The EAT-Lancet Diet Index, Plasma Proteins, and Risk of Heart Failure in a Population-Based Cohort.

BACKGROUND: The landmark EAT-Lancet Commission proposed that a planetary health diet is comprised mainly of plant-based foods. However, studies examining whether this diet is associated with heart failure (HF) are currently lacking. In addition, the potential proteomics mechanism on the association between diet and HF warrants further elucidation. OBJECTIVES: This study aims to both examine the association between the EAT-Lancet diet index and risk of HF and identify plasma proteins underlying such an association. METHODS: This prospective cohort study included 23,260 participants. HF cases during the follow-up were identified through the Swedish national register. An EAT-Lancet diet index (score range: 0-42) was created to assess adherence to the EAT-Lancet reference diet. In a subcohort (n = 4,742), fasting plasma proteins were quantified. RESULTS: During a median follow-up of 25.0 years, 1,768 incident HF cases were documented. After adjusting for sociodemographic, lifestyle, diabetes, hypertension, use of lipid-lowering drugs, and body mass index, the HR per 3-point increase of the EAT-Lancet diet index was 0.93 (95% CI: 0.88-0.97). This association was robust in several sensitivity analyses. Among the included 136 plasma proteins, a total of 8 proteins (AM, GDF15, IL6, TIM, CTSD, CCL20, FS, and FUR) were both inversely associated with the EAT-Lancet diet index and positively associated with risk of HF; the overall proteomic score mediated 9.4% (95% CI: 2.2%-32.1%) of the association. CONCLUSIONS: Higher adherence to the EAT-Lancet diet was associated with a lower risk of HF. The identified eight plasma proteins provide information on potential pathways mediating such an association.

Accelerometer-based physical activity is associated with the gut microbiota in 8416 individuals in SCAPIS.

BACKGROUND: Previous population-based studies investigating the relationship between physical activity and the gut microbiota have relied on self-reported activity, prone to reporting bias. Here, we investigated the associations of accelerometer-based sedentary (SED), moderate-intensity (MPA), and vigorous-intensity (VPA) physical activity with the gut microbiota using cross-sectional data from the Swedish CArdioPulmonary bioImage Study. METHODS: In 8416 participants aged 50-65, time in SED, MPA, and VPA were estimated with hip-worn accelerometer. Gut microbiota was profiled using shotgun metagenomics of faecal samples. We applied multivariable regression models, adjusting for sociodemographic, lifestyle, and technical covariates, and accounted for multiple testing. FINDINGS: Overall, associations between time in SED and microbiota species abundance were in opposite direction to those for MPA or VPA. For example, MPA was associated with lower, while SED with higher abundance of Escherichia coli. MPA and VPA were associated with higher abundance of the butyrate-producers Faecalibacterium prausnitzii and Roseburia spp. We observed discrepancies between specific VPA and MPA associations, such as a positive association between MPA and Prevotella copri, while no association was detected for VPA. Additionally, SED, MPA and VPA were associated with the functional potential of the microbiome. For instance, MPA was associated with higher capacity for acetate synthesis and SED with lower carbohydrate degradation capacity. INTERPRETATION: Our findings suggest that sedentary and physical activity are associated with a similar set of gut microbiota species but in opposite directions. Furthermore, the intensity of physical activity may have specific effects on certain gut microbiota species. FUNDING: European Research Council, Swedish Heart-Lung Foundation, Swedish Research Council, Knut and Alice Wallenberg Foundation.

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.

Streptococcus Species Abundance in the Gut Is Linked to Subclinical Coronary Atherosclerosis in 8973 Participants From the SCAPIS Cohort.

BACKGROUND: Gut microbiota have been implicated in atherosclerotic disease, but their relation with subclinical coronary atherosclerosis is unclear. This study aimed to identify associations between the gut microbiome and computed tomography-based measures of coronary atherosclerosis and to explore relevant clinical correlates. METHODS: We conducted a cross-sectional study of 8973 participants (50 to 65 years of age) without overt atherosclerotic disease from the population-based SCAPIS (Swedish Cardiopulmonary Bioimage Study). Coronary atherosclerosis was measured using coronary artery calcium score and coronary computed tomography angiography. Gut microbiota species abundance and functional potential were assessed with shotgun metagenomics sequencing of fecal samples, and associations with coronary atherosclerosis were evaluated with multivariable regression models adjusted for cardiovascular risk factors. Associated species were evaluated for association with inflammatory markers, metabolites, and corresponding species in saliva. RESULTS: The mean age of the study sample was 57.4 years, and 53.7% were female. Coronary artery calcification was detected in 40.3%, and 5.4% had at least 1 stenosis with >50% occlusion. Sixty-four species were associated with coronary artery calcium score independent of cardiovascular risk factors, with the strongest associations observed for Streptococcus anginosus and Streptococcus oralis subsp oralis (P<1×10-5). Associations were largely similar across coronary computed tomography angiography-based measurements. Out of the 64 species, 19 species, including streptococci and other species commonly found in the oral cavity, were associated with high-sensitivity C-reactive protein plasma concentrations, and 16 with neutrophil counts. Gut microbial species that are commonly found in the oral cavity were negatively associated with plasma indole propionate and positively associated with plasma secondary bile acids and imidazole propionate. Five species, including 3 streptococci, correlated with the same species in saliva and were associated with worse dental health in the Malmö Offspring Dental Study. Microbial functional potential of dissimilatory nitrate reduction, anaerobic fatty acid ß-oxidation, and amino acid degradation were associated with coronary artery calcium score. CONCLUSIONS: This study provides evidence of an association of a gut microbiota composition characterized by increased abundance of Streptococcus spp and other species commonly found in the oral cavity with coronary atherosclerosis and systemic inflammation markers. Further longitudinal and experimental studies are warranted to explore the potential implications of a bacterial component in atherogenesis.

The EAT-Lancet diet, genetic susceptibility and risk of atrial fibrillation in a population-based cohort.

BACKGROUND: The EAT-Lancet Commission proposed a global reference diet with both human health benefits and environmental sustainability in 2019. However, evidence regarding the association of such a diet with the risk of atrial fibrillation (AF) is lacking. In addition, whether the genetic risk of AF can modify the effect of diet on AF remains unclear. This study aimed to assess the association of the EAT-Lancet diet with the risk of incident AF and examine the interaction between the EAT-Lancet diet and genetic susceptibility of AF. METHODS: This prospective study included 24,713 Swedish adults who were free of AF, coronary events, and stroke at baseline. Dietary habits were estimated with a modified diet history method, and an EAT-Lancet diet index was constructed to measure the EAT-Lancet reference diet. A weighted genetic risk score was constructed using 134 variants associated with AF. Cox proportional hazards regression models were applied to estimate the hazard ratio (HR) and 95% confidence interval (CI). RESULTS: During a median follow-up of 22.9 years, 4617 (18.7%) participants were diagnosed with AF. The multivariable HR (95% CI) of AF for the highest versus the lowest group for the EAT-Lancet diet index was 0.84 (0.73, 0.98) (P for trend < 0.01). The HR (95% CI) of AF per one SD increment of the EAT-Lancet diet index for high genetic risk was 0.92 (0.87, 0.98) (P for interaction = 0.15). CONCLUSIONS: Greater adherence to the EAT-Lancet diet index was significantly associated with a lower risk of incident AF. Such association tended to be stronger in participants with higher genetic risk, though gene-diet interaction was not significant.

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 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.

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.

Metabolome-Defined Obesity and the Risk of Future Type 2 Diabetes and Mortality.

OBJECTIVE: Obesity is a key risk factor for type 2 diabetes; however, up to 20% of patients are normal weight. Our aim was to identify metabolite patterns reproducibly predictive of BMI and subsequently to test whether lean individuals who carry an obese metabolome are at hidden high risk of obesity-related diseases, such as type 2 diabetes. RESEARCH DESIGN AND METHODS: Levels of 108 metabolites were measured in plasma samples of 7,663 individuals from two Swedish and one Italian population-based cohort. Ridge regression was used to predict BMI using the metabolites. Individuals with a predicted BMI either >5 kg/m2 higher (overestimated) or lower (underestimated) than their actual BMI were characterized as outliers and further investigated for obesity-related risk factors and future risk of type 2 diabetes and mortality. RESULTS: The metabolome could predict BMI in all cohorts (r2 = 0.48, 0.26, and 0.19). The overestimated group had a BMI similar to individuals correctly predicted as normal weight, had a similar waist circumference, were not more likely to change weight over time, but had a two times higher risk of future type 2 diabetes and an 80% increased risk of all-cause mortality. These associations remained after adjustments for obesity-related risk factors and lifestyle parameters. CONCLUSIONS: We found that lean individuals with an obesity-related metabolome have an increased risk for type 2 diabetes and all-cause mortality compared with lean individuals with a healthy metabolome. Metabolomics may be used to identify hidden high-risk individuals to initiate lifestyle and pharmacological interventions.

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.

Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol.

OBJECTIVE: LDL cholesterol (LDLc)-lowering drugs modestly increase body weight and type 2 diabetes risk, but the extent to which the diabetogenic effect of lowering LDLc is mediated through increased BMI is unknown. RESEARCH DESIGN AND METHODS: We conducted summary-level univariable and multivariable Mendelian randomization (MR) analyses in 921,908 participants to investigate the effect of lowering LDLc on type 2 diabetes risk and the proportion of this effect mediated through BMI. We used data from 92,532 participants from 14 observational studies to replicate findings in individual-level MR analyses. RESULTS: A 1-SD decrease in genetically predicted LDLc was associated with increased type 2 diabetes odds (odds ratio [OR] 1.12 [95% CI 1.01, 1.24]) and BMI (ß = 0.07 SD units [95% CI 0.02, 0.12]) in univariable MR analyses. The multivariable MR analysis showed evidence of an indirect effect of lowering LDLc on type 2 diabetes through BMI (OR 1.04 [95% CI 1.01, 1.08]) with a proportion mediated of 38% of the total effect (P = 0.03). Total and indirect effect estimates were similar across a number of sensitivity analyses. Individual-level MR analyses confirmed the indirect effect of lowering LDLc on type 2 diabetes through BMI with an estimated proportion mediated of 8% (P = 0.04). CONCLUSIONS: These findings suggest that the diabetogenic effect attributed to lowering LDLc is partially mediated through increased BMI. Our results could help advance understanding of adipose tissue and lipids in type 2 diabetes pathophysiology and inform strategies to reduce diabetes risk among individuals taking LDLc-lowering medications.

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.

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.