New connections of medication use and polypharmacy with the gut microbiota composition and functional potential in a large population.

Medication can affect the gut microbiota composition and function. The aim of this study was to investigate connections between use of common non-antibiotic medicines and the gut microbiota composition and function in a large Swedish cohort (N = 2223). Use of 67 medications and polypharmacy (≥ 5 medications), based on self-reported and prescription registry data, were associated with the relative abundance of 881 gut metagenomic species (> 5% prevalence) and 103 gut metabolic modules (GMMs). Altogether, 97 associations of 26 medications with 40 species and of four medications with five GMMs were observed (false discovery rate < 5%). Several earlier findings were replicated like the positive associations of proton pump inhibitors (PPIs) with numerous oral species, and those of metformin with Escherichia species and with lactate consumption I and arginine degradation II. Several new associations were observed between, among others, use of antidepressants, beta-blockers, nonsteroidal anti-inflammatory drugs and calcium channel blockers, and specific species. Polypharmacy was positively associated with Enterococcus faecalis, Bacteroides uniformis, Rothia mucilaginosa, Escherichia coli and Limosilactobacillus vaginalis, and with 13 GMMs. We confirmed several previous findings and identified numerous new associations between use of medications/polypharmacy and the gut microbiota composition and functional potential. Further studies are needed to confirm the new findings.

Food biodiversity and gastrointestinal cancer risk in nine European countries: Analysis within a prospective cohort study.

BACKGROUND: Food biodiversity in human diets has potential co-benefits for both public health and sustainable food systems. However, current evidence on the potential relationship between food biodiversity and cancer risk, and particularly gastrointestinal cancers typically related to diet, remains limited. This study evaluated how dietary species richness (DSR) was associated with gastrointestinal cancer risk in a pan-European population. METHODS: Associations between DSR and subsequent gastrointestinal cancer risk were examined among 450,111 adults enrolled in the European Prospective Investigation into Cancer and Nutrition cohort (EPIC, initiated in 1992), free of cancer at baseline. Usual dietary intakes were assessed at recruitment with country-specific dietary questionnaires. DSR of an individual's yearly diet was calculated based on the absolute number of unique biological species in each food and drink item. Associations between DSR and cancer risk were assessed by multivariable Cox proportional hazards regression models. FINDINGS: During a median follow-up time of 14.1 years (SD=3.9), 10,705 participants were diagnosed with gastrointestinal cancer. Hazard ratios (HRs) and 95 % confidence intervals (CIs) comparing overall gastrointestinal cancer risk in the highest versus lowest quintiles of DSR indicated inverse associations in multivariable-adjusted models [HR (95 % CI): 0.77 (0.69-0.87); P-value < 0·0001] (Table 2). Specifically, inverse associations were observed between DSR and oesophageal squamous cell carcinoma, proximal colon, colorectal, and liver cancer risk (p-trend<0.05 for all cancer types). INTERPRETATION: Greater food biodiversity in the diet may lower the risk of certain gastrointestinal cancers. Further research is needed to replicate these novel findings and to understand potential mechanisms.

Unraveling the metabolomic architecture of autism in a large Danish population-based cohort.

BACKGROUND: The prevalence of autism in Denmark has been increasing, reaching 1.65% among 10-year-old children, and similar trends are seen elsewhere. Although there are several factors associated with autism, including genetic, environmental, and prenatal factors, the molecular etiology of autism is largely unknown. Here, we use untargeted metabolomics to characterize the neonatal metabolome from dried blood spots collected shortly after birth. METHODS: We analyze the metabolomic profiles of a subset of a large Danish population-based cohort (iPSYCH2015) consisting of over 1400 newborns, who later are diagnosed with autism and matching controls and in two Swedish population-based cohorts comprising over 7000 adult participants. Mass spectrometry analysis was performed by a timsTOF Pro operated in QTOF mode, using data-dependent acquisition. By applying an untargeted metabolomics approach, we could reproducibly measure over 800 metabolite features. RESULTS: We detected underlying molecular perturbations across several metabolite classes that precede autism. In particular, the cyclic dipeptide cyclo-leucine-proline (FDR-adjusted p = 0.003) and the carnitine-related 5-aminovaleric acid betaine (5-AVAB) (FDR-adjusted p = 0.03), were associated with an increased probability for autism, independently of known prenatal and genetic risk factors. Analysis of genetic and dietary data in adults revealed that 5-AVAB was associated with increased habitual dietary intake of dairy (FDR-adjusted p < 0.05) and with variants near SLC22A4 and SLC22A5 (p < 5.0e - 8), coding for a transmembrane carnitine transporter protein involved in controlling intracellular carnitine levels. CONCLUSIONS: Cyclo-leucine-proline and 5-AVAB are associated with future diagnosis of autism in Danish neonates, both representing novel early biomarkers for autism. 5-AVAB is potentially modifiable and may influence carnitine homeostasis.

A systematic evaluation of seven different scores representing the EAT-Lancet reference diet and mortality, stroke, and greenhouse gas emissions in three cohorts.

Different approaches have been used for translation of the EAT-Lancet reference diet into dietary scores that can be used to assess health and environmental impact. Our aim was to compare the different EAT-Lancet diet scores, and to estimate their associations with all-cause mortality, stroke incidence, and greenhouse gas emissions. We did a systematic review (PROSPERO, CRD42021286597) to identify different scores representing adherence to the EAT-Lancet reference diet. We then qualitatively compared the diet adherence scores, including their ability to group individuals according the EAT-Lancet reference diet recommendations, and quantitatively assessed the associations of the diet scores with health and environmental outcome data in three diverse cohorts: the Danish Diet, Cancer and Health Cohort (DCH; n=52 452), the Swedish Malmö Diet and Cancer Cohort (MDC; n=20 973), and the Mexican Teachers' Cohort (MTC; n=30 151). The DCH and MTC used food frequency questionnaires and the MDC used a modified diet history method to assess dietary intake, which we used to compute EAT-Lancet diet scores and evaluate the associations of scores with hazard of all-cause mortality and stroke. In the MDC, dietary greenhouse gas emission values were summarised for every participant, which we used to predict greenhouse gas emissions associated with varying diet adherence scores on each scoring system. In our review, seven diet scores were identified (Knuppel et al, 2019; Trijsburg et al, 2020; Cacau et al, 2021; Hanley-Cook et al, 2021; Kesse-Guyot et al, 2021; Stubbendorff et al, 2022; and Colizzi et al, 2023). Two of the seven scores (Stubbendorff and Colizzi) were among the most consistent in grouping participants according to the EAT-Lancet reference diet recommendations across cohorts, and higher scores (greater diet adherence) were associated with decreased risk of mortality (in the DCH and MDC), decreased risk of incident stroke (in the DCH and MDC for the Stubbendorff score; and in the DCH for the Colizzi score), and decreased predicted greenhouse gas emissions in the MDC. We conclude that the seven different scores representing the EAT-Lancet reference diet had differences in construction, interpretation, and relation to disease and climate-related outcomes. Two scores generally performed well in our evaluation. Future studies should carefully consider which diet score to use and preferably use multiple scores to assess the robustness of estimations, given that public health and environmental policy rely on these estimates.

The association between water intake and future cardiometabolic disease outcomes in the Malmö Diet and Cancer cardiovascular cohort.

The aim of this study was to explore the longitudinal association between reported baseline water intake and incidence of coronary artery disease (CAD) and type 2 diabetes in the Malmö Diet and Cancer Cohort (n = 25,369). Using cox proportional hazards models, we separately modelled the effect of plain and total (all water, including from food) water on CAD and type 2 diabetes risk, whilst adjusting for age, sex, diet collection method, season, smoking status, alcohol intake, physical activity, education level, energy intake, energy misreporting, body mass index, hypertension, lipid lowering medication, apolipoprotein A, apolipoprotein B, and dietary variables. Sensitivity analyses were run to assess validity. After adjustment, no association was found between tertiles of plain or total water intake and type 2 diabetes risk. For CAD, no association was found comparing moderate to low intake tertiles from plain or total water, however, risk of CAD increased by 12% (95% CI 1.03, 1.21) when comparing high to low intake tertiles of plain water, and by 17% (95% CI 1.07, 1.27) for high versus low tertiles of total water. Sensitivity analyses were largely in agreement. Overall, baseline water intake was not associated with future type 2 diabetes risk, whilst CAD risk was higher with higher water intakes. Our findings are discordant with prevailing literature suggesting higher water intakes should reduce cardiometabolic risk. These findings may be an artefact of limitations within the study, but future research is needed to understand if there is a causal underpinning.

Clusters of carbohydrate-rich foods and associations with type 2 diabetes incidence: a prospective cohort study.

BACKGROUND: About one in ten adults are living with diabetes worldwide. Intake of carbohydrates and carbohydrate-rich foods are often identified as modifiable risk factors for incident type 2 diabetes. However, strong correlation between food variables can make it difficult to identify true associations. The purpose of this study was to identify clusters of carbohydrate-rich foods and analyse their associations with type 2 diabetes incidence in the Malmö Diet and Cancer Study cohort in southern Sweden. METHODS: Dietary intake of 26 622 participants was assessed using a validated three-part diet history method: a 7-day food diary, a 168-item food frequency questionnaire, and a 60-minute interview. K-means clustering analysis identified five clusters from 21 food variables. The Cox proportional hazard regression model was applied to calculate hazard ratios (HR) and 95% confidence intervals (CI) of the association between clusters and incident type 2 diabetes. RESULTS: The cluster analysis resulted in five clusters; high vegetables/low added sugar, high sugar-sweetened beverages, high juice, high fruit, and high refined carbohydrates/low fruit & vegetables (reference). During mean follow-up of 18 years, 4046 type 2 diabetes cases were identified. After adjustment for potential confounding (including lifestyle, body mass index, and diet), a high fruit cluster (HR 0.86; 95% CI 0.78, 0.94) was inversely associated with type 2 diabetes compared to the reference cluster. No other significant associations were identified. CONCLUSIONS: A dietary pattern defined by a high intake of fruits was associated with a lower incidence of type 2 diabetes. The findings provide additional evidence of a potential protective effect from fruit intake in reducing type 2 diabetes risk. Future studies are needed to explore this association further.

Comparisons of Different Carbohydrate Quality Indices for Risk of Type 2 Diabetes in the Malmö Diet and Cancer Study.

Carbohydrate quality might be more important than quantity to reduce type 2 diabetes (T2D) risk. Various metrics of carbohydrate quality exist; however, their associations with T2D have only been studied to a limited extent. Consequently, the aim was to investigate the association between four different pre-defined carbohydrate quality indices, with various amounts of fiber (≥1 g) and free sugar (<1 or <2 g) per 10 g of carbohydrates, and T2D risk among 26,622 individuals without diabetes from the Malmö Diet and Cancer cohort. Dietary data were collected through a food diary, diet frequency questionnaire, and interview. After a mean follow-up of 18 years, 4046 cases were identified through registers. After adjusting for potential confounders, no statistically significant associations were found for any of the indices. When excluding individuals with past dietary changes and potential misreporting of energy (36% of the population), lower risk was found for the following intake ratios: 10:1:2 carbohydrate:fiber:free sugar (HR = 0.82; 95% CI = 0.70-0.97), and 10:1&1:2 carbohydrate:fiber and fiber:free sugar, respectively (HR = 0.84; 95% CI = 0.72-0.97). Our findings indicate that adherence to a diet with high amounts of fiber and moderate amounts of free sugar in relation to total carbohydrate intake may be associated with a lower risk of T2D.

Adherence to the EAT-Lancet diet and risk of coronary events in the Malmö Diet and Cancer cohort study.

BACKGROUND: The EAT-Lancet Commission proposed a globally environmentally sustainable dietary pattern featuring mainly plant-based foods in 2019. However, evidence on this dietary pattern in preventing coronary events is minimal. OBJECTIVES: We aimed to examine the association between the EAT-Lancet diet and risk of coronary events. METHODS: The Malmö Diet and Cancer cohort study (recruited between 1991 and 1996) included 23,877 participants aged 44.5-73.6 y (62.5% women) without CVDs and diabetes at baseline. A modified diet history was used to collect the dietary data. An EAT-Lancet diet index (range, 0-42 points) was applied on the basis of 14 food components scored 0 (nonadherence) to 3 (adherence). Coronary events were extracted from the registers. Cox proportional hazards models were used to estimate the HRs and 95% confidential intervals (CIs). RESULTS: Over a median of 24.9 y of follow-up, 3031 coronary events occurred (incidence rate: 5.89/1000 person-years). After adjusting for age, sex, dietary assessment methods, season, total energy intake, leisure-time physical activity, alcohol consumption, smoking status, educational level, and BMI, the multivariable HR (95% CI) for coronary events among participants who had the highest adherence to the EAT-Lancet diet index (≥23 points, 8.1%) was 0.80 (0.67, 0.96) compared with those who had the lowest adherence (≤13 points, 9.7%) (P-trend = 0.01 across 5 groups of the EAT-Lancet diet). The inverse association was consistent in men and women and was robust after excluding those with misreported energy and significant diet changes or excluding coronary events occurred within the first 2 y of follow-up. CONCLUSIONS: Our data indicate that adherence to the EAT-Lancet diet was associated with a lower risk of coronary events.

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.

Adherence to the EAT-Lancet diet, genetic susceptibility, and risk of type 2 diabetes in Swedish adults.

BACKGROUND AND AIMS: In 2019, the EAT-Lancet Commission proposed a mainly plant-based diet that nurtures human health and supports environmental sustainability. However, its association with type 2 diabetes (T2D) has not been widely studied, and it remains unclear whether genetic susceptibility for T2D can modify this association. The aim was therefore to investigate the association between the EAT-Lancet diet and risk of T2D and assess whether the association differs by the genetic predisposition to T2D. METHODS: A total of 24,494 participants from the Malmö Diet and Cancer study were analyzed. Dietary intake was assessed using a modified diet history methodology, and an EAT-Lancet diet index (range from 0 to 42 points) was constructed based on the EAT-Lancet reference diet. National and local registers were used to identify T2D cases during follow-up. Cox proportional hazards regression model was applied to estimate the association between the EAT-Lancet diet index and risk of T2D. Genetic predisposition to T2D was captured based on 116 single nucleotide polymorphisms. RESULTS: During a median of 24.3 years of follow-up, 4197 (17.1 %) T2D cases were documented. Compared with those with the lowest adherence to the EAT-Lancet diet (≤13 points), participants who had the highest adherence (≥23 points) showed an 18 % (95 % CI: 4 %-30 %) lower risk of T2D (P for trend <0.01). There was no significant multiplicative interaction between genetic predisposition to T2D and the EAT-Lancet diet index (P = 0.59). Also, no significant additive interaction between the genetic risk and the EAT-Lancet diet was seen (P = 0.44). The highest risk was observed among the 22.9 % of the individuals with high genetic risk and low EAT-Lancet diet score (HR = 1.79; 95 % CI: 1.63, 1.96). CONCLUSIONS: Our findings indicate that high adherence to the EAT-Lancet diet was associated with decreased risk of incident T2D among people with different genetic risks.

Mycotoxin Exposure and Renal Cell Carcinoma Risk: An Association Study in the EPIC European Cohort.

BACKGROUND: Mycotoxins have been suggested to contribute to a spectrum of adverse health effects in humans, including at low concentrations. The recognition of these food contaminants being carcinogenic, as co-occurring rather than as singularly present, has emerged from recent research. The aim of this study was to assess the potential associations of single and multiple mycotoxin exposures with renal cell carcinoma risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. METHODS: Food questionnaire data from the EPIC cohort were matched to mycotoxin food occurrence data compiled by the European Food Safety Authority (EFSA) from European Member States to assess long-term dietary mycotoxin exposures, and to associate these with the risk of renal cell carcinoma (RCC, n = 911 cases) in 450,112 EPIC participants. Potential confounding factors were taken into account. Analyses were conducted using Cox's proportional hazards regression models to compute hazard ratios (HRs) and 95% confidence intervals (95% CIs) with mycotoxin exposures expressed as µg/kg body weight/day. RESULTS: Demographic characteristics differed between the RCC cases and non-cases for body mass index, age, alcohol intake at recruitment, and other dietary factors. In addition, the mycotoxin exposure distributions showed that a large proportion of the EPIC population was exposed to some of the main mycotoxins present in European foods such as deoxynivalenol (DON) and derivatives, fumonisins, Fusarium toxins, Alternaria toxins, and total mycotoxins. Nevertheless, no statistically significant associations were observed between the studied mycotoxins and mycotoxin groups, and the risk of RCC development. CONCLUSIONS: These results show an absence of statistically significant associations between long-term dietary mycotoxin exposures and RCC risk. However, these results need to be validated in other cohorts and preferably using repeated dietary exposure measurements. In addition, more occurrence data of, e.g., citrinin and fumonisins in different food commodities and countries in the EFSA database are a prerequisite to establish a greater degree of certainty.

A healthy dietary metabolic signature is associated with a lower risk for type 2 diabetes and coronary artery disease.

BACKGROUND: The global burden of cardiovascular disease and type 2 diabetes could be decreased by improving dietary factors, but identification of groups suitable for interventional approaches can be difficult. Reporting of dietary intake is prone to errors, and measuring of metabolites has shown promise in determining habitual dietary intake. Our aim is to create a metabolic signature that is associated with healthy eating and test if it associates with type 2 diabetes and coronary artery disease risk. METHODS: Using plasma metabolite data consisting of 111 metabolites, partial least square (PLS) regression was used to identify a metabolic signature associated with a health conscious food pattern in the Malmö Offspring Study (MOS, n = 1538). The metabolic signature's association with dietary intake was validated in the Malmö Diet and Cancer study (MDC, n = 2521). The associations between the diet-associated metabolic signature and incident type 2 diabetes and coronary artery disease (CAD) were tested using Cox regression in MDC and logistic regression in Malmö Preventive Project (MPP, n = 1083). Modelling was conducted unadjusted (model 1), adjusted for potential confounders (model 2) and additionally for potential mediators (model 3). RESULTS: The metabolic signature was associated with lower risk for type 2 diabetes in both MDC (hazard ratio: 0.58, 95% CI 0.52-0.66, per 1 SD increment of the metabolic signature) and MPP (odds ratio: 0.54, 95% CI 0.44-0.65 per 1 SD increment of the metabolic signature) in model 2. The results were attenuated but remained significant in model 3 in both MDC (hazard ratio 0.73, 95% CI 0.63-0.83) and MPP (odds ratio 0.70, 95% CI 0.55-0.88). The diet-associated metabolic signature was also inversely associated with lower risk of CAD in both MDC and MPP in model 1, but the association was non-significant in model 3. CONCLUSIONS: In this proof-of-concept study, we identified a healthy diet-associated metabolic signature, which was inversely associated with future risk for type 2 diabetes and coronary artery disease in two different cohorts. The association with diabetes was independent of traditional risk factors and might illustrate an effect of health conscious dietary intake on cardiometabolic health.

Development of an EAT-Lancet index and its relation to mortality in a Swedish population.

BACKGROUND: Current global food systems threaten human health and environmental sustainability. In 2019, the EAT-Lancet Commission on healthy diets from sustainable food systems defined the first global reference diet to improve both areas, but there is no consensus on how to quantify the EAT-Lancet reference diet as a diet index, and its relation to mortality has not been widely studied. OBJECTIVES: We sought to develop a new dietary index to quantify adherence to the EAT-Lancet diet and assess its association with mortality in a large, population-based Swedish cohort. We also examined food components included in the index and their individual associations with mortality. METHODS: We used the Malmö Diet and Cancer cohort (n = 22,421; 45-73 years old at baseline). Dietary data were collected using a modified diet history method. The EAT-Lancet index was developed based on intake levels and reference intervals of 14 food components defined in the EAT-Lancet diet (0-3 points per component; 0-42 points in total). Associations with mortality were examined based on registers during a mean of 20 years of follow-up and were adjusted for potential confounders. RESULTS: Divided into 5 adherence groups, the highest adherence to the EAT-Lancet diet (≥23 points) was associated with lower all-cause mortality (HR, 0.75; 95% CI, 0.67-0.85), cancer mortality (HR, 0.76; 95% CI, 0.63-0.92), and cardiovascular mortality (HR, 0.68; 95% CI, 0.54-0.84) than the lowest adherence (≤13 points). Several food components included in the index contributed to the observed reductions in mortality. CONCLUSIONS: We developed a new dietary index to investigate adherence to the EAT-Lancet diet. The findings indicate a 25% lower risk of mortality among those with the highest adherence to the EAT-Lancet diet, as defined using our index, which adds to the evidence base for the development of sustainable dietary guidelines.

Evaluation of protein and amino acid intake estimates from the EPIC dietary questionnaires and 24-h dietary recalls using different food composition databases.

BACKGROUND AND AIMS: This study aimed to expand the European Prospective Investigation into Cancer and Nutrition (EPIC) nutrient database (ENDB) by adding amino acid (AA) values, using the U.S. nutrient database (USNDB). Additionally, we aimed to evaluate these new protein and AA intake estimates from the EPIC dietary questionnaires (DQ) and 24-h dietary recalls (24-HDR) using different matching procedures. METHODS AND RESULTS: Dietary energy, protein and AA intakes were assessed via DQ and 24-HDR by matching with the USNDB food composition table. Energy and protein intakes calculated using USNDB matching were compared with those calculated using ENDB, that uses country specific food composition tables. Pearson correlations, Cohen's weighted kappa statistic and Bland-Altman plots were used to compare data resulting from USNDB matching with our reference from ENDB matching. Very high correlations were found when comparing daily energy (r = 0.99) and dietary protein intakes (r = 0.97) assessed via USNDB with those obtained via ENDB (matching for DQ and 24-HDR). Significant positive correlations were also found with energy and protein intakes acquired via 24-HDRs in the EPIC calibration sample. CONCLUSION: Very high correlations between total energy and protein intake obtained via the USDA matching and those available in ENDB suggest accuracy in the food matching. Individual AA have been included in the extended EPIC Nutrient database that will allow important analyses on AA disease prospective associations in the EPIC study.

A Prospective Diet-Wide Association Study for Risk of Colorectal Cancer in EPIC.

BACKGROUND & AIMS: Evidence regarding the association of dietary exposures with colorectal cancer (CRC) risk is not consistent with a few exceptions. Therefore, we conducted a diet-wide association study (DWAS) in the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate the associations between several dietary exposures with CRC risk. METHODS: The association of 92 food and nutrient intakes with CRC risk was assessed in 386,792 participants, 5069 of whom developed incident CRC. Correction for multiple comparisons was performed using the false discovery rate, and emerging associations were examined in the Netherlands Cohort Study (NLCS). Multiplicative gene-nutrient interactions were also tested in EPIC based on known CRC-associated loci. RESULTS: In EPIC, alcohol, liquor/spirits, wine, beer/cider, soft drinks, and pork were positively associated with CRC, whereas milk, cheese, calcium, phosphorus, magnesium, potassium, riboflavin, vitamin B6, beta carotene, fruit, fiber, nonwhite bread, banana, and total protein intakes were inversely associated. Of these 20 associations, 13 were replicated in the NLCS, for which a meta-analysis was performed, namely alcohol (summary hazard ratio [HR] per 1-SD increment in intake: 1.07; 95% confidence interval [CI], 1.04-1.09), liquor/spirits (HR per 1-SD increment in intake, 1.04; 95% CI, 1.02-1.06), wine (HR per 1-SD increment in intake, 1.04; 95% CI, 1.02-1.07), beer/cider (HR per 1-SD increment in intake, 1.06; 95% CI, 1.04-1.08), milk (HR per 1-SD increment in intake, 0.95; 95% CI, 0.93-0.98), cheese (HR per 1-SD increment in intake, 0.96; 95% CI, 0.94-0.99), calcium (HR per 1-SD increment in intake, 0.93; 95% CI, 0.90-0.95), phosphorus (HR per 1-SD increment in intake, 0.92; 95% CI, 0.90-0.95), magnesium (HR per 1-SD increment in intake, 0.95; 95% CI, 0.92-0.98), potassium (HR per 1-SD increment in intake, 0.96; 95% CI, 0.94-0.99), riboflavin (HR per 1-SD increment in intake, 0.94; 95% CI, 0.92-0.97), beta carotene (HR per 1-SD increment in intake, 0.96; 95% CI, 0.93-0.98), and total protein (HR per 1-SD increment in intake, 0.94; 95% CI, 0.92-0.97). None of the gene-nutrient interactions were significant after adjustment for multiple comparisons. CONCLUSIONS: Our findings confirm a positive association for alcohol and an inverse association for dairy products and calcium with CRC risk, and also suggest a lower risk at higher dietary intakes of phosphorus, magnesium, potassium, riboflavin, beta carotene, and total protein.

Dairy Consumption, Lactase Persistence, and Mortality Risk in a Cohort From Southern Sweden.

Background: Whether high dairy consumption is related to longevity is still unclear, and additional studies of prospective cohorts with high-quality dietary data from populations with wide consumption ranges are needed. Objective: To examine the association between dairy consumption and mortality in a Swedish cohort. Design: Among 26,190 participants (62% females, 45-73 years old) without diabetes and cardiovascular disease from the population-based Malmö Diet and Cancer cohort, 7,156 individuals died during a mean follow-up time of 19 years. Data on intake of dairy (non-fermented milk, fermented milk, cheese, cream and butter) were collected from 7 day food records and food questionnaires. A genetic marker (rs4988235) associated with lactase persistence was detected among 22,234 individuals born in Sweden. Results: Higher intakes up to 1,000 g/day of non-fermented milk were associated with only marginal higher mortality rates after adjusting for potential confounders. However, intakes above 1,000 g/day (1.5% of the population) were associated with 34% (95% CI: 14, 59%, p-trend=0.002) higher mortality compared to that with < 200 g/day. Fermented milk and cheese intake were inversely associated with mortality. Cream showed a protective association only among men. Butter was not associated with mortality. CT/TT genotype carriers (i.e., individuals with lactase persistence) had a 27% higher reported consumption of non-fermented milk, and non-significant higher mortality risk (HR = 1.08; 95% CI = 0.96, 1.23; p = 0.20) than CC genotype carriers. Conclusions: Higher mortality rates were mainly observed among participants consuming more than 1,000 g of non-fermented milk per day. In contrast, fermented milk and cheese were associated with lower mortality. Because dairy products differ in composition, it is important to examine them separately in their relation to health and disease. The use of a genetic variant as an objective marker of lactose-containing milk intake should be examined in relation to mortality in a larger population.

Dietary Fatty Acids, Macronutrient Substitutions, Food Sources and Incidence of Coronary Heart Disease: Findings From the EPIC-CVD Case-Cohort Study Across Nine European Countries.

Background There is controversy about associations between total dietary fatty acids, their classes (saturated fatty acids [SFAs], monounsaturated fatty acids, and polyunsaturated fatty acids), and risk of coronary heart disease (CHD). Specifically, the relevance of food sources of SFAs to CHD associations is uncertain. Methods and Results We conducted a case-cohort study involving 10 529 incident CHD cases and a random subcohort of 16 730 adults selected from a cohort of 385 747 participants in 9 countries of the EPIC (European Prospective Investigation into Cancer and Nutrition) study. We estimated multivariable adjusted country-specific hazard ratios (HRs) and 95% CIs per 5% of energy intake from dietary fatty acids, with and without isocaloric macronutrient substitutions, using Prentice-weighted Cox regression models and pooled results using random-effects meta-analysis. We found no evidence for associations of the consumption of total or fatty acid classes with CHD, regardless of macronutrient substitutions. In analyses considering food sources, CHD incidence was lower per 1% higher energy intake of SFAs from yogurt (HR, 0.93 [95% CI, 0.88-0.99]), cheese (HR, 0.98 [95% CI, 0.96-1.00]), and fish (HR, 0.87 [95% CI, 0.75-1.00]), but higher for SFAs from red meat (HR, 1.07 [95% CI, 1.02-1.12]) and butter (HR, 1.02 [95% CI, 1.00-1.04]). Conclusions This observational study found no strong associations of total fatty acids, SFAs, monounsaturated fatty acids, and polyunsaturated fatty acids, with incident CHD. By contrast, we found associations of SFAs with CHD in opposite directions dependent on the food source. These findings should be further confirmed, but support public health recommendations to consider food sources alongside the macronutrients they contain, and suggest the importance of the overall food matrix.

Co-benefits from sustainable dietary shifts for population and environmental health: an assessment from a large European cohort study.

BACKGROUND: Unhealthy diets, the rise of non-communicable diseases, and the declining health of the planet are highly intertwined, where food production and consumption are major drivers of increases in greenhouse gas emissions, substantial land use, and adverse health such as cancer and mortality. To assess the potential co-benefits from shifting to more sustainable diets, we aimed to investigate the associations of dietary greenhouse gas emissions and land use with all-cause and cause-specific mortality and cancer incidence rates. METHODS: Using data from 443 991 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, a multicentre prospective cohort, we estimated associations between dietary contributions to greenhouse gas emissions and land use and all-cause and cause-specific mortality and incident cancers using Cox proportional hazards regression models. The main exposures were modelled as quartiles. Co-benefits, encompassing the potential effects of alternative diets on all-cause mortality and cancer and potential reductions in greenhouse gas emissions and land use, were estimated with counterfactual attributable fraction intervention models, simulating potential effects of dietary shifts based on the EAT-Lancet reference diet. FINDINGS: In the pooled analysis, there was an association between levels of dietary greenhouse gas emissions and all-cause mortality (adjusted hazard ratio [HR] 1·13 [95% CI 1·10-1·16]) and between land use and all-cause mortality (1·18 [1·15-1·21]) when comparing the fourth quartile to the first quartile. Similar associations were observed for cause-specific mortality. Associations were also observed between all-cause cancer incidence rates and greenhouse gas emissions, when comparing the fourth quartile to the first quartile (adjusted HR 1·11 [95% CI 1·09-1·14]) and between all-cause cancer incidence rates and land use (1·13 [1·10-1·15]); however, estimates differed by cancer type. Through counterfactual attributable fraction modelling of shifts in levels of adherence to the EAT-Lancet diet, we estimated that up to 19-63% of deaths and up to 10-39% of cancers could be prevented, in a 20-year risk period, by different levels of adherence to the EAT-Lancet reference diet. Additionally, switching from lower adherence to the EAT-Lancet reference diet to higher adherence could potentially reduce food-associated greenhouse gas emissions up to 50% and land use up to 62%. INTERPRETATION: Our results indicate that shifts towards universally sustainable diets could lead to co-benefits, such as minimising diet-related greenhouse gas emissions and land use, reducing the environmental footprint, aiding in climate change mitigation, and improving population health. FUNDING: European Commission (DG-SANCO), the International Agency for Research on Cancer (IARC), MRC Early Career Fellowship (MR/M501669/1).

Dietary Methyl-Group Donor Intake and Breast Cancer Risk in the European Prospective Investigation into Cancer and Nutrition (EPIC).

(1) Background: Methyl-group donors (MGDs), including folate, choline, betaine, and methionine, may influence breast cancer (BC) risk through their role in one-carbon metabolism; (2) Methods: We studied the relationship between dietary intakes of MGDs and BC risk, adopting data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort; (3) Results: 318,686 pre- and postmenopausal women were followed between enrolment in 1992-2000 and December 2013-December 2015. Dietary MGD intakes were estimated at baseline through food-frequency questionnaires. Multivariable Cox proportional hazards regression models were used to quantify the association between dietary intake of MGDs, measured both as a calculated score based on their sum and individually, and BC risk. Subgroup analyses were performed by hormone receptor status, menopausal status, and level of alcohol intake. During a mean follow-up time of 14.1 years, 13,320 women with malignant BC were identified. No associations were found between dietary intakes of the MGD score or individual MGDs and BC risk. However, a potential U-shaped relationship was observed between dietary folate intake and overall BC risk, suggesting an inverse association for intakes up to 350 µg/day compared to a reference intake of 205 µg/day. No statistically significant differences in the associations were observed by hormone receptor status, menopausal status, or level of alcohol intake; (4) Conclusions: There was no strong evidence for an association between MGDs involved in one-carbon metabolism and BC risk. However, a potential U-shaped trend was suggested for dietary folate intake and BC risk. Further research is needed to clarify this association.