Source-specific nitrate intake and all-cause mortality in the Danish Diet, Cancer, and Health Study.

INTRODUCTION: Nitrate and nitrite are naturally occurring in both plant- and animal-sourced foods, are used as additives in the processing of meat, and are found in water. There is growing evidence that they exhibit a spectrum of health effects, depending on the dietary source. The aim of the study was to examine source-dependent associations between dietary intakes of nitrate/nitrite and both all-cause and cause-specific mortality. METHODS: In 52,247 participants of the Danish Diet, Cancer and Health Study, associations between source-dependent nitrate and nitrite intakes--calculated using comprehensive food composition and national drinking water quality monitoring databases--and all-cause, cardiovascular disease (CVD)-related, and cancer-related mortality over 27 years were examined using restricted cubic splines within Cox proportional hazards models adjusting for demographic, lifestyle, and dietary confounders. Analyses were stratified by factors hypothesised to influence the formation of carcinogenic N-nitroso compounds (namely, smoking and dietary intakes of vitamin C, vitamin E, folate, and polyphenols). RESULTS: Plant-sourced nitrate intake was inversely associated with all-cause mortality [HRQ5vsQ1: 0.83 (0.80, 0.87)] while higher risks of all-cause mortality were seen for higher intakes of naturally occurring animal-sourced nitrate [1.09 (1.04, 1.14)], additive permitted meat-sourced nitrate [1.19 (1.14, 1.25)], and tap water-sourced nitrate [1.19 (1.14, 1.25)]. Similar source-dependent associations were seen for nitrite and for CVD-related and cancer-related mortality except that naturally occurring animal-sourced nitrate and tap water-sourced nitrate were not associated with cancer-related mortality and additive permitted meat-sourced nitrate was not associated with CVD-related mortality. No clear patterns emerged in stratified analyses. CONCLUSION: Nitrate/nitrite from plant sources are inversely associated while those from naturally occurring animal-sources, additive-permitted meat sources, and tap water-sources are positively associated with mortality.

Inflammation and Gut Barrier Function-Related Genes and Colorectal Cancer Risk in Western European Populations.

Gut barrier dysfunction and related inflammation are known to be associated with the development and progression of colorectal cancer (CRC). We investigated associations of 292 single-nucleotide polymorphisms (SNPs) from 27 genes related to endotoxins/lipopolysaccharide (LPS) sensing and tolerance, mucin synthesis, inflammation, and Crohn's disease with colon and rectal cancer risks. Incident CRC cases (N=1,374; colon=871, rectum=503) were matched 1:1 to controls nested within the European Prospective Investigation into Cancer and Nutrition cohort. Previously measured serum concentrations of gut barrier function and inflammation biomarkers (flagellin/LPS-specific immunoglobulins and C-reactive protein [CRP]) were available for a sub-set of participants (Ncases=1,001; Ncontrols=667). Forty-two unique SNPs from 19 different genes were associated with serum biomarkers at Punadjusted≤0.05 among controls. Among SNPs associated with a gut permeability score, 24 SNPs were in genes related to LPS sensing and mucin synthesis. Nine out of 12 SNPs associated with CRP were in genes related to inflammation or Crohn's disease. TLR4 was associated with colon cancer at the SNP level (nine SNPs, all Punadjusted≤0.04) and at the gene level (Punadjusted≤0.01). TLR4 rs10759934 was associated with rectal cancer but not colon cancer. Similarly, IL10 was associated with rectal cancer risk at a SNP and gene level (both Punadjusted ≤ 0.01), but not colon cancer. Genes and SNPs were selected a priori therefore we present unadjusted P-values. However, no association was statistically significant after multiple testing correction. This large and comprehensive study has identified gut barrier function and inflammation-related genes possibly contributing to CRC risk in European populations and is consistent with potential etiological links between host genetic background, gut barrier permeability, microbial endotoxemia and CRC development.

Dietary intake of plant- and animal-derived protein and incident cardiovascular diseases: the pan-European EPIC-CVD case-cohort study.

BACKGROUND: Epidemiological evidence suggests that a potential association between dietary protein intake and cardiovascular disease (CVD) may depend on the protein source, that is, plant- or animal-derived, but past research was limited and inconclusive. OBJECTIVES: To evaluate the association of dietary plant- or animal-derived protein consumption with risk of CVD, and its components ischemic heart disease (IHD) and stroke. METHODS: This analysis in the European Prospective Investigation into Cancer and Nutrition (EPIC)-CVD case-cohort study included 16,244 incident CVD cases (10,784 IHD and 6423 stroke cases) and 15,141 subcohort members from 7 European countries. We investigated the association of estimated dietary protein intake with CVD, IHD, and stroke (total, fatal, and nonfatal) using multivariable-adjusted Prentice-weighted Cox regression. We estimated isocaloric substitutions of replacing fats and carbohydrates with plant- or animal-derived protein and replacing food-specific animal protein with plant protein. Multiplicative interactions between dietary protein and prespecified variables were tested. RESULTS: Neither plant- nor animal-derived protein intake was associated with incident CVD, IHD, or stroke in adjusted analyses without or with macronutrient-specified substitution analyses. Higher plant-derived protein intake was associated with 22% lower total stroke incidence among never smokers [HR 0.78, 95% confidence intervals (CI): 0.62, 0.99], but not among current smokers (HR 1.08, 95% CI: 0.83, 1.40, P-interaction = 0.004). Moreover, higher plant-derived protein (per 3% total energy) when replacing red meat protein (HR 0.52, 95% CI: 0.31, 0.88), processed meat protein (HR 0.39, 95% CI: 0.17, 0.90), and dairy protein (HR 0.54, 95% CI: 0.30, 0.98) was associated with lower incidence of fatal stroke. CONCLUSION: Plant- or animal-derived protein intake was not associated with overall CVD. However, the association of plant-derived protein consumption with lower total stroke incidence among nonsmokers, and with lower incidence of fatal stroke highlights the importance of investigating CVD subtypes and potential interactions. These observations warrant further investigation in diverse populations with varying macronutrient intakes and dietary patterns.

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.

Interaction of genetic risk and lifestyle on the incidence of atrial fibrillation.

BACKGROUND: The relationship between combined genetic predisposition and lifestyle and the risk of incident atrial fibrillation (AF) is unclear. Therefore, we aimed to assess a possible interaction between lifestyle and genetics on AF risk. METHODS: We included AF cases and a randomly drawn subcohort of 4040 participants from the Danish Diet, Cancer and Health cohort. Lifestyle risk factors were assessed, a score was calculated, and participants were categorised as having a poor, intermediate, or ideal lifestyle. We calculated a genetic risk score comprising 142 variants, and categorised participants into low (quintile 1), intermediate (quintiles 2-4) or high (quintile 5) genetic risk of AF. RESULTS: 3094 AF cases occurred during a median follow-up of 12.9 years. Regardless of genetic risk, incidence rates per 1000 person-years were gradually higher with worse lifestyle. For participants with high genetic risk, the incidence rates of AF per 1000 person-years were 5.0 (95% CI 3.4 to 7.3) among individuals with ideal lifestyle, 6.6 (95% CI 5.4 to 8.1) among those with intermediate lifestyle and 10.4 (95% CI 9.2 to 11.8) among participants with poor lifestyle. On an additive scale, there was a positive statistically significant interaction between genetic risk and lifestyle (relative excess risk due to interaction=0.86, 95% CI 0.68 to 1.03, p<0.001). CONCLUSIONS: The rates of AF increased gradually with worse lifestyle within each category of genetic risk. We found a positive interaction on an additive scale between genetic risk and lifestyle, suggesting that risk factor modification is especially important in individuals with a high genetic risk of AF.

Age at Menopause and the Risk of Stroke: Observational and Mendelian Randomization Analysis in 204 244 Postmenopausal Women.

Background Observational studies have shown that women with an early menopause are at higher risk of stroke compared with women with a later menopause. However, associations with stroke subtypes are inconsistent, and the causality is unclear. Methods and Results We analyzed data of the UK Biobank and EPIC-CVD (European Prospective Investigation Into Cancer and Nutrition-Cardiovascular Diseases) study. A total of 204 244 postmenopausal women without a history of stroke at baseline were included (7883 from EPIC-CVD [5292 from the subcohort], 196 361 from the UK Biobank). Pooled mean baseline age was 58.9 years (SD, 5.8), and pooled mean age at menopause was 47.8 years (SD, 6.2). Over a median follow-up of 12.6 years (interquartile range, 11.8-13.3), 6770 women experienced a stroke (5155 ischemic strokes, 1615 hemorrhagic strokes, 976 intracerebral hemorrhages, and 639 subarachnoid hemorrhages). In multivariable adjusted observational Cox regression analyses, the pooled hazard ratios per 5 years younger age at menopause were 1.09 (95% CI, 1.07-1.12) for stroke, 1.09 (95% CI, 1.06-1.13) for ischemic stroke, 1.10 (95% CI, 1.04-1.16) for hemorrhagic stroke, 1.14 (95% CI, 1.08-1.20) for intracerebral hemorrhage, and 1.00 (95% CI, 0.84-1.20) for subarachnoid hemorrhage. When using 2-sample Mendelian randomization analysis, we found no statistically significant association between genetically proxied age at menopause and risk of any type of stroke. Conclusions In our study, earlier age at menopause was related to a higher risk of stroke. We found no statistically significant association between genetically proxied age at menopause and risk of stroke, suggesting no causal relationship.

Self-reported and measured anthropometric variables in association with cardiometabolic markers: A Danish cohort study.

General obesity is a recognized risk factor for various metabolically related diseases, including hypertension, dyslipidemia, and pre-diabetes. In epidemiological studies, anthropometric variables such as height and weight are often self-reported. However, misreporting of self-reported data may bias estimates of associations between anthropometry and health outcomes. Further, few validation studies have compared self-reported and measured waist circumference (WC). This study aimed to quantify the agreement between self-reported and measured height, weight, body mass index (BMI), WC, and waist-to-height ratio (WHtR), and to investigate associations of these anthropometric measures with cardiometabolic biomarkers. A total of 39,514 participants aged above 18 years were included into the Diet, Cancer, and Health-Next Generation Cohort in 2015-19. Self-reported and measured anthropometric variables, blood pressure, and cardiometabolic biomarkers (HbA1c, lipid profiles, C-reactive protein and creatinine) were collected by standard procedures. Pearson correlations (r) and Lin's concordance correlations were applied to evaluate misreporting. Misreporting by age, sex and smoking status was investigated in linear regression models. Multivariable regression models and Receiver Operating Characteristic analyses assessed associations of self-reported and measured anthropometry with cardiometabolic biomarkers. Self-reported height was overreported by 1.07 cm, and weight was underreported by 0.32 kg on average. Self-reported BMI and WC were 0.42 kg/m2 and 0.2 cm lower than measured, respectively. Self-reported and measured height, weight, BMI, WC and WtHR were strongly correlated (r = 0.98, 0.99, 0.98, 0.88, 0.86, respectively). Age, sex, smoking, and BMI contributed to misreporting of all anthropometric measures. Associations between self-reported or measured anthropometric measures and cardiometabolic biomarkers were similar in direction and strength. Concordance between self-reported and measured anthropometric measures, including WC, was very high. Self-reported anthropometric measures were reliable when estimating associations with cardiometabolic biomarkers.

Corrigendum: Characterization of the degree of food processing in the European Prospective Investigation into Cancer and Nutrition: application of the Nova classification and validation using selected biomarkers of food processing.

[This corrects the article DOI: 10.3389/fnut.2022.1035580.].

A body shape index (ABSI) is associated inversely with post-menopausal progesterone-receptor-negative breast cancer risk in a large European cohort.

BACKGROUND: Associations of body shape with breast cancer risk, independent of body size, are unclear because waist and hip circumferences are correlated strongly positively with body mass index (BMI). METHODS: We evaluated body shape with the allometric "a body shape index" (ABSI) and hip index (HI), which compare waist and hip circumferences, correspondingly, among individuals with the same weight and height. We examined associations of ABSI, HI, and BMI (per one standard deviation increment) with breast cancer overall, and according to menopausal status at baseline, age at diagnosis, and oestrogen and progesterone receptor status (ER+/-PR+/-) in multivariable Cox proportional hazards models using data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. RESULTS: During a mean follow-up of 14.0 years, 9011 incident breast cancers were diagnosed among 218,276 women. Although there was little evidence for association of ABSI with breast cancer overall (hazard ratio HR = 0.984; 95% confidence interval: 0.961-1.007), we found borderline inverse associations for post-menopausal women (HR = 0.971; 0.942-1.000; n = 5268 cases) and breast cancers diagnosed at age ≥ 55 years (HR = 0.976; 0.951-1.002; n = 7043) and clear inverse associations for ER + PR- subtypes (HR = 0.894; 0.822-0.971; n = 726) and ER-PR- subtypes (HR = 0.906; 0.835-0.983 n = 759). There were no material associations with HI. BMI was associated strongly positively with breast cancer overall (HR = 1.074; 1.049-1.098), for post-menopausal women (HR = 1.117; 1.085-1.150), for cancers diagnosed at age ≥ 55 years (HR = 1.104; 1.076-1.132), and for ER + PR + subtypes (HR = 1.122; 1.080-1.165; n = 3101), but not for PR- subtypes. CONCLUSIONS: In the EPIC cohort, abdominal obesity evaluated with ABSI was not associated with breast cancer risk overall but was associated inversely with the risk of post-menopausal PR- breast cancer. Our findings require validation in other cohorts and with a larger number of PR- breast cancer cases.

Circulating amino acid levels and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition and UK Biobank cohorts.

BACKGROUND: Amino acid metabolism is dysregulated in colorectal cancer patients; however, it is not clear whether pre-diagnostic levels of amino acids are associated with subsequent risk of colorectal cancer. We investigated circulating levels of amino acids in relation to colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) and UK Biobank cohorts. METHODS: Concentrations of 13-21 amino acids were determined in baseline fasting plasma or serum samples in 654 incident colorectal cancer cases and 654 matched controls in EPIC. Amino acids associated with colorectal cancer risk following adjustment for the false discovery rate (FDR) were then tested for associations in the UK Biobank, for which measurements of 9 amino acids were available in 111,323 participants, of which 1221 were incident colorectal cancer cases. RESULTS: Histidine levels were inversely associated with colorectal cancer risk in EPIC (odds ratio [OR] 0.80 per standard deviation [SD], 95% confidence interval [CI] 0.69-0.92, FDR P-value=0.03) and in UK Biobank (HR 0.93 per SD, 95% CI 0.87-0.99, P-value=0.03). Glutamine levels were borderline inversely associated with colorectal cancer risk in EPIC (OR 0.85 per SD, 95% CI 0.75-0.97, FDR P-value=0.08) and similarly in UK Biobank (HR 0.95, 95% CI 0.89-1.01, P=0.09) In both cohorts, associations changed only minimally when cases diagnosed within 2 or 5 years of follow-up were excluded. CONCLUSIONS: Higher circulating levels of histidine were associated with a lower risk of colorectal cancer in two large prospective cohorts. Further research to ascertain the role of histidine metabolism and potentially that of glutamine in colorectal cancer development is warranted.

The association between body fatness and mortality among breast cancer survivors: results from a prospective cohort study.

Evidence linking body fatness to breast cancer (BC) prognosis is limited. While it seems that excess adiposity is associated with poorer BC survival, there is uncertainty over whether weight changes reduce mortality. This study aimed to assess the association between body fatness and weight changes pre- and postdiagnosis and overall mortality and BC-specific mortality among BC survivors. Our study included 13,624 BC survivors from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, with a mean follow-up of 8.6 years after diagnosis. Anthropometric data were obtained at recruitment for all cases and at a second assessment during follow-up for a subsample. We measured general obesity using the body mass index (BMI), whereas waist circumference and A Body Shape Index were used as measures of abdominal obesity. The annual weight change was calculated for cases with two weight assessments. The association with overall mortality and BC-specific mortality were based on a multivariable Cox and Fine and Gray models, respectively. We performed Mendelian randomization (MR) analysis to investigate the potential causal association. Five-unit higher BMI prediagnosis was associated with a 10% (95% confidence interval: 5-15%) increase in overall mortality and 7% (0-15%) increase in dying from BC. Women with abdominal obesity demonstrated a 23% (11-37%) increase in overall mortality, independent of the association of BMI. Results related to weight change postdiagnosis suggested a U-shaped relationship with BC-specific mortality, with higher risk associated with losing weight or gaining > 2% of the weight annually. MR analyses were consistent with the identified associations. Our results support the detrimental association of excess body fatness on the survival of women with BC. Substantial weight changes postdiagnosis may be associated with poorer survival.

Dietary intake of total, heme and non-heme iron and the risk of colorectal cancer in a European prospective cohort study.

BACKGROUND: Iron is an essential micronutrient with differing intake patterns and metabolism between men and women. Epidemiologic evidence on the association of dietary iron and its heme and non-heme components with colorectal cancer (CRC) development is inconclusive. METHODS: We examined baseline dietary questionnaire-assessed intakes of total, heme, and non-heme iron and CRC risk in the EPIC cohort. Sex-specific multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using Cox regression. We modelled substitution of a 1 mg/day of heme iron intake with non-heme iron using the leave one-out method. RESULTS: Of 450,105 participants (318,680 women) followed for 14.2 ± 4.0 years, 6162 (3511 women) developed CRC. In men, total iron intake was not associated with CRC risk (highest vs. lowest quintile, HRQ5vs.Q1:0.88; 95%CI:0.73, 1.06). An inverse association was observed for non-heme iron (HRQ5vs.Q1:0.80, 95%CI:0.67, 0.96) whereas heme iron showed a non-significant association (HRQ5vs.Q1:1.10; 95%CI:0.96, 1.27). In women, CRC risk was not associated with intakes of total (HRQ5vs.Q1:1.11, 95%CI:0.94, 1.31), heme (HRQ5vs.Q1:0.95; 95%CI:0.84, 1.07) or non-heme iron (HRQ5vs.Q1:1.03, 95%CI:0.88, 1.20). Substitution of heme with non-heme iron demonstrated lower CRC risk in men (HR:0.94; 95%CI: 0.89, 0.99). CONCLUSIONS: Our findings suggest potential sex-specific CRC risk associations for higher iron consumption that may differ by dietary sources.

Dietary patterns related to biological mechanisms and survival after breast cancer diagnosis: results from a cohort study.

BACKGROUND: Inflammatory, insulin and oestrogenic pathways have been linked to breast cancer (BC). We aimed to examine the relationship between pre-diagnostic dietary patterns related to these mechanisms and BC survival. METHODS: The diabetes risk reduction diet (DRRD), inflammatory score of diet (ISD) and oestrogen-related dietary pattern (ERDP) were calculated using dietary data from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Cox proportional hazards models were used to assess associations between dietary patterns and overall mortality and competing risk models for associations with BC-specific mortality. RESULTS: We included 13,270 BC cases with a mean follow-up after diagnosis of 8.6 years, representing 2340 total deaths, including 1475 BC deaths. Higher adherence to the DRRD score was associated with lower overall mortality (HR1-SD 0.92; 95%CI 0.87-0.96). Greater adherence to pro-inflammatory diets was borderline associated with 6% higher mortality HR1-SD 1.06; 95%CI 1.00-1.12. No significant association with the oestrogen-related dietary pattern was observed. None of the dietary patterns were associated with BC-specific mortality. CONCLUSIONS: Greater adherence to an anti-diabetic and anti-inflammatory diet prior to diagnosis is associated with lower overall mortality among BC survivors. Long-term adherence to these dietary patterns could be a means to improve the prognosis of BC survivors.

Adherence to the EAT-Lancet diet is associated with a lower risk of type 2 diabetes: the Danish Diet, Cancer and Health cohort.

PURPOSE: Type 2 diabetes is a global health problem. While a healthy diet lowers risk of type 2 diabetes, less is known about diets with low climate impact. This study aimed to investigate adherence to the EAT-Lancet diet and risk of type 2 diabetes in a Danish setting. METHODS: In the Danish Diet, Cancer and Health cohort, dietary data were collected using a validated 192-item food frequency questionnaire, at recruitment in 1993-1997. In total, 54,232 participants aged 50-64 years at baseline with no previous cancer or diabetes diagnoses were included in the current analyses. The EAT-Lancet diet score was used to assess adherence to the EAT-Lancet diet. Participants scored 0 (non-adherence) or 1 (adherence) point for each of the 14 dietary components of the diet score (range 0-14 points). Participants were followed through register linkage until type 2 diabetes diagnosis or censoring. Hazard ratios and 95% confidence intervals (CI) were estimated using multivariable-adjusted Cox regression models. RESULTS: During a median 15-year follow-up period, 7130 participants developed type 2 diabetes. The hazard ratio for developing type 2 diabetes was 0.78 (95% CI 0.71; 0.86) for those with highest EAT-Lancet diet scores (11-14 points) compared to those with lowest scores (0-7 points) after adjusting for potential confounders. After further adjusting for potential mediators, including BMI, the corresponding hazard ratio was 0.83 (95% CI 0.76; 0.92). CONCLUSION: Greater adherence to the EAT-Lancet diet was associated with a lower risk of developing type 2 diabetes in a middle-aged Danish population.

Changes in Lifestyle and Risk of Colorectal Cancer in the European Prospective Investigation Into Cancer and Nutrition.

INTRODUCTION: We investigated the impact of changes in lifestyle habits on colorectal cancer (CRC) risk in a multicountry European cohort. METHODS: We used baseline and follow-up questionnaire data from the European Prospective Investigation into Cancer cohort to assess changes in lifestyle habits and their associations with CRC development. We calculated a healthy lifestyle index (HLI) score based on smoking status, alcohol consumption, body mass index, and physical activity collected at the 2 time points. HLI ranged from 0 (most unfavorable) to 16 (most favorable). We estimated the association between HLI changes and CRC risk using Cox regression models and reported hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: Among 295,865 participants, 2,799 CRC cases were observed over a median of 7.8 years. The median time between questionnaires was 5.7 years. Each unit increase in HLI from the baseline to the follow-up assessment was associated with a statistically significant 3% lower CRC risk. Among participants in the top tertile at baseline (HLI > 11), those in the bottom tertile at follow-up (HLI ≤ 9) had a higher CRC risk (HR 1.34; 95% CI 1.02-1.75) than those remaining in the top tertile. Among individuals in the bottom tertile at baseline, those in the top tertile at follow-up had a lower risk (HR 0.77; 95% CI 0.59-1.00) than those remaining in the bottom tertile. DISCUSSION: Improving adherence to a healthy lifestyle was inversely associated with CRC risk, while worsening adherence was positively associated with CRC risk. These results justify and support recommendations for healthy lifestyle changes and healthy lifestyle maintenance for CRC prevention.

Mediating Role of Lifestyle Behaviors in the Association between Education and Cancer: Results from the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Many studies have shown that socioeconomic position (SEP) is associated with the incidence of malignant tumors at different sites. This study aims to estimate the association between educational level (as proxy for SEP) and cancer incidence and to understand whether the observed associations might be partially explained by lifestyle behaviors. METHODS: The analyses were performed on data from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, globally and by sex. We used Cox proportional hazards models together with mediation analysis to disentangle the total effect (TE) of educational level [measured through the Relative Index of Inequality (RII)] on cancer incidence into pure direct (PDE) and total indirect (TIE) effect, unexplained and explained by mediators, respectively. PDE and TIE were then combined to compute the proportions mediated (PM). RESULTS: After an average of 14 years of follow-up, 52,422 malignant tumors were ascertained. Low educated participants showed higher risk of developing stomach, lung, kidney (in women), and bladder (in men) cancers, and, conversely, lower risk of melanoma and breast cancer (in post-menopausal women), when compared with more educated participants. Mediation analyses showed that portions of the TE of RII on cancer could be explained by site-specific related lifestyle behaviors for stomach, lung, and breast (in women). CONCLUSIONS: Cancer incidence in Europe is determined at least in part by a socioeconomically stratified distribution of risk factors. IMPACT: These observational findings support policies to reduce cancer occurrence by altering mediators, such as lifestyle behaviors, particularly focusing on underprivileged strata of the population.

Baseline and lifetime alcohol consumption and risk of skin cancer in the European Prospective Investigation into Cancer and Nutrition cohort (EPIC).

Experimental evidence suggests that alcohol induces cutaneous carcinogenesis, yet epidemiological studies on the link between alcohol intake and skin cancer have been inconsistent. The European Prospective Investigation into Cancer and Nutrition (EPIC) is a prospective cohort initiated in 1992 in 10 European countries. Alcohol intake at baseline and average lifetime alcohol intake were assessed using validated country-specific dietary and lifestyle questionnaires. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated in Cox models. A total of 14 037 skin cancer cases (melanoma: n = 2457; basal-cell carcinoma (BCC): n = 8711; squamous-cell carcinoma (SCC): n = 1928; unknown: n = 941) were identified among 450 112 participants (average follow-up: 15 years). Baseline alcohol intake was positively associated with SCC (>15 vs 0.1-4.9 g/day: HR = 1.44, 95% CI = 1.17-1.77; Ptrend  = .001), BCC (HR = 1.12, 95% CI = 1.01-1.23; Ptrend  = .04), and melanoma risks in men (HR = 1.17, 95% CI = 0.95-1.44; Ptrend  = .17), while associations were more modest in women (SCC: HR = 1.09, 95% CI = 0.90-1.30; Ptrend  = .13; BCC: HR = 1.08, 95% CI = 1.00-1.17, Ptrend  = .03; melanoma: HR = 0.93, 95% CI = 0.80-1.08, Ptrend  = .13). Associations were similar for lifetime alcohol intake, with an attenuated linear trend. Lifetime liquor/spirit intake was positively associated with melanoma (fourth vs first quartile: HR = 1.47, 95% CI = 1.08-1.99; Ptrend  = .0009) and BCC risks in men (HR = 1.17, 95% CI = 1.04-1.31; Ptrend  = .14). Baseline and lifetime intakes of wine were associated with BCC risk (HR = 1.25 in men; HR = 1.11-1.12; in women). No statistically significant associations were found between beverage types and SCC risk. Intake of beer was not associated with skin cancer risk. Our study suggests positive relationships between alcohol intake and skin cancer risk, which may have important implications for the primary prevention of skin cancer.

Adherence to the EAT-Lancet diet in midlife and development in weight or waist circumference after five years in a Danish cohort.

Purpose: The EAT-Lancet reference diet has been proposed as a healthy dietary pattern to reduce food-related climate impacts, but little is known regarding associations with bodyweight development. This study investigated adherence to the EAT-Lancet diet in midlife and development in weight and waist circumference (WC) after five years. Design: The Danish Diet, Cancer and Health cohort recruited participants in 1993-1997. At baseline, data on diet, lifestyle, and anthropometry were collected. Participants self-reported weight and WC five years later. In total, 44,194 participants were included in analyses of weight (43,678 for WC). Baseline adherence to the EAT-Lancet diet was scored 0-14 points. Multiple linear regression was used to estimate associations between the EAT-Lancet diet and development in weight and WC after five years. Poisson regression was used to estimate risk ratios (RR) of obesity (≥30 kg/m2) or elevated WC. Results: Adherence to the EAT-Lancet diet was not associated with follow-up weight, adjusting for baseline weight and confounders (11-14 vs 0-7 points ß: -0.08, 95% CI: -0.27, 0.11 kg), but was associated with lower follow-up WC adjusting for baseline WC and confounders (ß: -0.38, 95% CI: -0.69, -0.07 cm), and was associated with lower risk of obesity and elevated WC (RR 0.89, 95% CI: 0.82, 0.98, and 0.95, 95% CI: 0.93, 0.96, respectively). Conclusion: Adherence to the EAT-Lancet diet in midlife was associated with lower WC but not weight after five years follow up, taking baseline into account. Our findings suggest that greater adherence to the EAT-Lancet diet does not contribute to development of obesity.

A longitudinal evaluation of alcohol intake throughout adulthood and colorectal cancer risk.

BACKGROUND: Alcohol intake is an established risk factor for colorectal cancer (CRC); however, there is limited knowledge on whether changing alcohol drinking habits during adulthood modifies CRC risk. OBJECTIVE: Leveraging longitudinal exposure assessments on alcohol intake at different ages, we examined the relationship between change in alcohol intake and subsequent CRC risk. METHODS: Within the European Prospective Investigation into Cancer and Nutrition, changes in alcohol intake comparing follow-up with baseline assessments were investigated in relation to CRC risk. The analysis included 191,180, participants and 1530 incident CRC cases, with exclusion of the first three years of follow-up to minimize reverse causation. Trajectory profiles of alcohol intake, assessed at ages 20, 30, 40, 50 years, at baseline and during follow-up, were estimated using latent class mixed models and related to CRC risk, including 407,605 participants and 5,008 incident CRC cases. RESULTS: Mean age at baseline was 50.2 years and the follow-up assessment occurred on average 7.1 years later. Compared to stable intake, a 12 g/day increase in alcohol intake during follow-up was positively associated with CRC risk (HR = 1.15, 95%CI 1.04, 1.25), while a 12 g/day reduction was inversely associated with CRC risk (HR = 0.86, 95%CI 0.78, 0.95). Trajectory analysis showed that compared to low alcohol intake, men who increased their alcohol intake from early- to mid- and late-adulthood by up to 30 g/day on average had significantly increased CRC risk (HR = 1.24; 95%CI 1.08, 1.42), while no associations were observed in women. Results were consistent by anatomical subsite. CONCLUSIONS: Increasing alcohol intake during mid-to-late adulthood raised CRC risk, while reduction lowered risk.

Cigarette Smoking and Endometrial Cancer Risk: Observational and Mendelian Randomization Analyses.

BACKGROUND: Current epidemiologic evidence indicates that smoking is associated with a lower endometrial cancer risk. However, it is unknown if this association is causal or confounded. To further elucidate the role of smoking in endometrial cancer risk, we conducted complementary observational and Mendelian randomization (MR) analyses. METHODS: The observational analyses included 286,415 participants enrolled in the European Prospective Investigation into Cancer and Nutrition and 179,271 participants in the UK Biobank, and multivariable Cox proportional hazards models were used. In two-sample MR analyses, genetic variants robustly associated with lifetime amount of smoking (n = 126 variants) and ever having smoked regularly (n = 112 variants) were selected and their association with endometrial cancer risk (12,906 cancer/108,979 controls from the Endometrial Cancer Association Consortium) was examined. RESULTS: In the observational analysis, lifetime amount of smoking and ever having smoked regularly were associated with a lower endometrial cancer risk. In the MR analysis accounting for body mass index, a genetic predisposition to a higher lifetime amount of smoking was not associated with endometrial cancer risk (OR per 1-SD increment: 1.15; 95% confidence interval: 0.91-1.44). Genetic predisposition to ever having smoked regularly was not associated with risk of endometrial cancer. CONCLUSIONS: Smoking was inversely associated with endometrial cancer in the observational analyses, although unsupported by the MR. Additional studies are required to better understand the possible confounders and mechanisms underlying the observed associations between smoking and endometrial cancer. IMPACT: The results from this analysis indicate that smoking is unlikely to be causally linked with endometrial cancer risk.