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Background: Thyroid hormones play a key role in differentiation and metabolism and are known regulators of gene expression through both genomic and epigenetic processes including DNA methylation. The aim of this study was to examine associations between thyroid hormones and DNA methylation. Methods: We carried out a fixed-effect meta-analysis of epigenome-wide association study (EWAS) of blood DNA methylation sites from 8 cohorts from the ThyroidOmics Consortium, incorporating up to 7073 participants of both European and African ancestry, implementing a discovery and replication stage. Statistical analyses were conducted using normalized beta CpG values as dependent and log-transformed thyrotropin (TSH), free thyroxine, and free triiodothyronine levels, respectively, as independent variable in a linear model. The replicated findings were correlated with gene expression levels in whole blood and tested for causal influence of TSH and free thyroxine by two-sample Mendelian randomization (MR). Results: Epigenome-wide significant associations (p-value

Purpose Higher folate and vitamin-B12 have been linked to lower risk of overweight. However, whether this is a causal effect of these B-vitamins on obesity risk remains unclear and evidence in older individuals is scarce. This study aimed to assess the role of B-vitamin supplementation and levels on body composition in older individuals. Methods A double-blind, randomized controlled trial in 2919 participants aged ≥ 65 years with elevated homocysteine levels. The intervention comprised a 2-year supplementation with a combination of folic acid (400 µg) and vitamin B12 (500 µg), or with placebo. Serum folate, vitamin-B12, active vitamin-B12 (HoloTC), methylmalonic acid (MMA), and anthropometrics were measured at baseline and after 2 years of follow-up. Dietary intake of folate and vitamin-B12 was measured at baseline in a subsample (n = 603) using a validated food-frequency questionnaire. Fat mass index (FMI) and fat-free mass index (FFMI) were assessed with Dual Energy X-ray absorptiometry (DXA). Results Cross-sectional analyses showed that a 1 nmol/L higher serum folate was associated with a 0.021 kg/m2 lower BMI (95% CI − 0.039; − 0.004). Higher HoloTC (per pmol/L log-transformed) was associated with a 0.955 kg/m2 higher FMI (95% CI 0.262; 1.647), and higher MMA (per μgmol/L) was associated with a 1.108 kg/m2 lower FMI (95% CI − 1.899; − 0.316). However, random allocation of B-vitamins did not have a significant effect on changes in BMI, FMI or FFMI during 2 years of intervention. Conclusions Although observational data suggested that folate and vitamin B12 status are associated with body composition, random allocation of a supplement with both B-vitamins combined versus placebo did not confirm an effect on BMI or body composition. Electronic supplementary material The online version of this article (10.1007/s00394-019-01985-8) contains supplementary material, which is available to authorized users.

Sex is a major determinant of cardiometabolic risk. DNA methylation (DNAm), an important epigenetic mechanism that differs between sexes, has been associated with cardiometabolic diseases. Therefore, we aimed to systematically review studies in adults investigating sex-specific associations of DNAm with intermediate cardiometabolic traits and incident cardiovascular disease including stroke, myocardial infarction (MI) and coronary heart disease (CHD). Five bibliographic databases were searched from inception to 15 July 2019. We selected 35 articles (based on 30 unique studies) from 17,023 references identified, with a total of 14,020 participants of European, North American or Asian ancestry. Four studies reported sex differences between global DNAm and blood lipid levels and stroke risk. In 25 studies that took a genome wide or candidate gene approach, DNAm at 31 gene sites was associated with sex differences in cardiometabolic diseases. The identified genes were PLA2G7, BCL11A, KDM6A, LIPC, ABCG1, PLTP, CETP, ADD1, CNN1B, HOOK2, GFBP-7,PTPN1, GCK, PTX3, ABCG1, GALNT2, CDKN2B, APOE, CTH, GNASAS, INS, PON1, TCN2, CBS, AMT, KDMA6A, FTO, MAP3K13, CCDC8, MMP-2 and ER-α. Prioritized pathway connectivity analysis associated these genes with biological pathways such as vitamin B12 metabolism, statin pathway, plasma lipoprotein, plasma lipoprotein assembly, remodeling and clearance and cholesterol metabolism. Our findings suggest that DNAm might be a promising molecular strategy for understanding sex differences in the pathophysiology of cardiometabolic diseases and that future studies should investigate the effects of sex on epigenetic mechanisms in cardiometabolic risk. In addition, we emphasize the gap between the translational potential and the clinical utilization of cardiometabolic epigenetics.

Supplemental Digital Content is available in the text., Background: ChREBP (carbohydrate responsive element binding protein) is a transcription factor that responds to sugar consumption. Sugar-sweetened beverage (SSB) consumption and genetic variants in the CHREBP locus have separately been linked to HDL-C (high-density lipoprotein cholesterol) and triglyceride concentrations. We hypothesized that SSB consumption would modify the association between genetic variants in the CHREBP locus and dyslipidemia. Methods: Data from 11 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (N=63 599) and the UK Biobank (N=59 220) were used to quantify associations of SSB consumption, genetic variants, and their interaction on HDL-C and triglyceride concentrations using linear regression models. A total of 1606 single nucleotide polymorphisms within or near CHREBP were considered. SSB consumption was estimated from validated questionnaires, and participants were grouped by their estimated intake. Results: In a meta-analysis, rs71556729 was significantly associated with higher HDL-C concentrations only among the highest SSB consumers (β, 2.12 [95% CI, 1.16–3.07] mg/dL per allele; P

Summary Background & aims Protein intake in infancy promotes growth, but excessive intake may lead to adiposity in children. However, whether this increased adiposity persists throughout childhood and is independent of diet in later life remains unclear. Therefore, we studied the associations of total protein intake and protein from different sources at age 1 year with repeatedly measured growth and body composition up to age 10 years. Additionally, we examined whether these associations are independent of protein intake and overall diet quality at age 8 years. Methods We included 3573 children from the Generation R study, a population-based prospective cohort in the Netherlands. Dietary intakes were assessed with food-frequency questionnaires at ages 1 and 8 years and macronutrient intakes were expressed as energy percentages (E%). Height and weight were measured at eight time points between ages 1 and 10 years. Fat and fat-free masses were measured at ages 6 and 10 years with dual-energy X-ray-absorptiometry. We calculated body mass index (BMI), fat mass index (FMI) and fat-free mass index (FFMI). Outcomes were standardized for sex and age and expressed as standard deviation scores (SDS). Associations of protein intake with growth and body composition trajectories were examined with multivariable linear mixed models. Results After adjustment for confounders, 5E% additional protein intake at age 1 year was associated with a 0.10 SDS higher weight (95% CI 0.04, 0.16), 0.10 SDS higher BMI (95% CI 0.04, 0.16), and 0.07 SDS higher FMI (95% CI 0.01, 0.13) up to age 10 years. These associations were explained by protein from animal sources and not plant sources. Associations were independent of protein intake and overall diet quality at age 8 years, and were independent of whether higher protein was consumed at the expense of carbohydrates or fat in the diet. Conclusions Our study suggests that high protein intake in infancy, particularly from animal food sources, is persistently associated with adiposity up to age 10 years. Restricting protein intake in this critical period of development may aid in the early prevention of adiposity in childhood.

OBJECTIVES: Given its popularity, there is an increasing interest in the study of coffee intake and its effect on health. Previous studies linked coffee consumption to lower type 2 diabetes (T2D) risk. However, potential underlying mechanisms remain unclear. We hypothesized that coffee's effects on systemic inflammation may play a role. We studied cross sectional and longitudinal associations of habitual coffee consumption with T2D risk and inflammation. METHODS: Participants from UK Biobank (UKB, n = 145,370) and Rotterdam Study (RS, n = 7172) cohorts were included. Coffee intake data were collected through self-administrated food frequency questionnaire or during home interviews. We studied associations of coffee intake with incident T2D using cox proportional hazard models; with longitudinally measured insulin resistance (HOMA IR) through linear mixed effect models; with serum baseline levels of inflammation markers using linear regressions; and the role of inflammation in coffee-T2D associations using mediation analysis. Models were adjusted for sociodemographic, lifestyle and health factors. Results were respectively expressed as hazard ratio (HR); β log transformed HOMA IR level; β log transformed ug/mL; and percentage mediated; and 95% confidence interval [95% CI]. RESULTS: UKB participants were 58% female and 55.2 years in average; RS were 59.7% female and 65.1 years. The median follow up was 7 (UKB) and 9 (RS) years. The modal coffee consumption was 0.5–2 cups/day (UKB) and 3–4 cups/day (RS). An increase of one coffee cup/day was associated with 4–6% lower T2D risk (RS HR 0.94 [95% CI 0.90; 0.98]; UKB HR 0.96 [0.94; 0.98]); lower HOMA IR (RS β −0.017 [−0.024; −0.010]); lower C reactive protein (CRP, RS β −0.014 [−0.022; −0.005]; UKBB β −0.011 [−0.012; −0.009] and higher adiponectin (RS β 0.025 [0.007; 0.042]. About coffee types, habitual consumers of filtered coffee had the lowest T2D risk (UKB HR 0.88 [0.83; 0.93]), compared to decaffeinated or instantaneous coffee. CRP levels mediated 9.6% (UKB) and 3.4% (RS) of the total effect of coffee on T2D. Adiponectin also showed evidence for mediation. CONCLUSIONS: Coffee's beneficial effects on lower T2D risk may be partially mediated by improvements in systemic inflammation. Among coffee drinkers, filtered coffee may be of preference. FUNDING SOURCES: Partially funded by the Institute for Scientific Information on Coffee.

Background: Coffee intake has been linked to lower type 2 diabetes (T2D) risk. We hypothesized this may be mediated by coffee’s effects on inflammation. Methods: Using participants from the UK Biobank (UKB n=145370) and Rotterdam Study (RS n=7172) cohorts, we studied associations of coffee intake with incident T2D; longitudinally measured insulin resistance (HOMA IR); serum levels of inflammation markers; and the mediating role of inflammation. Statistical regression models were adjusted for sociodemographic, lifestyle and health factors. Results: The median follow up was 7 (UKB) and 9 (RS) years. An increase of one coffee cup/day was associated with 4-6% lower T2D risk (RS HR=0.94 [95% CI 0.90; 0.98]; UKB HR=0.96 [0.94; 0.98]); lower HOMA IR (RS β=-0.017 [-0.024; -0.010]); with lower C reactive protein (CRP) and higher adiponectin (Figure1). Consumers of filtered coffee had the lowest T2D risk (UKB HR=0.88 [0.83; 0.93]). CRP levels mediated 9.6% (UKB) and 3.4% (RS) of the total effect of coffee on T2D (Figure 1). Conclusions: We suggest that coffee’s beneficial effects on lower T2D risk are partially mediated by improvements in systemic inflammation.Figure 1. a CRP and a adiponectin refer to the effect of coffee intake on CRP and adiponectin levels. a CRP RS : β=-0.014 (-0.022; -0.005); UKBB a CRP UKB : β=-0.011 (-0.012; -0.009) and RS a adiponectin : β=0.025 (0.007; 0.042). b CRP and b adiponectin refer to the effect of coffee related levels in CRP and adiponectin on incident T2D, independent of coffee. RS b CRP : HR=1.17 (1.04; 1.31); UKB b CRP : HR=1.45 (1.37; 1.54); and b adiponectin : HR=0.58 (0.32; 0.83). c′ refers to coffee’ effect on T2D going directly or via others mediators. UKB c′ independent of CRP : HR=0.96 (0.94; 0.99); RS c′ independent of CRP : HR=0.94 (0.90; 0.99); and RS c′ independent of CRP+adiponectin : HR=0.90 (0.80; 1.01). Coffee related changes in CRP may partially explain the beneficial link between coffee and T2D, mediating a 3.4% (0.6; 4.8, RS) and 9.6% (5.7; 24.4, UKB). Evidence of mediation was also found for adiponectin.

Coffee and tea are extensively consumed beverages worldwide which have received considerable attention regarding health. Intake of these beverages is consistently linked to, among others, reduced risk of diabetes and liver diseases; however, the mechanisms of action remain elusive. Epigenetics is suggested as a mechanism mediating the effects of dietary and lifestyle factors on disease onset. Here we report the results from epigenome-wide association studies (EWAS) on coffee and tea consumption in 15,789 participants of European and African-American ancestries from 15 cohorts. EWAS meta-analysis of coffee consumption reveals 11 CpGs surpassing the epigenome-wide significance threshold (P-value, While coffee and tea consumption has been associated with risk of diseases, their mechanisms of action remain elusive. Here the authors present a large EWAS on coffee and tea consumption in cohorts of European and African-American ancestries, finding that coffee consumption is associated with differential DNA methylation levels at multiple CpGs.

Summary Background & aims Dietary intake of several specific macronutrients has been linked to risk of coronary heart disease (CHD). However, these associations may depend on overall macronutrient composition rather than effects of one single macronutrient. Therefore, we aimed to investigate the associations of macronutrient intake and CHD and its related risk factors, by taking into account different macronutrient substitutions. Methods This study was performed among 5873 participants from the Rotterdam Study, a population-based cohort study. Macronutrient intake was measured using a semi-quantitative food-frequency questionnaire. Cox proportional hazard regression analyses were used to examine associations between intakes of macronutrients and CHD incidence; and linear regression analyses were used to examine associations with the related risk factors, including triglycerides, total, high-density and low-density cholesterol levels, body mass index (BMI), fat mass index (FMI), and fat-free mass index (FFMI). Results We documented 669 CHD cases during 74,776 person-years of follow-up. In multivariable-adjusted models we observed no statistically significant associations between macronutrients and CHD incidence. Although non-significant, a higher plant protein intake tended to be associated with a lower risk of CHD when consumed at the expense of any of the other macronutrients. This association was strongest when 5% of energy (5 E%) of plant protein was consumed at the expense of animal protein (HR = 0.61; 95% CI 0.31, 1,21), mono- and disaccharides (HR = 0.62; 95% CI 0.29, 1.35) or saturated fat (HR = 0.61; 95% CI 0.31, 1.20). No consistent associations were observed for risk factors related to CHD. Conclusions Macronutrient composition was not significantly associated with CHD incidence or cardiometabolic risk factors in an adult population. Future studies should further investigate food sources and quality of macronutrients.

Background: High intake of sugar-containing beverages (SCBs) has been linked to increased risk of obesity. However, associations of SCB intake during pregnancy with child body composition have been unclear.Objectives: We explored whether SCB intake during pregnancy was associated with children's body mass index (BMI) and detailed measures of body composition. In addition, we examined different types of SCBs (i.e., fruit juice, soda, and concentrate).Design: We included 3312 mother-child pairs of the Generation R Study, a prospective cohort from fetal life onward in the Netherlands. Energy-adjusted SCB intake was assessed in the first trimester with a food-frequency questionnaire. Anthropometric data of the children were collected repeatedly ≤6 y of age, and BMI was calculated. At 6 y of age, we further measured fat mass index (FMI) and fat-free mass index with dual-energy X-ray absorptiometry. All outcomes were sex- and age-standardized. Associations of SCB intake with children's BMI trajectories and body composition were analyzed with multivariable linear mixed and regression models.Results: Results from linear mixed models showed that, after adjustment for confounders including the SCB intake of the child itself, mothers' total SCB intake was positively associated with children's BMI ≤6 y of age [per serving per day: 0.04 SD score (SDS); 95% CI: 0.00, 0.07 SDS]. In addition, intakes of total SCBs and fruit juice, but not of soda or concentrate, were associated with a higher FMI [total SCBs: 0.05 SDS (95% CI: 0.01, 0.08 SDS); fruit juice: 0.04 SDS (95% CI: 0.01, 0.06 SDS)] of the 6-y-old children. These associations remained significant (P < 0.05) after additional adjustment for gestational weight gain, birth weight, and children's insulin concentrations.Conclusion: Our study suggests that maternal SCB intake during pregnancy is positively associated with children's BMI during early childhood and particularly with higher fat mass.

Introduction: Associations between time spent on physical activity, sedentary behavior, and sleep and quality of life are usually studied without considering that their combined time is fixed. This study investigates the reallocation of time spent on physical activity, sedentary behavior, and sleep during the 24-hour day and their associations with quality of life. Methods: Data from the 2011–2016 Rotterdam Study were used to perform this cross-sectional analysis among 1,934 participants aged 51–94 years. Time spent in activity levels (sedentary, light-intensity physical activity, moderate-to-vigorous physical activity, and sleep) were objectively measured with a wrist-worn accelerometer combined with a sleep diary. Quality of life was measured using the EuroQoL 5D-3L questionnaire. The compositional isotemporal substitution method was used in 2018 to examine the association between the distribution of time spent in different activity behaviors and quality of life. Results: Reallocation of 30 minutes from sedentary behavior, light-intensity physical activity, or sleep to moderate-to-vigorous physical activity was associated with a higher quality of life, whereas reallocation from moderate-to-vigorous physical activity to sedentary behavior, light-intensity physical activity, or sleep was associated with lower quality of life. To illustrate this, a reallocation of 30 minutes from sedentary behavior to moderate-to-vigorous physical activity was associated with a 3% (95% CI=2, 4) higher quality of life score. By contrast, a reallocation of 30 minutes from moderate-to-vigorous physical activity to sedentary behavior was associated with a 4% (95% CI=2, 6) lower quality of life score. Conclusions: Moderate-to-vigorous physical activity is important with regard to the quality of life of middle-aged and elderly individuals. The benefits of preventing less time spent in moderate-to-vigorous physical activity were greater than the benefits of more time spent in moderate-to-vigorous physical activity. These results could shift the attention to interventions focused on preventing reductions in moderate-to-vigorous physical activity levels. Further longitudinal studies are needed to confirm these findings and explore causality.

Objective To investigate whether the genetic burden of type 2 diabetes modifies the association between the quality of dietary fat and the incidence of type 2 diabetes. Design Individual participant data meta-analysis. Data sources Eligible prospective cohort studies were systematically sourced from studies published between January 1970 and February 2017 through electronic searches in major medical databases (Medline, Embase, and Scopus) and discussion with investigators. Review methods Data from cohort studies or multicohort consortia with available genome-wide genetic data and information about the quality of dietary fat and the incidence of type 2 diabetes in participants of European descent was sought. Prospective cohorts that had accrued five or more years of follow-up were included. The type 2 diabetes genetic risk profile was characterized by a 68-variant polygenic risk score weighted by published effect sizes. Diet was recorded by using validated cohort-specific dietary assessment tools. Outcome measures were summary adjusted hazard ratios of incident type 2 diabetes for polygenic risk score, isocaloric replacement of carbohydrate (refined starch and sugars) with types of fat, and the interaction of types of fat with polygenic risk score. Results Of 102 305 participants from 15 prospective cohort studies, 20 015 type 2 diabetes cases were documented after a median follow-up of 12 years (interquartile range 9.4-14.2). The hazard ratio of type 2 diabetes per increment of 10 risk alleles in the polygenic risk score was 1.64 (95% confidence interval 1.54 to 1.75, I 2 =7.1%, τ 2 =0.003). The increase of polyunsaturated fat and total omega 6 polyunsaturated fat intake in place of carbohydrate was associated with a lower risk of type 2 diabetes, with hazard ratios of 0.90 (0.82 to 0.98, I 2 =18.0%, τ 2 =0.006; per 5% of energy) and 0.99 (0.97 to 1.00, I 2 =58.8%, τ 2 =0.001; per increment of 1 g/d), respectively. Increasing monounsaturated fat in place of carbohydrate was associated with a higher risk of type 2 diabetes (hazard ratio 1.10, 95% confidence interval 1.01 to 1.19, I 2 =25.9%, τ 2 =0.006; per 5% of energy). Evidence of small study effects was detected for the overall association of polyunsaturated fat with the risk of type 2 diabetes, but not for the omega 6 polyunsaturated fat and monounsaturated fat associations. Significant interactions between dietary fat and polygenic risk score on the risk of type 2 diabetes (P>0.05 for interaction) were not observed. Conclusions These data indicate that genetic burden and the quality of dietary fat are each associated with the incidence of type 2 diabetes. The findings do not support tailoring recommendations on the quality of dietary fat to individual type 2 diabetes genetic risk profiles for the primary prevention of type 2 diabetes, and suggest that dietary fat is associated with the risk of type 2 diabetes across the spectrum of type 2 diabetes genetic risk.

OBJECTIVES: DNA methylation may play a role in the development of type 2 diabetes (T2D). DNA methylation can be influenced by methyl donor nutrients such as vitamins B2, B6, B12, folate, and methionine, which are all central to one carbon metabolism. Using 3 large cohorts of US health professionals, we examined whether intake of these nutrients from food or supplements is associated with T2D risk. METHODS: We included 69,949 women from the Nurses’ Health Study (1984–2012), 90,239 women from the Nurses’ Health Study II (1991–2011), and 40,539 men from the Health Professionals Follow-Up Study (1986–2010). Dietary data were collected every 2–4 years using a validated semi-quantitative FFQ, from which dietary intakes of vitamin B2, vitamin B6, vitamin B12, folate, and methionine were calculated. We used Cox proportional hazards model with time-varying covariates and adjusted for several sociodemographic and lifestyle variables. We also adjusted for cereal fiber, animal protein, polyunsaturated and saturated fatty acids ratio. Food sources of vitamins were additionally adjusted for multivitamin use while supplemental sources of vitamins were adjusted for a measure of overall diet quality. RESULTS: During 1763,428 years of follow-up, we documented 8141 T2D cases. In pooled multivariable-adjusted analyses, compared to those in the lowest quintile, those in the highest quintile of vitamins B2 and B6 had a 10% (95% CI 3%–16%) and 11% (95% CI 3%–16%) lower T2D risk, respectively. Total vitamin B12 intake was not associated with T2D. However, when analyses were stratified by source, vitamin B12 from food sources was associated with a higher T2D risk (HR [95% CI] = 1.11 [1.02–1.19]). On the other hand, supplemental vitamin B12 was associated with lower T2D risk (HR [95% CI] for Q5 vs Q1 = 0.92 [0.85–0.98]). We found no evidence for an association between intakes of folate and methionine and T2D risk. CONCLUSIONS: Our study suggests that higher intakes of vitamin B2 and vitamin B6 are associated with a lower T2D risk. A higher vitamin B12 intake from food seems to be associated with a higher T2D risk, which may be due to consumption of animal products. FUNDING SOURCES: The analysis was supported by grants from the National Institutes of Health.

Background: New evidence suggests the potential involvement of epigenetic mechanisms in type 2 diabetes (T2D) as a crucial interface between the effects of genetic predisposition and environmental influences.Aim: To systematically review studies investigating the association between epigenetic marks (DNA methylation and histone modifications) with T2D and glycemic traits (glucose and insulin levels, insulin resistance measured by HOMA-IR).Method and Results: Six bibliographic databases (Embase.com, Medline (Ovid), Web-of-Science, PubMed, Cochrane Central and Google Scholar) were screened until 28th August 2015. We included randomized controlled trials, cohort, case-control and cross-sectional studies in humans that examined the association between epigenetic marks (global, candidate or genome-wide methylation of DNA and histone modifications) with T2D, glucose and insulin levels and insulin metabolism.Of the initially identified 3879 references, 53 articles, based on 47 unique studies met our inclusion criteria. Overall, data were available on 10,823 participants, with a total of 3358 T2D cases. There was no consistent evidence for an association between global DNA-methylation with T2D, glucose, insulin and insulin resistance. The studies reported epigenetic regulation of several candidate genes for diabetes susceptibility in blood cells, muscle, adipose tissue and placenta to be related with T2D without any general overlap between them. Histone modifications in relation to T2D were reported only in 3 observational studies.Conclusions and relevance: Current evidence supports an association between epigenetic marks and T2D. However, overall evidence is limited, highlighting the need for further larger-scale and prospective investigations to establish whether epigenetic marks may influence the risk of developing T2D. (C) 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Background: High protein intake in infancy might lead to a higher body mass index (BMI) in childhood. However, whether these associations differ between different sources of protein is unclear. Objective: We investigated associations between the intake of total protein, protein from different sources, and individual amino acids in early childhood and repeatedly measured height, weight, and BMI up to the age of 9 y. Methods: This study was performed in 3564 children participating in the Generation R Study, a population-based prospective cohort study in Rotterdam, Netherlands. Intakes of total protein, animal protein, vegetable protein, and individual amino acids (including methionine, arginine, lysine, threonine, valine, leucine, isoleucine, phenylalanine, tryptophan, histidine, cysteine, tyrosine, alanine, asparagine, glutamine, glycine, proline, and serine) at 1 y were assessed by using a food-frequency questionnaire. Height and weight were measured at the approximate ages of 14, 18, 24, 30, 36, and 45 mo and at 6 and 9 y, and BMI was calculated. Results: After adjustment for confounders, linear mixed models showed that a 10-g higher total protein intake/d at 1 y was significantly associated with a 0.03-SD greater height (95% CI: 0.00, 0.06), a 0.06-SD higher weight (95% CI: 0.03, 0.09), and a 0.05-SD higher BMI (95% CI: 0.03, 0.08) up to the age of 9 y. Associations were stronger for animal than for vegetable protein intake but did not differ between dairy and nondairy animal protein or between specific amino acids. Conclusions: A higher intake of protein, especially animal protein, at 1 y of age was associated with a greater height, weight, and BMI in childhood up to 9 y of age. Future studies should explore the role of growth hormones and investigate whether protein intake in early childhood affects health later in life.

High sugar intake in childhood has been linked to obesity. However, the role of macronutrient substitutions and associations with metabolic health remain unclear. We examined associations of carbohydrate intake and its subtypes with body composition and metabolic health among 3573 children participating in a population-based cohort in the Netherlands. Intake of total carbohydrate, monosaccharides and disaccharides, and polysaccharides at age 1 year was assessed with a food-frequency questionnaire. We repeatedly measured children&rsquo, s height and weight to calculate BMI between their ages of 1 and 10 years. At ages 6 and 10 years, fat and fat-free mass were measured with dual-energy X-ray-absorptiometry and blood concentrations of triglycerides, cholesterol, and insulin were obtained. For all outcomes, we calculated age and sexspecific SD-scores. In multivariable-adjusted linear mixed models, we found no associations of intake of carbohydrates or its subtypes with children&rsquo, s BMI or body composition. A higher intake of monosaccharides and disaccharides was associated with higher triglyceride concentrations (0.02 SDS per 10 g/d, 95% CI: 0.01, 0.04). Higher monosaccharide and disaccharide intake was also associated with lower HDL-cholesterol (&minus, 0.03 SDS, 95% CI: &minus, 0.04, &minus, 0.01), especially when it replaced polysaccharides. Overall, our findings suggest associations of higher monosaccharide and disaccharide intake in early childhood with higher triglyceride and lower HDL-cholesterol concentrations, but do not support associations with body composition.

OBJECTIVES: Carbohydrate intake has been reported to be associated with higher type 2 diabetes (T2D) risk, but high and low quality of carbohydrate may have different effects. Furthermore, these effects may differ depending on overall macronutrient composition. We aimed to examine associations of isocalorically substituting high quality carbohydrates (HQC) and low quality carbohydrates (LQC) with other macronutrients on T2D risk. METHODS: We included 69,949 women from the Nurses’ Health Study, 90,239 women from the Nurses’ Health Study 2, and 40,539 men from the Health Professionals Follow-up Study. Dietary data were collected every 2–4 years using a semi-quantitative food frequency questionnaire, from which dietary intake of LQC and HQC were calculated. LQC was defined as the percentage of energy (E%) from carbohydrates from refined grains, sugary foods, and potatoes, and HQC as E% from carbohydrate from whole grains. Hazard ratios were estimated using Cox proportional hazard regression analyses with time-varying covariates. RESULTS: During 4389,996 years of follow-up, we documented 11,872 T2D cases. In pooled multivariable-adjusted analyses, substituting 5E% from saturated fat with 5E% from LQC was associated with a higher T2D (HR[95% CI] = 1.05[1.00–1.09]) while substitution with HQC was associated with a lower T2D risk (HR[95% CI] = 0.93[0.87–0.99]). Isocaloric substitution of other macronutrients with LQC was not associated with T2D risk. On the other hand, isocaloric substitution of HQC was associated with lower T2D risk when the replacement nutrient was monounsaturated fat (HR[95% CI] = 0.88[0.83–0.94]), polyunsaturated fat (HR[95% CI] = 0.92[0.86–0.98]), trans fat (HR[95% CI] = 0.90[0.85–0.97]), animal protein (HR[95% CI] = 0.88[0.83–0.93]), and vegetable protein (HR[95% CI] = 0.90[0.84–0.96]). CONCLUSIONS: Our study suggests that higher intake of HQC, especially from whole grains, is associated with a lower T2D risk, irrespective of the macronutrient it replaces. In contrast, a higher intake of LQC is associated with a higher risk of type 2 diabetes, but only when it replaces saturated fat. Our findings highlight the importance of making a distinction between carbohydrate from high and low quality sources and taking into account different substitutions when examining macronutrients. FUNDING SOURCES: National Institutes of Health.

The risk of cardiometabolic disease such as type II diabetes and cardiovascular disease (CVD) increases with age. Both of these diseases are important determinants of overall health and longevity. Although environmental and genetic studies have improved our understanding of the etiology and pathophysiologic mechanisms associated with diabetes and CVD, the etiology for the majority of these traits remains poorly understood. Alterations in the epigenetic mechanisms, including DNA methylation and histone modification, have been recently implicated in the onset and progression of cardiometabolic outcomes and may account for the missing heritability determinants of these diseases. Despite a growing body of literature addressing the role of the environment in gene expression affecting cardiometabolic risk, little is known about the epigenetic pathways involved in the pathophysiology of diabetes and CVD. In this chapter we describe the current knowledge about epigenetic control mechanisms in the development of cardiometabolic diseases.

The importance of polyunsaturated fatty acid (PUFA) intake in fetal life and infancy has been widely studied in relation to child cognitive and visual development, but whether early life PUPA exposure is related to cardiometabolic risk factors is unclear. The focus of this systematic review was to evaluate the effects of PUFA dietary intake and blood levels during pregnancy, lactation, or early childhood (

Epigenetic mechanisms, including DNA methylation and histone modifications, might be involved in the regulation of blood lipid concentration variability and may thereby affect cardiovascular health. We aimed to systematically review studies investigating the association between epigenetic marks and plasma concentrations of triacylglycerol, total cholesterol, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol. Six medical databases were searched until September 3rd 2015, reference lists were screened, and experts in the field were contacted. Of the 757 identified references, 31 articles reporting on 23 unique studies met all inclusion criteria. These studies included data on 8027 unique participants. Overall, no consistent associations were observed between global DNA methylation and blood lipids. Candidate gene and epigenome-wide association studies reported epigenetic regulation of several genes to be related with blood lipids, of which results for ABCG1, CPT1A, TNNT1, MIR33B, SREBF1, and TNIP were replicated. To date, no studies have been performed on histone modification in relation to blood lipids. To conclude, promising results have been reported in the field of epigenetics and dyslipidaemia, however, further rigorous studies are needed to expand our understanding on the role of epigenetics in regulating human's blood lipid levels and its effects on health and disease.

Background DNA methylation is a key epigenetic mechanism that is suggested to be associated with blood lipid levels. We aimed to identify CpG sites at which DNA methylation levels are associated with blood levels of triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and total cholesterol in 725 participants of the Rotterdam Study, a population-based cohort study. Subsequently, we sought replication in a non-overlapping set of 760 participants. Results Genome-wide methylation levels were measured in whole blood using the Illumina Methylation 450 array. Associations between lipid levels and DNA methylation beta values were examined using linear mixed-effect models. All models were adjusted for sex, age, smoking, white blood cell proportions, array number, and position on array. A Bonferroni-corrected p value lower than 1.08 × 10−7 was considered statistically significant. Five CpG sites annotated to genes including DHCR24, CPT1A, ABCG1, and SREBF1 were identified and replicated. Four CpG sites were associated with triglycerides, including CpG sites annotated to CPT1A (cg00574958 and cg17058475), ABCG1 (cg06500161), and SREBF1 (cg11024682). Two CpG sites were associated with HDL-C, including ABCG1 (cg06500161) and DHCR24 (cg17901584). No significant associations were observed with LDL-C or total cholesterol. Conclusions We report an association of HDL-C levels with methylation of a CpG site near DHCR24, a protein-coding gene involved in cholesterol biosynthesis, which has previously been reported to be associated with other metabolic traits. Furthermore, we confirmed previously reported associations of methylation of CpG sites within CPT1A, ABCG1, and SREBF1 and lipids. These results provide insight in the mechanisms that are involved in lipid metabolism. Electronic supplementary material The online version of this article (doi:10.1186/s13148-016-0304-4) contains supplementary material, which is available to authorized users.

Previous studies suggest that high protein intake in infancy leads to a higher body mass index (BMI) in later childhood. We examined the associations of total, animal and vegetable protein intake in early childhood with detailed measures of body composition at the age of 6 years.This study was performed in 2911 children participating in a population-based cohort study. Protein intake at the age of 1 year was assessed with a validated food-frequency questionnaire and was adjusted for total energy intake. At the children's age of 6 years, we measured their anthropometrics and body fat (with dual-energy X-ray absorptiometry). We calculated age- and sex-specific s.d. scores for BMI, fat mass index (FMI) and fat-free mass index (FFMI).After adjustment for confounders, a 10 g per day higher total protein intake at 1 year of age was associated with a 0.05 s.d. (95% confidence interval (CI) 0.00, 0.09) higher BMI at age 6. This association was fully driven by a higher FMI (0.06 s.d. (95%CI 0.01, 0.11)) and not FFMI (-0.01 s.d. (95%CI -0.06, 0.05)). The associations of protein intake with FMI at 6 years remained significant after adjustment for BMI at the age of 1 year. Additional analyses showed that the associations of protein intake with FMI were stronger in girls than in boys (P for interaction=0.03), stronger among children who had catch-up growth in the first year of life (P for interaction0.01) and stronger for intake of animal protein (both dairy and non-dairy protein) than protein from vegetable sources.Our results suggest that high protein intake in early childhood is associated with higher body fat mass, but not fat-free mass. Future studies are needed to investigate whether these changes persist into adulthood and to examine the optimal range of protein intake for infants and young children.

Dietary fiber (DF) intake may be beneficial for cardiometabolic health. However, whether this already occurs in early childhood is unclear. We investigated associations between DF intake in infancy and cardiometabolic health in childhood among 2032 children participating in a population-based cohort in The Netherlands. Information on DF intake at a median age of 12.9 months was collected using a food-frequency questionnaire. DF was adjusted for energy intake using the residual method. At age 6 years, body fat percentage, high-density lipoprotein (HDL)-cholesterol, insulin, triglycerides, and blood pressure were assessed and expressed in age- and sex-specific standard deviation scores (SDS). These five factors were combined into a cardiometabolic risk factor score. In models adjusted for several parental and child covariates, a higher DF intake was associated with a lower cardiometabolic risk factor score. When we examined individual cardiometabolic factors, we observed that a 1 g/day higher energy-adjusted DF intake was associated with 0.026 SDS higher HDL-cholesterol (95% CI 0.009, 0.042), and 0.020 SDS lower triglycerides (95% CI −0.037, −0.003), but not with body fat, insulin, or blood pressure. Results were similar for DF with and without adjustment for energy intake. Our findings suggest that higher DF intake in infancy may be associated with better cardiometabolic health in later childhood.

Background: Deficiency of vitamin B-6, vitamin B-12, folate, folic acid, or methionine may lead to dysregulation of DNA methylation, which might lead to disturbed energy and lipid metabolism. Objective: We aimed to explore whether intakes of vitamin B-6, vitamin B-12, folate, folic acid, and methionine at 1 y are associated with measures of growth and body composition at the age of 6 y. Methods: This study was performed in 2922 children participating in The Generation R Study, a population-based prospective cohort study. Dietary intakes of vitamins B-6 and B-12, folate, folic acid, and methionine were assessed at a median age of 12.9 mo by using a validated food-frequency questionnaire. At the age of 6 y, height and weight were measured, and body mass index (BMI; in kg/m 2 ) was calculated. Body fat was measured with dual-energy X-ray absorptiometry, and body fat percentage and the ratio of android fat mass to gynoid fat mass (android:gynoid) were calculated. Results: In models adjusted for maternal and child characteristics, children with folic acid intakes in the highest tertile had a 0.16 SD score (SDS) lower weight (95% CI: 20.31, 20.02 SDS) and a 0.14 SDS lower BMI (95% CI: 20.26, 20.01 SDS) than children in the lowest tertile. Children with vitamin B-12 intakes in the highest tertile had a 0.13 SDS higher android:gynoid (95% CI: 0.00, 0.25 SDS) than children in the lowest tertile. In addition, children with intakes in the highest tertile of methionine had a 0.09 SDS higher BMI (95% CI: 0.01, 0.17) and a 0.12 SDS higher android:gynoid (95% CI: 0.02, 0.22) than children in the lowest tertile. Vitamin B-6 and folate intakes were not associated with any of the body composition outcomes measured. Conclusions: In this population of children, early high folic acid intakes were associated with a lower body weight and BMI at the age of 6 y. In contrast, early higher methionine intakes were associated with unfavorable body composition at the age of 6 y. Future studies should investigate long-term consequences of these outcomes on health. JN utr2015;145:2123‐9.