Hepatic steatosis, metabolic dysfunction and risk of mortality: findings from a multinational prospective cohort study.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS) are implicated in the aetiology of non-communicable diseases. Our study aimed to evaluate associations between NAFLD and MetS with overall and cause-specific mortality. METHODS: We used dietary, lifestyle, anthropometric and metabolic biomarker data from a random subsample of 15,784 EPIC cohort participants. NAFLD was assessed using the fatty liver index (FLI) and MetS using the revised definition. Indices for metabolic dysfunction-associated fatty liver disease (MAFLD) were calculated. The individual associations of these indices with overall and cause-specific mortality were assessed using multivariable Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (95%CIs). As a subobjective, risk associations with adaptations of new classifications of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic and alcohol-related liver disease (MetALD) were also assessed. RESULTS: Among the 15,784 sub-cohort participants, a total of 1997 deaths occurred (835 due to cancer, 520 to CVD, 642 to other causes) over a median 15.6 (IQR, 12.3-17.1) years of follow-up. Compared to an FLI < 30, FLI ≥ 60 was associated with increased risks of overall mortality (HR = 1.44, 95%CI = 1.27-1.63), and deaths from cancer (HR = 1.32, 95%CI = 1.09-1.60), CVD (HR = 2.06, 95% CI = 1.61-2.63) or other causes (HR = 1.21, 95%CI = 0.97-1.51). Mortality risk associations were also elevated for individuals with MAFLD compared to those without. Individuals with MetS were at increased risk of all mortality endpoints, except cancer-specific mortality. MASLD and MetALD were associated with higher risk of overall mortality. CONCLUSIONS: Our findings based on a prospective cohort suggest that individuals with hepatic steatosis or metabolic dysfunction have a higher overall and cause-specific mortality risk.

Blood levels of persistent organic pollutants among women in France in the 90's: Main profiles and individual determinants.

CONTEXT AND OBJECTIVES: Persistent organic pollutants (POPs) are a group of organic chemical compounds potentially toxic to human health. The objectives of this study were 1) to describe the levels of POPs biomarkers in blood samples from French women collected during the 1990s and to compare them with levels measured in two more recent French studies, 2) to identify POPs exposure profiles, and 3) to explore their main determinants. METHODS: 73 POPs biomarkers were measured in the blood of 468 women from the French E3N cohort (aged 45-73 years), collected between 1994 and 1999: 28 per- and polyfluoroalkyl substances, 27 organochlorine pesticides, 14 polychlorinated biphenyls and 4 polybrominated diphenyl ethers. POPs biomarker levels were described and compared with levels measured in two more recent French studies conducted by the French National Public Health Agency, the ENNS and Esteban studies. Principal component analysis was performed on POPs quantified in at least 75% of samples to identify the main exposure profiles. Linear regression models were used to estimate the associations between anthropometric, socio-demographic and lifestyle characteristics and exposure to these profiles. RESULTS: Among the 73 biomarkers measured, 41 were quantified in more than 75% of samples. Levels of most pollutants that were also measured in the Esteban of ENNS studies have decreased over time. Six POPs exposure profiles were revealed, explaining 62.1% of the total variance. Most of the characteristics studied were associated with adherence to at least one of these profiles. CONCLUSION: This study highlighted that most of the pollutants for which a comparison was possible decreased over the 10 or 20 years following the E3N blood collection, and identified those which, on the contrary, tended to increase. The health effects of the profiles identified could be assessed in future studies. The determinants identified should be confirmed in larger populations.

Healthy lifestyle change and all-cause and cancer mortality in the European Prospective Investigation into Cancer and Nutrition cohort.

BACKGROUND: Healthy lifestyles are inversely associated with the risk of noncommunicable diseases, which are leading causes of death. However, few studies have used longitudinal data to assess the impact of changing lifestyle behaviours on all-cause and cancer mortality. METHODS: Within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, lifestyle profiles of 308,497 cancer-free adults (71% female) aged 35-70 years at recruitment across nine countries were assessed with baseline and follow-up questionnaires administered on average of 7 years apart. A healthy lifestyle index (HLI), assessed at two time points, combined information on smoking status, alcohol intake, body mass index, and physical activity, and ranged from 0 to 16 units. A change score was calculated as the difference between HLI at baseline and follow-up. Associations between HLI change and all-cause and cancer mortality were modelled with Cox regression, and the impact of changing HLI on accelerating mortality rate was estimated by rate advancement periods (RAP, in years). RESULTS: After the follow-up questionnaire, participants were followed for an average of 9.9 years, with 21,696 deaths (8407 cancer deaths) documented. Compared to participants whose HLIs remained stable (within one unit), improving HLI by more than one unit was inversely associated with all-cause and cancer mortality (hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.81, 0.88; and HR: 0.87; 95% CI: 0.82, 0.92; respectively), while worsening HLI by more than one unit was associated with an increase in mortality (all-cause mortality HR: 1.26; 95% CI: 1.20, 1.33; cancer mortality HR: 1.19; 95% CI: 1.09, 1.29). Participants who worsened HLI by more than one advanced their risk of death by 1.62 (1.44, 1.96) years, while participants who improved HLI by the same amount delayed their risk of death by 1.19 (0.65, 2.32) years, compared to those with stable HLI. CONCLUSIONS: Making healthier lifestyle changes during adulthood was inversely associated with all-cause and cancer mortality and delayed risk of death. Conversely, making unhealthier lifestyle changes was positively associated with mortality and an accelerated risk of death.

High adherence to the French dietary guidelines decreases type 2 diabetes risk in females through pathways of obesity markers: Evidence from the E3N-EPIC prospective cohort study.

OBJECTIVE: Obesity and type 2 diabetes (T2D) have been associated with low adherence to the 2017 French food-based dietary guidelines, as assessed by the Programme National Nutrition Santé - guidelines score 2 (PNNS-GS2). Whether the association between T2D and PNNS-GS2 is direct or mediated by obesity has been little investigated. RESEARCH METHODS: The study included 71,450 women from the E3N-EPIC cohort, mean age of 52.9 y (SD 6.7). The simplified PNNS-GS2 was derived via food history questionnaire. Multivariable Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of T2D. Causal mediation analyses were used to decompose the total effect of sPNNS-GS2 on T2D into a direct effect and indirect effect mediated by body mass index (BMI) or the waist-hip ratio (WHR). RESULTS: During a mean follow-up of 19 y, 3679 incident T2D cases were identified and validated. There was a linear association between adherence to sPNNS-GS2 and T2D (P-nonlinearity = 0.92). In the fully adjusted model, each 1-SD increase in the sPNNS-GS2 was associated with a lower T2D risk [HR (95% CI), 0.92 (0.89, 0.95)]. The overall associations were mainly explained by sPNNS-GS2-associated excess weight, with BMI and WHR mediating 52% and 58% of the associations, respectively. CONCLUSIONS: Higher adherence to French food-based dietary guidelines was associated with a lower risk of T2D in women, and a significant portion of this effect could be attributed to excess weight measured by BMI or WHR. This finding helps better understand the mechanisms underlying the diet-T2D association.

Lifestyle changes in middle age and risk of cancer: evidence from the European Prospective Investigation into Cancer and Nutrition.

In this study, we aimed to provide novel evidence on the impact of changing lifestyle habits on cancer risk. In the EPIC cohort, 295,865 middle-aged participants returned a lifestyle questionnaire at baseline and during follow-up. At both timepoints, we calculated a healthy lifestyle index (HLI) score based on cigarette smoking, alcohol consumption, body mass index and physical activity. HLI ranged from 0 (most unfavourable) to 16 (most favourable). We estimated the association between HLI change and risk of lifestyle-related cancers-including cancer of the breast, lung, colorectum, stomach, liver, cervix, oesophagus, bladder, and others-using Cox regression models. We reported hazard ratios (HR) with 95% confidence intervals (CI). Median time between the two questionnaires was 5.7 years, median age at follow-up questionnaire was 59 years. After the follow-up questionnaire, we observed 14,933 lifestyle-related cancers over a median follow-up of 7.8 years. Each unit increase in the HLI score was associated with 4% lower risk of lifestyle-related cancers (HR 0.96; 95%CI 0.95-0.97). Among participants in the top HLI third at baseline (HLI > 11), those in the bottom third at follow-up (HLI ≤ 9) had 21% higher risk of lifestyle-related cancers (HR 1.21; 95%CI 1.07-1.37) than those remaining in the top third. Among participants in the bottom HLI third at baseline, those in the top third at follow-up had 25% lower risk of lifestyle-related cancers (HR 0.75; 95%CI 0.65-0.86) than those remaining in the bottom third. These results indicate that lifestyle changes in middle age may have a significant impact on cancer risk.

Dietary vitamin D intake and the bladder cancer risk: A pooled analysis of prospective cohort studies.

BACKGROUND & AIMS: Diet may play an essential role in the aetiology of bladder cancer (BC). Vitamin D is involved in various biological functions which have the potential to prevent BC development. Besides, vitamin D also influences the uptake of calcium and phosphorus, thereby possibly indirectly influencing the risk of BC. The aim of the present study was to investigate the relation between vitamin D intake and BC risk. METHODS: Individual dietary data were pooled from ten cohort studies. Food item intake was converted to daily intakes of vitamin D, calcium and phosphorus. Pooled multivariate hazard ratios (HRs), with corresponding 95% confidence intervals (CIs) were obtained using Cox-regression models. Analyses were adjusted for gender, age and smoking status (Model 1), and additionally for the food groups fruit, vegetables and meat (Model 2). Dose-response relationships (Model 1) were examined using a nonparametric test for trend. RESULTS: In total, 1994 cases and 518,002 non-cases were included in the analyses. The present study showed no significant associations between individual nutrient intake and BC risk. A significant decreased BC risk was observed for high vitamin D intake with moderate calcium and low phosphorus intake (Model 2: HRhigh vitD, mod Ca, low P: 0.77, 95% CI: 0.59-1.00). No significant dose-response analyses were observed. CONCLUSION: The present study showed a decreased BC risk for high dietary vitamin D intake in combination with low calcium intake and moderate phosphorus intake. The study highlights the importance of examining the effect of a nutrient in combination with complementary nutrients for risk assessment. Future research should focus on nutrients in a wider context and in nutritional patterns.

Challenges of studying the dietary exposure to chemical mixtures: Example of the association with mortality risk in the E3N French prospective cohort.

Food is contaminated by many chemicals which interact with each other, resulting in additive, synergistic or antagonistic effects. It is thus necessary to study the health effects of dietary exposure to chemical mixtures rather than single contaminants. We aimed to investigate the association between dietary exposure to chemical mixtures and mortality risk in the E3N French prospective cohort. We included 72,585 women from the E3N cohort who completed a food frequency questionnaire in 1993. From 197 chemicals, and using sparse non-negative matrix under-approximation (SNMU), we identified six main chemical mixtures to which these women were chronically exposed through the diet. We estimated the associations between dietary exposure to these mixtures and all-cause or cause-specific mortality using Cox proportional hazard models. During the follow-up (1993-2014), 6441 deaths occurred. We observed no association between dietary exposure to three mixtures and all-cause mortality, and a non-monotonic inverse association for the three other mixtures. These results could be explained by the fact that, despite the different dietary adjustment strategies tested, we did not fully succeed in excluding the residual confounding from the overall effect of the diet. We also questioned the number of chemicals to include in mixtures' studies, as a balance needs to be reached between including a large number of chemicals and the interpretability of the results. Integrating a priori knowledge, such as toxicological data, could lead to the identification of more parsimonious mixtures, thus to more interpretable results. Moreover, as the SNMU is a non-supervised method, which identifies the mixtures only on the basis of the correlations between the exposure variables, and not in relation to the outcome, it would be interesting to test supervised methods. Finally, further studies are needed to identify the most adequate approach to investigate the health effects of dietary exposure to chemical mixtures in observational studies.

Positive association between dietary exposure to polybrominated diphenyl ethers and breast cancer risk in the French E3N cohort: The role of vegetable oil consumption.

Exposure to endocrine-disrupting chemicals, like Polybrominated diphenyl ethers (PBDEs), is suspected of playing a role in the occurrence of breast cancer. Moreover, there is growing evidence that food chemical contaminants, especially lipophilic ones such as PBDEs, could interact with different components of the diet. The objective of the present study was to assess the association between dietary intake of PBDEs and breast cancer risk in the French E3N cohort study, and to investigate the potential modification of this association by vegetable oil consumption. The study included 67879 women. Intakes of eight PBDEs were estimated using food consumption data from a validated semi-quantitative food frequency questionnaire, and food contamination levels measured by the French Agency for Food, Environmental and Occupational Health and Safety (ANSES). Cox proportional hazards models were used to estimate Hazard Ratios (HR) and 95% Confidence Intervals (CI) for the association between total PBDEs dietary intake and breast cancer risk. Interaction measures for vegetable oil consumption were estimated on both additive and multiplicative scales. The women were followed for a maximum of 21.4 years, and 5 686 developed an incident breast cancer. A positive linear trend was highlighted between dietary intake of PBDEs in quintile groups and breast cancer risk, borderline with statistical significance (p-trend = 0.06, HRQ5vsQ1 and 95% CI: 1.09 [0.99;1.20]). Interaction measures for vegetable oil consumption were significant in both additive and multiplicative scales. Higher effect sizes of the association were highlighted in high consumers of vegetable oil, i.e. ≥4.6 g/day (HRQ5vsQ1 and 95% CI: 1.23 [1.08; 1.40]), and almost no effect were found in low consumers (HRQ5vsQ1 and 95% CI: 0.97 [0.86; 1.10]). Highlighting such interactions between nutrients and chemicals is crucial to develop efficient dietary recommendations to limit the negative health effects associated with exposure to food chemical contaminants.

Maternal diet during pregnancy and child neurodevelopment up to age 3.5 years: the nationwide Étude Longitudinale Française depuis l'Enfance (ELFE) birth cohort.

BACKGROUND: Dietary guidelines available to pregnant women are made to improve maternal health and fetal development. But their adequacy to sustain offspring neurodevelopment has remained understudied. OBJECTIVES: We assessed the association between compliance with nutritional guidelines during pregnancy and neurodevelopment in preschool children. METHODS: The analyses were based on data for 6780 to 11,278 children from the Étude Longitudinale Française depuis l'Enfance (ELFE) study, a nationwide birth cohort. Maternal diet during the last 3 mo of pregnancy was evaluated at delivery by using a validated 125-item FFQ. From this FFQ, food group consumption, a diet quality score (adapted National Health and Nutrition Program Guideline Score), and a nutrient intake score (Probability of Adequate Nutrient intake based Diet quality index) were calculated and dietary patterns were derived by principal component analysis. Child neurodevelopment was reported by parents at 1 and 3.5 y with the Child Development Inventory (CDI-1, CDI-3.5) and at 2 y with the MacArthur-Bates Communicative Development Inventories (MB-2), and assessed by a trained investigator at 3.5 y with the Picture Similarities test (British Ability Scales, PS-3.5). Associations between maternal diet and child neurodevelopment were assessed by multivariable linear regression models on standardized variables. RESULTS: Higher nutrient intake score was associated with higher neurodevelopmental scores from 1 to 3.5 y (ß = 0.04; 95% CI: 0.02, 0.06 for CDI-1; ß = 0.03; 95% CI: 0.01, 0.05 for MB-2; and ß = 0.03; 95% CI: 0.01, 0.05 for CDI-3.5). Higher fruit and vegetables or fish intake and lower pork-meat products intake were related to higher CDI-3.5 scores (ß = 0.03; 95% CI: 0.01, 0.05 for fruit and vegetables; ß = 0.03; 95% CI: 0.01, 0.05 for fish; and ß = -0.02; 95% CI: -0.04, 0.00 for pork-meat products). A higher score on the processed food pattern was associated with poorer neurodevelopmental score at 1 y (ß = -0.05; 95% CI: -0.06, -0.03). CONCLUSIONS: Higher diet quality during pregnancy was associated with higher parent-reported neurodevelopmental scores in early childhood. The negative association of pork-meat products consumption with early neurodevelopmental scores needs to be further confirmed.

Association between polycyclic aromatic hydrocarbons (PAH) dietary exposure and mortality risk in the E3N cohort.

Most studies have explored the adverse health effects of polycyclic aromatic hydrocarbons (PAH) occupational exposure. However, the general population is also exposed to PAH, mainly through the diet. The goal of the present study is thus to investigate the association between PAH dietary exposure and mortality risk in middle-aged women of the E3N (Étude Épidémiologique auprès de femmes de la mutuelle générale de l'Éducation Nationale) French prospective cohort. The study included 72,513 women, whom completed a validated semi-quantitative food frequency questionnaire on 208 food items in 1993. Food contamination levels were assessed using data provided by the Anses (French Agency for Food, Environmental and Occupational Health & Safety) in the framework of the French second total diet study. PAH dietary exposure was studied as the sum of four PAH (PAH4), namely benzo[a]pyrene (BaP), chrysene (CHR), benzo[a]anthracene (BaA) and benzo[b]fluoranthene (BbF). Cox proportional hazard models were used to estimate hazard ratios (HR) and their 95 % confidence intervals (CI) for the risk of all-cause mortality as well as all-cancer, specific cancer (separately from breast, lung/tracheal, and colorectal cancer), cardiovascular disease (CVD), and specific CVD (including only stroke and coronary heart disease) mortality. During follow-up (1993-2011), 4620 validated deaths were reported, of which 2726 due to cancer and 584 to CVD. The median PAH4 dietary intake was 66.1 ng/day. There was no significant association between PAH4 dietary intake and the risk of all-cause, all-cancer, breast cancer, colorectal cancer, all-CVD and stroke and coronary heart disease mortality. On the contrary, we observed a positive and statistically significant association between PAH4 dietary intake and lung/tracheal cancer mortality risk, with a stronger association among current smokers than among former smokers and never smokers. In this study, we observed an association between PAH dietary exposure and lung/tracheal cancer mortality risk, especially among current smokers.