Prospective Investigation Into Research Articles

Impact of Cigarette Smoking on Cancer Risk in the European Prospective Investigation into Cancer and Nutrition Study

Our aim was to assess the impact of cigarette smoking on the risk of the tumors classified by the International Agency for Research on Cancer as causally associated with smoking, referred to as tobacco-related cancers (TRC). The study population included 441,211 participants (133,018 men and 308,193 women) from the European Prospective Investigation Into Cancer and Nutrition. We investigated 14,563 participants who developed a TRC during an average follow-up of 11 years. The impact of smoking cigarettes on cancer risk was assessed by the population attributable fraction (AF(p)), calculated using the adjusted hazard ratios and 95% CI for current and former smokers, plus either the prevalence of smoking among cancer cases or estimates from surveys in representative samples of the population in each country. The proportion of all TRC attributable to cigarette smoking was 34.9% (95% CI, 32.5 to 37.4) using the smoking prevalence among cases and 36.2% (95% CI, 33.7 to 38.6) using the smoking prevalence from the population. The AF(p) were above 80% for cancers of the lung and larynx, between 20% and 50% for most respiratory and digestive cancers and tumors from the lower urinary tract, and below 20% for the remaining TRC. Using data on cancer incidence for 2008 and our AF(p) estimates, about 270,000 new cancer diagnoses per year can be considered attributable to cigarette smoking in the eight European countries with available data for both men and women (Italy, Spain, United Kingdom, the Netherlands, Greece, Germany, Sweden, Denmark).

Physical Activity and Mortality in Individuals With Diabetes Mellitus

BACKGROUND Physical activity (PA) is considered a cornerstone of diabetes mellitus management to prevent complications, but conclusive evidence is lacking. METHODS This prospective cohort study and meta-analysis of existing studies investigated the association between PA and mortality in individuals with diabetes. In the EPIC study (European Prospective Investigation Into Cancer and Nutrition), a cohort was defined of 5859 individuals with diabetes at baseline. Associations of leisure-time and total PA and walking with cardiovascular disease (CVD) and total mortality were studied using multivariable Cox proportional hazards regression models. Fixed- and random-effects meta-analyses of prospective studies published up to December 2010 were pooled with inverse variance weighting. RESULTS In the prospective analysis, total PA was associated with lower risk of CVD and total mortality. Compared with physically inactive persons, the lowest mortality risk was observed in moderately active persons: hazard ratios were 0.62 (95% CI, 0.49-0.78) for total mortality and 0.51 (95% CI, 0.32-0.81) for CVD mortality. Leisure-time PA was associated with lower total mortality risk, and walking was associated with lower CVD mortality risk. In the meta-analysis, the pooled random-effects hazard ratio from 5 studies for high vs low total PA and all-cause mortality was 0.60 (95% CI, 0.49-0.73). CONCLUSIONS Higher levels of PA were associated with lower mortality risk in individuals with diabetes. Even those undertaking moderate amounts of activity were at appreciably lower risk for early death compared with inactive persons. These findings provide empirical evidence supporting the widely shared view that persons with diabetes should engage in regular PA.

Famine Exposure in the Young and the Risk of Type 2 Diabetes in Adulthood

The developmental origins hypothesis proposes that undernutrition during early development is associated with an increased type 2 diabetes risk in adulthood. We investigated the association between undernutrition during childhood and young adulthood and type 2 diabetes in adulthood. We studied 7,837 women from Prospect-EPIC (European Prospective Investigation Into Cancer and Nutrition) who were exposed to the 1944–1945 Dutch famine when they were between age 0 and 21 years. We used Cox proportional hazards regression models to explore the effect of famine on the risk of subsequent type 2 diabetes in adulthood. We adjusted for potential confounders, including age at famine exposure, smoking, and level of education. Self-reported famine exposure during childhood and young adulthood was associated with an increased type 2 diabetes risk in a dose-dependent manner. In those who reported moderate famine exposure, the age-adjusted type 2 diabetes hazard ratio (HR) was 1.36 (95% CI [1.09–1.70]); in those who reported severe famine exposure, the age-adjusted HR was 1.64 (1.26–2.14) relative to unexposed women. These effects did not change after adjustment for confounders. This study provides the first direct evidence, using individual famine exposure data, that a short period of moderate or severe undernutrition during postnatal development increases type 2 diabetes risk in adulthood.

525 Epigenome-wide Association Study in the European Prospective Investigation Into Cancer and Nutrition (EPIC-Turin) Identifies Novel Genes Associated With Smoking

525 Epigenome-wide Association Study in the European Prospective Investigation Into Cancer and Nutrition (EPIC-Turin) Identifies Novel Genes Associated With Smoking

PWE-248 Docosahexanoeic acid in the aetiology of Crohn's disease—data from a European prospective cohort study (EPIC)

IntroductionDocosahexaenoic acid (DHA) is an n-3 polyunsaturated fatty acid, present in fish oils, which possess anti-inflammatory properties, including biological effects on genetic expression, immune cell function and the production of...

Tu1277 Docosahexanoeic Acid and Eicosapentaenoic Acid in the Aetiology of Crohn's Disease - Data From a European Prospective Cohort Study (EPIC)

Introduction Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are both n-3 polyunsaturated fatty acids which possess anti-inflammatory properties, including biological effects on genetic expression, immune cell function and the production of inflammatory eicosonoids. The aim of this investigation was to conduct the first prospective cohort study to determine if low dietary intakes of these nutrients were associated with the development of incident Crohn9s disease. Methods A total of 229 702 healthy participants aged 30–74 years of age were recruited in a prospective cohort study (EPIC – European Prospective Investigation Into Cancer) who were resident in either: Sweden, Denmark, The Netherlands, Germany or The UK. At baseline, participants completed food frequency questionnaires from which their intakes of both DHA and EPA was determined. The cohort was followed up between 1992 and 2004 to identify those who developed Crohn9s disease, with each diagnosis medically confirmed by a review of the medical notes. Each case was matched with four controls for gender, age at recruitment and centre and the analysis performed using conditional logistic regression, adjusted for smoking and total energy intake. Results In the cohort, 84 participants developed incident Crohn9s disease (64% women) at a mean age of 59.8 years (SD=9.8 years). The four higher quintiles of DHA intake were all negatively associated with the development of Crohn9s disease, with odds ratios of similar magnitudes, with two reaching borderline statistical significance (OR=0.47 95% CI=0.20 to 1.10, p=0.08 for 3 rd highest vs lowest quintile). There was threshold effect for DHA with a summation of the four higher quintiles, compared to the lowest quintile (daily intake of >0.07 g/day, showing a negative association (0R=0.50, 95% CI=0.25 to 1.02, p=0.06). There were no associations with dietary EPA intake (Trend HR=0.93, 95% CI=0.74 to 1.17, p=0.53). Conclusion The data suggest a potential protective effect for a threshold level of dietary DHA in the aetiology of Crohn9s disease, although longer follow-up time is required to accrue more cases and precisely define the effect size. DHA should be measured in future aetiological studies of this disease and could be assessed as a dietary treatment in clinical trials of patients.

Biomarkers of Oxidative Stress and Risk of Developing Colorectal Cancer: A Cohort-nested Case-Control Study in the European Prospective Investigation Into Cancer and Nutrition

Oxidative stress has been shown to play an important role in carcinogenesis, but prospective evidence for an association between biomarkers of oxidative stress and colorectal cancer (CRC) risk is limited. The authors investigated the association between prediagnostic serum levels of oxidative stress indicators (i.e., reactive oxygen metabolites (ROM) and ferric reducing ability of plasma (FRAP)) and CRC risk. This was examined in a nested case-control study (1,064 CRC cases, 1,064 matched controls) in the European Prospective Investigation Into Cancer and Nutrition cohort (1992-2003). Incidence rate ratios and 95% confidence intervals were calculated using conditional logistic regression analyses. ROM were associated with overall CRC risk (highest tertile vs. lowest: adjusted incidence rate ratio (IRR(adj)) = 1.91, 95% confidence interval (CI): 1.47, 2.48), proximal (IRR(adj) = 1.89, 95% CI: 1.06, 3.36) and distal (IRR(adj) = 2.31, 95% CI: 1.37, 3.89) colon cancer, and rectal cancer (IRR(adj) = 1.69, 95% CI: 1.05, 2.72). When results were stratified by tertile of follow-up time, the association remained significant only in participants with less than 2.63 years of follow-up (IRR(adj) = 2.28, 95% CI: 1.78, 2.94; P-heterogeneity < 0.01). FRAP was not associated with CRC risk. In conclusion, prediagnostic serum ROM levels were associated with increased risk of CRC. However, this association was seen only in subjects with relatively short follow-up, suggesting that the association results from production of reactive oxygen species by preclinical tumors.

Invited Commentary: More Surprises From a Gene Desert

Pleiotropy across the 8q24 region is perhaps the most intriguing of the genome-wide association findings relating to cancer. This region of chromosome 8 is a gene desert, far from any recognized genes. Guarrera et al., whose work is reported in this issue (Am J Epidemiol. 2012;175(6):479-487), took an epidemiologic approach to learn more about the 8q24 region. They capitalized on their ascertainment of other endpoints in members of the cohort at the Turin site of the European Prospective Investigation Into Cancer and Nutrition to investigate multiple outcomes for additional pleiotropic effects in the 8q24 region. Alternative design options might involve genotyping of more variants, incorporation of more cases, or use of a single control group close to the size of the most common case group. Their analytic methods reflect the uncertainty of the underlying biology. The findings sharpen the scientific question about how variation in the 8q24 region affects pathogenesis. The genome-wide association effort is possible because of the economy of scale afforded by extremely dense genotyping. Strict adherence to the hypothesis-driven approach would ignore information that is obtainable at a trivial cost. The genome-wide association strategy tests whether agnostic data-mining methods can advance knowledge alongside or even in place of the standard hypothesis-driven approach, which is the conventional scientific method children learn in kindergarten and onward, even through graduate school and beyond.

Ecological-Level Associations Between Highly Processed Food Intakes and Plasma Phospholipid Elaidic Acid Concentrations: Results From a Cross-Sectional Study Within the European Prospective Investigation Into Cancer and Nutrition (EPIC)

Elaidic acid is the main unnatural trans fatty acid isomer occurring during partial hydrogenation of vegetable oils used as ingredients for the formulation of processed foods. The main objective is to assess associations between processed food intakes and plasma phospholipid elaidic acid concentrations within the European Prospective Investigation into Cancer and Nutrition study. A cross-sectional study was used to determine fatty acid profiles in 3,003 subjects from 16 centers. Single 24-h dietary recalls (24-HDR) were collected using a standardized computerized interview program. Food intakes were computed according to their degree of processing (moderately/nonprocessed foods, processed staple foods, highly processed foods). Adjusted ecological and individual correlations were calculated between processed food intakes and plasma elaidic acid levels. At the population level, mean intakes of highly processed foods were strongly correlated with mean levels of plasma elaidic acid in men (P = 0.0016) and in women (P = 0.0012). At the individual level, these associations remained but at a much lower level in men (r = 0.08, P = 0.006) and in women (r = 0.09, P = 0.0001). The use of an averaged 24-HDR measure of highly processed food intakes is adequate for predicting mean levels of plasma elaidic acid among European populations.

Expression of the human apoE2 isoform in adipocytes: altered cellular processing and impaired adipocyte lipogenesis

Expression of apoE in adipocytes has been shown to have an important role in modulating adipocyte triglyceride (TG) metabolism and gene expression that is independent of circulating and extracellular apoE. The impact of adipocyte expression of common human apoE isoforms was evaluated using adipocytes harvested from human apoE2, -3, and -4 knock-in mice. Expression of the apoE2 isoform was associated with an increase in adipocyte apoE gene expression and apoE synthesis. Newly synthesized apoE2 was unstable in adipocytes and demonstrated increased degradation and decreased secretion. ApoE2-expressing mice were hyperlipidemic, and had increased size of gonadal fat pads and of adipocytes, compared with apoE3 mice. In isolated cells, however, expression of the apoE2 isoform produced defective lipogenesis and increased TG hydrolysis. Incubation of adipose tissue with apoE3-containing TG-rich lipoproteins resulted in a significant increase in TG in adipose tissue from apoE3 and -E4 mice, but not apoE2 mice. Reduced capacity to internalize FFA as lipogenic substrate contributed to defective lipogenesis. Newly synthesized apoE2 is unstable in adipocytes and results in decreased adipocyte TG synthesis and defective FA uptake. These changes recapitulate those observed in apoE knockout adipocytes and have implications for understanding metabolic disturbances in humans expressing the E2 isoform.

Mediterranean Diet and Type 2 Diabetes Risk in the European Prospective Investigation Into Cancer and Nutrition (EPIC) Study

OBJECTIVETo study the association between adherence to the Mediterranean dietary pattern (MDP) and risk of developing type 2 diabetes, across European countries.RESEARCH DESIGN AND METHODSWe established a case-cohort study including 11,994 incident type 2 diabetic case subjects and a stratified subcohort of 15,798 participants selected from a total cohort of 340,234 participants with 3.99 million person-years of follow-up, from eight European cohorts participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The relative Mediterranean diet score (rMED) (score range 0–18) was used to assess adherence to MDP on the basis of reported consumption of nine dietary components characteristic of the Mediterranean diet. Cox proportional hazards regression, modified for the case-cohort design, was used to estimate the association between rMED and risk of type 2 diabetes, adjusting for confounders.RESULTSThe multiple adjusted hazard ratios of type 2 diabetes among individuals with medium (rMED 7–10 points) and high adherence to MDP (rMED 11–18 points) were 0.93 (95% CI 0.86–1.01) and 0.88 (0.79–0.97), respectively, compared with individuals with low adherence to MDP (0–6 points) (P for trend 0.013). The association between rMED and type 2 diabetes was attenuated in people <50 years of age, in obese participants, and when the alcohol, meat, and olive oil components were excluded from the score.CONCLUSIONSIn this large prospective study, adherence to the MDP, as defined by rMED, was associated with a small reduction in the risk of developing type 2 diabetes in this European population.

Association Between Plasma Vitamin C Concentrations and Blood Pressure in the European Prospective Investigation Into Cancer-Norfolk Population-Based Study

The effect of fruit and vegetable consumption and blood pressure is unclear. A population-based cross-sectional study was conducted in 20 926 men and women aged 40 to 79 years participating in the European Prospective Investigation Into Cancer-Norfolk who completed a health questionnaire and attended a clinic from 1993 to 1997. The relationship between plasma vitamin C concentrations, as an indicator of fruit and vegetable intake, and systolic BP was examined. The magnitude of their association was assessed using dichotomized values of high (≥140 mm Hg) and low (<140 mm Hg) systolic blood pressure. A total of 20 926 participants (46% men; mean [SD] 58.5 years [9.2 years]) were included after excluding participants with any missing data for variables of interest. People with high vitamin C concentrations had lower clinic blood pressure. The likelihood of having high blood pressure was 22% lower (odds ratio: 0.78 [95% CI: 0.71 to 0.86]) for those who were in the top quartiles of plasma vitamin C levels compared with the bottom quartiles after adjusting for age, sex, body mass index, cholesterol, prevalent medical conditions, smoking, physical activity, alcohol consumption, social class, education, use of vitamin C-containing supplement, and antihypertensive medication. Sex-specific analysis, as well as repeated analysis after exclusion of people who used vitamin C-containing supplements or who were taking antihypertensive medication, did not alter the results. There appears to be a strong association between vitamin C concentrations, an indicator of fruit and vegetable consumption, and a lower level of blood pressure. This may provide further evidence for health benefits of dietary patterns with higher fruit and vegetable consumption.

Dietary Arachidonic Acid and the Aetiology of Ulcerative Colitis – Data From a UK Prospective Cohort Study, Using 7-Day Food Diaries

Introduction There is emerging evidence that arachidonic acid (AA), an n-6 polyunsaturated fatty acid (n-6 PUFA), is involved in the aetiology of ulcerative colitis. The biological mechanism may involve the production from AA, of the pro-inflammatory eicosonoids prostaglandin E2 (PGE2) and leukotriene B4 (LTB4), which are present in higher concentrations in the colonic mucosa of patients. The aim of this study was to investigate, for the first time in a prospective cohort study using nutrient data from 7-day food diaries (7-DFDs), whether an increased dietary AA intake was associated with the development of incident ulcerative colitis. Methods A total of 23 658 men and women aged 40–78 years, in Norfolk, UK, were recruited into EPIC (European Prospective Investigation Into Cancer). At baseline, participants completed detailed 7-DFDs which recorded their dietary intake of food types, brands, quantities, frequency of consumption and cooking methods. Each diary was coded by nutritionists, using a specifically designed computer programme which contained information on the nutrient content of 11 000 food items, including AA. The cohort was then monitored for participants who subsequently developed incident ulcerative colitis, with each case confirmed by review of the medical notes. Each case was matched for age at recruitment, date of recruitment, gender and follow-up time, with four controls, and the odds ratios calculated for the risk of ulcerative colitis and tertiles of AA intake. The analysis was adjusted for cigarette smoking, total energy intake and other dietary fatty acids affecting AA metabolism. Results In the cohort, 26 participants (58% men) developed incident ulcerative colitis after a median follow-up time of 3.8 years (range 0.5–8.3 years). The extent of the colonic inflammation was up to the splenic flexure in 53% of patients. Higher AA intakes were associated with an increased risk of UC (highest vs lowest tertile OR= 6.09, 95% CI=1.05 to 35.23, p=0.04) with a positive trend across tertiles (OR=1.94, 95% CI =0.88 to 4.29, p=0.10). The attributable fraction for the two higher tertiles of AA intake and incident cases of UC was 57%. Conclusion An increased dietary intake of arachidonic acid, as measured from 7-DFDs (the most accurate feasible method of measuring diet in large epidemiological studies), was associated with an increased risk of developing UC. While it is possible that preclinical disease might influence, dietary intake, these results further support a role for AA and n-6 PUFAs in the pathogenesis of UC, and their intake should be measured in future aetiological work.

Dietary arachidonic acid and the aetiology of ulcerative colitis: data from a UK prospective cohort study, using 7-day food diaries

IntroductionThere is emerging evidence that arachidonic acid (AA), an n-6 polyunsaturated fatty acid (n-6 PUFA), is involved in the aetiology of ulcerative colitis. The biological mechanism may involve the production...

Docosahexanoeic acid and eicosapentaenoic acid in the aetiology of crohn's disease: data from a european prospective cohort study (EPIC)

IntroductionDocosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are both n-3 polyunsaturated fatty acids which possess anti-inflammatory properties, including biological effects on genetic expression, immune cell function and the production of...

Mediterranean dietary pattern and cancer risk in the EPIC cohort

Background:Although several studies have investigated the association of the Mediterranean diet with overall mortality or risk of specific cancers, data on overall cancer risk are sparse.Methods:We examined the association between adherence to Mediterranean dietary pattern and overall cancer risk using data from the European Prospective Investigation Into Cancer and nutrition, a multi-centre prospective cohort study including 142 605 men and 335 873. Adherence to Mediterranean diet was examined using a score (range: 0–9) considering the combined intake of fruits and nuts, vegetables, legumes, cereals, lipids, fish, dairy products, meat products, and alcohol. Association with cancer incidence was assessed through Cox regression modelling, controlling for potential confounders.Results:In all, 9669 incident cancers in men and 21 062 in women were identified. A lower overall cancer risk was found among individuals with greater adherence to Mediterranean diet (hazard ratio=0.96, 95% CI 0.95–0.98) for a two-point increment of the Mediterranean diet score. The apparent inverse association was stronger for smoking-related cancers than for cancers not known to be related to tobacco (P (heterogeneity)=0.008). In all, 4.7% of cancers among men and 2.4% in women would be avoided in this population if study subjects had a greater adherence to Mediterranean dietary pattern.Conclusion:Greater adherence to a Mediterranean dietary pattern could reduce overall cancer risk.

Alternative Methods of Accounting for Underreporting and Overreporting When Measuring Dietary Intake-Obesity Relations

Misreporting characterized by the reporting of implausible energy intakes may undermine the valid estimation of diet-disease relations, but the methods to best identify and account for misreporting are unknown. The present study compared how alternate approaches affected associations between selected dietary factors and body mass index (BMI) by using data from the European Prospective Investigation Into Cancer and Nutrition-Spain. A total of 24,332 women and 15,061 men 29-65 years of age recruited from 1992 to 1996 for whom measured height and weight and validated diet history data were available were included. Misreporters were identified on the basis of disparities between reported energy intakes and estimated requirements calculated using the original Goldberg method and 2 alternatives: one that substituted basal metabolic rate equations that are more valid at higher BMIs and another that used doubly labeled water-predicted total energy expenditure equations. Compared with results obtained using the original method, underreporting was considerably lower and overreporting higher with alternative methods, which were highly concordant. Accounting for misreporters with all methods yielded diet-BMI relations that were more consistent with expectations; alternative methods often strengthened associations. For example, among women, multivariable-adjusted differences in BMI for the highest versus lowest vegetable intake tertile (β = 0.37 (standard error, 0.07)) were neutral after adjusting with the original method (β = 0.01 (standard error, 07)) and negative using the predicted total energy expenditure method with stringent cutoffs (β = -0.15 (standard error, 0.07)). Alternative methods may yield more valid associations between diet and obesity-related outcomes.

Re: Fruit and Vegetable Intake and Overall Cancer Risk in the European Prospective Investigation Into Cancer and Nutrition

Boffetta et al. (1) reported in the Journal a weak but statistically significant association between fruit and vegetable intake and the overall cancer risk by analyzing data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The reduced cancer risk associated with an increased daily intake of 200 g of fruits and vegetables combined was 3% (95% confidence intervals = 1% to 4%) only. The large health campaigns organized in several countries using TV commercials or other public media to encourage the population to eat five daily portions of fruits and vegetables at first seem disproportionate for such a small benefit. However, in our opinion, the associations that are limited to overall cancer risk are not sufficient to provide adequate information on the benefit of increased daily intake of fruits and vegetables for cancer prevention. Such associations should be assessed in the context of other EPIC results. Despite the weak association between fruit and vegetable intake and overall cancer risk, a strong association could be observed for some specific cancer sites, in particular among smokers. For breast, prostate, renal, and pancreatic cancers, previous EPIC results showed no association between fruit and vegetable intake and overall cancer risk (2–5). For epithelial ovarian, esophageal, and stomach cancers, the association was small or limited to some food items or histological subtypes of the tumors (6,7). For lung, upper aerodigestive, and colon cancers, the association was strong with the following results: 1) lung cancer risk was reduced by 40% in the highest vs the lowest quintile of fruit intake (8); the association between fruit and reduced cancer risk was particularly strong in Northern Europe, where the overall median intake of fruits and vegetables is lower than in other parts of Europe; 2) lung cancer risk was reduced in current smokers by 10% and 22%, per 100 g increase in daily intake of fruits and vegetables, respectively (9); 3) upper aerodigestive tract cancer risk was reduced by 9%, per 80 g increase in daily intake of fruits and vegetables combined (10); and 4) colon cancer risk was reduced by 24% in the highest vs the lowest quintile of fruits and vegetables combined (11). Because these cancers represent approximately 30% of cancers in men and 20% of cancers in women, the association between nutrition and overall cancer risk is diluted.

Re: Fruit and Vegetable Intake and Overall Cancer Risk in the European Prospective Investigation Into Cancer and Nutrition

The excellent article in the Journal by Boffetta et al. (1) on fruit and vegetable intake and cancer risk offers a nice example on why inferences based on P values are problematic in large studies that show associations of very small magnitude. The reported associations between high fruit and vegetable intake and cancer risk reached nominal levels of statistical significance (P = .006 and P < .001, respectively), and the authors conclude that the study “supports the notion of a modest cancer preventive effect of high intake of fruits and vegetables” (1). The respective hazard ratios per 100 g/d intake of fruits and vegetables were 0.99 and 0.98, respectively, and 0.97 per 200 g/d intake of fruits and vegetables combined. The authors are commended for being cautious that residual confounding can affect such hazard ratios of very small magnitude (1). The main problem, however, is that for associations of very small magnitude, P values alone do not suffice to make inferences, even if there is absolutely no residual confounding. The inferences depend critically on how strong the associations are expected to be based on previous results, biological reasoning, or practical considerations, that is, the associations that would be important from a clinical or public health perspective.

Response: Re: Fruit and Vegetable Intake and Overall Cancer Risk in the European Prospective Investigation Into Cancer and Nutrition

Response: Re: Fruit and Vegetable Intake and Overall Cancer Risk in the European Prospective Investigation Into Cancer and Nutrition