to explore new risk factors for pancreatic cancer presents clinical, logistic, and methodological challenges that are also relevant in research on other complex diseases. OBJECTIVES: First, to summarize the main design features of a prospective case-control study -nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort- on plasma concentrations of persistent organic pollutants (POPs) and pancreatic cancer risk. And second, to assess the main methodological challenges posed by associations among characteristics and habits of study participants, fasting status, time from blood draw to cancer diagnosis, disease progression bias, basis of cancer diagnosis, and plasma concentrations of lipids and POPs. Results from etiologic analyses on POPs and pancreatic cancer risk, and other analyses, will be reported in future articles. METHODS: Study subjects were 1533 participants (513 cases and 1020 controls matched by study centre, sex, age at blood collection, date and time of blood collection, and fasting status) enrolled between 1992 and 2000. Plasma concentrations of 22 POPs were measured by gas chromatography - triple quadrupole mass spectrometry (GC-MS/MS). To estimate the magnitude of the associations we calculated multivariate-adjusted odds ratios by unconditional logistic regression, and adjusted geometric means by General Linear Regression Models. RESULTS: There were differences among countries in subjects' characteristics (as age, gender, smoking, lipid and POP concentrations), and in study characteristics (as time from blood collection to index date, year of last follow-up, length of follow-up, basis of cancer diagnosis, and fasting status). Adjusting for centre and time of blood collection, no factors were significantly associated with fasting status. Plasma concentrations of lipids were related to age, body mass index, fasting, country, and smoking. We detected and quan
Schumacher FR, Olama AAA, Berndt SI, et al., 2019, Author Correction: Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci., Nat Genet, Vol: 51, Pages: 363-363
In the version of this article initially published, the name of author Manuela Gago-Dominguez was misspelled as Manuela Gago Dominguez. The error has been corrected in the HTML and PDF version of the article.
Huseinovic E, Winkvist A, Freisling H, et al., 2019, Timing of eating across ten European countries - results from the European Prospective Investigation into Cancer and Nutrition (EPIC) calibration study, Public Health Nutrition, Vol: 22, Pages: 324-335, ISSN: 1368-9800
OBJECTIVE: To examine timing of eating across ten European countries. DESIGN: Cross-sectional analysis of the European Prospective Investigation into Cancer and Nutrition (EPIC) calibration study using standardized 24 h diet recalls collected during 1995-2000. Eleven predefined food consumption occasions were assessed during the recall interview. We present time of consumption of meals and snacks as well as the later:earlier energy intake ratio, with earlier and later intakes defined as 06.00-14.00 and 15.00-24.00 hours, respectively. Type III tests were used to examine associations of sociodemographic, lifestyle and health variables with timing of energy intake. SETTING: Ten Western European countries. SUBJECTS: In total, 22 985 women and 13 035 men aged 35-74 years (n 36 020). RESULTS: A south-north gradient was observed for timing of eating, with later consumption of meals and snacks in Mediterranean countries compared with Central and Northern European countries. However, the energy load was reversed, with the later:earlier energy intake ratio ranging from 0·68 (France) to 1·39 (Norway) among women, and from 0·71 (Greece) to 1·35 (the Netherlands) among men. Among women, country, age, education, marital status, smoking, day of recall and season were all independently associated with timing of energy intake (all P<0·05). Among men, the corresponding variables were country, age, education, smoking, physical activity, BMI and day of recall (all P<0·05). CONCLUSIONS: We found pronounced differences in timing of eating across Europe, with later meal timetables but greater energy load earlier during the day in Mediterranean countries compared with Central and Northern European countries.
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