Social cohesion and associations with sedentary time, physical activity and dietary quality in The Maastricht Study.

INTRO: We aim to investigate the relationship between social cohesion and sedentary behavior (SB), total physical activity (PA), moderate-to-vigorous PA (MVPA), and dietary quality. Additionally, we assess whether these associations are independent of neighborhood walkability and the food environment. METHODS: A total of 7641 participants from The Maastricht Study in the Netherlands between the ages of 40 and 75 years were analyzed. Neighborhood social cohesion was obtained by participant questionnaire completed at baseline and measured by the Dutch Livability meter. Home addresses were linked to geographic information system (GIS) data from the Geoscience and Health Cohort Consortium (GECCO) to create neighborhood exposures of walkability and food environment. A thigh worn accelerometer collected data to measure sedentary time, total daily PA, and MVPA. Dietary quality was measured with a food frequency questionnaire. Multivariate linear regression analyses were adjusted for age, sex, socioeconomic position, neighborhood walkability, and food environment. RESULTS: Those living in the highest quartile area of perceived social cohesion had statistically significant lower levels of SB (Q4 B: -13.04; 95% CI = -20.23, -5.85), higher total PA (Q4 B: 4.39; 95% CI = 1.69, 7.10), and higher MVPA (Q4 B: 2.57; 95% CI = 0.83, 4.31) and better diet quality (Q4 B: 1.12; 95% CI = 0.24, 2.01) compared to the lowest quartile independent of walkability and food environment. Similar results were found using the Livability meter. CONCLUSION: We discovered neighborhood social cohesion as an important obesogenic determinant that should be considered in policymaking to encourage higher levels of PA and higher diet quality.

Association of kidney function with physical performance: the Maastricht study.

BACKGROUND: Kidney failure has been associated with decreased physical capacity, although evidence regarding the physical performance of individuals with earlier stages of chronic kidney disease (CKD) remains limited. METHODS: Cross-sectional data were derived from the prospective, population-based Maastricht Study. Multivariate linear regression models were fitted to assess the association of estimated glomerular filtration rate (eGFR) and albuminuria categories with physical performance test outcomes. RESULTS: Overall, 7396 participants were included. Compared to eGFR 60-90 ml/min/1.73 m2, values < 60 ml/min/1.73 m2 were associated with significantly shorter 6-min walk distance (ß: - 13.04 m, 95% confidence intervals-CI - 19.95; - 6.13), worse timed chair rise stand test time (ß: 0.91 s, 95% CI 0.36; 1.47), lower maximal grip (ß: - 0.83 kg, 95% CI - 1.50; - 0.15) and elbow flexion (ß: - 3.64 Nm, 95% CI - 7.11; - 0.16) strength. Additionally, eGFR > 90 ml/min/1.73 m2 was linked to significantly shorter 6-min walk distance (ß: - 6.13 m, 95% CI - 9.44; - 2.82). Urinary albumin excretion > 30 mg/24 h was associated with shorter 6-min walk distance (ß: - 12.48 m, 95% CI - 18.28; - 6.68), worse timed chair rise stand test time (ß: 0.51 s, 95% CI 0.11; 1.06), lower maximal grip (ß: - 1.34 kg, 95% CI - 1.91; - 0.76) and elbow flexion strength (ß: - 3.31 Nm, 95% CI - 5.80; - 0.82). CONCLUSIONS: Reduced eGFR and higher albuminuria levels were associated with worse physical performance, especially shorter 6-min walk distance and lower muscle strength. The relationship between eGFR and physical function was non-linear, with also high eGFR values being associated with worse performance, especially in the six-minute walk test.

Dietary sulfur amino acid restriction in humans with overweight and obesity: a translational randomized controlled trial.

BACKGROUND: Dietary sulfur amino acid restriction (SAAR) improves metabolic health in animals. In this study, we investigated the effect of dietary SAAR on body weight, body composition, resting metabolic rate, gene expression profiles in white adipose tissue (WAT), and an extensive blood biomarker profile in humans with overweight or obesity. METHODS: N = 59 participants with overweight or obesity (73% women) were randomized stratified by sex to an 8-week plant-based dietary intervention low (~ 2 g/day, SAAR) or high (~ 5.6 g/day, control group) in sulfur amino acids. The diets were provided in full to the participants, and both investigators and participants were blinded to the intervention. Outcome analyses were performed using linear mixed model regression adjusted for baseline values of the outcome and sex. RESULTS: SAAR led to a ~ 20% greater weight loss compared to controls (ß 95% CI - 1.14 (- 2.04, - 0.25) kg, p = 0.013). Despite greater weight loss, resting metabolic rate remained similar between groups. Furthermore, SAAR decreased serum leptin, and increased ketone bodies compared to controls. In WAT, 20 genes were upregulated whereas 24 genes were downregulated (FDR < 5%) in the SAAR group compared to controls. Generally applicable gene set enrichment analyses revealed that processes associated with ribosomes were upregulated, whereas processes related to structural components were downregulated. CONCLUSION: Our study shows that SAAR leads to greater weight loss, decreased leptin and increased ketone bodies compared to controls. Further research on SAAR is needed to investigate the therapeutic potential for metabolic conditions in humans. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04701346, registered Jan 8th 2021, https://www. CLINICALTRIALS: gov/study/NCT04701346.

Both short and long sleep durations are associated with type 2 diabetes, independent from traditional lifestyle risk factors-The Maastricht Study.

OBJECTIVES: This study examined the cross-sectional association between sleep duration, prediabetes, and type 2 diabetes, and its independence from the traditional lifestyle risk factors diet, physical activity, smoking behavior, and alcohol consumption. METHODS: Cross-sectional data from 5561 people aged 40-75 years recruited into The Maastricht Study between 2010 and 2018 were used (1:1 female:male and mean age: 60.1 years [standard deviation: 8.6]). Sleep duration was operationalized as in-bed time, algorithmically derived from activPAL3 accelerometer data (median 7 nights, IQR 1). Glucose metabolism status was determined with an oral glucose tolerance test. Multinomial logistic regression was used to assess the association of sleep duration as restricted cubic spline with prediabetes and type 2 diabetes. We adjusted for sex, age, educational level, the use of sleep medication or antidepressants, and the following lifestyle risk factors: diet quality, physical activity, smoking behavior, and alcohol consumption. RESULTS: A U-shaped association between sleep duration and type 2 diabetes was found. Compared to those with a sleep duration of 8 hours, participants with a sleep duration of 5 and 12 hours had higher odds of type 2 diabetes (OR: 2.9 [95% CI 1.9 to 4.4] and OR 3.2 [2.0 to 5.2], respectively). This association remained after further adjustment for the lifestyle risk factors (OR: 2.6 [1.7 to 4.1] and OR 1.8 [1.1 to 3.1]). No such association was observed between sleep duration and prediabetes. CONCLUSIONS: Both short and long sleep durations are associated positively and independently of lifestyle and cardiovascular risk factors with type 2 diabetes, but not with prediabetes.

Retinal Functional and Structural Neural Indices: Potential Biomarkers for the Monitoring of Cerebral Neurodegeneration: The Maastricht Study.

BACKGROUND: If retinal indices of neurodegeneration are to be biomarkers for the monitoring of cerebral neurodegeneration, it is important to establish whether potentially modifiable risk factors for dementia are associated with retinal neurodegenerative changes. OBJECTIVE: To study associations of dementia risk factors with retinal sensitivity, an index of retinal neural function, and retinal nerve fiber layer (RNFL) thickness, an index of retinal neural structure. METHODS: We used cross-sectional data from The Maastricht Study (up to 5,666 participants, 50.5% men, mean age 59.7), and investigated associations with regression analyses (adjusted for potential confounders). RESULTS: Most risk factors under study (i.e., hyperglycemia, unhealthy diet, lower cardiorespiratory fitness, smoking, alcohol consumption, and hypertension) were significantly associated with lower retinal sensitivity and lower RNFL thickness. CONCLUSION: Findings of this population-based study support the concept that retinal neural indices may be biomarkers for the monitoring of therapeutic strategies that aim to prevent early-stage cerebral neurodegeneration and, ultimately, dementia.

The Associations of Habitual Intake of Sulfur Amino Acids, Proteins and Diet Quality with Plasma Sulfur Amino Acid Concentrations: The Maastricht Study.

BACKGROUND: Plasma sulfur amino acids (SAAs), i.e., methionine, total cysteine (tCys), total homocysteine (tHcy), cystathionine, total glutathione (tGSH), and taurine, are potential risk factors for obesity and cardiometabolic disorders. However, except for plasma tHcy, little is known about how dietary intake modifies plasma SAA concentrations. OBJECTIVE: To investigate whether the intake of SAAs and proteins or diet quality is associated with plasma SAAs. METHODS: Data from a cross-sectional subset of The Maastricht Study (n = 1145, 50.5% men, 61 interquartile range: [55, 66] y, 22.5% with prediabetes and 34.3% with type 2 diabetes) were investigated. Dietary intake was assessed using a validated food frequency questionnaire. The intake of SAAs (total, methionine, and cysteine) and proteins (total, animal, and plant) was estimated from the Dutch and Danish food composition tables. Diet quality was assessed using the Dutch Healthy Diet Index, the Mediterranean Diet Score, and the Dietary Approaches to Stop Hypertension score. Fasting plasma SAAs were measured by liquid chromatography (LC) tandem mass spectrometry (MS) (LC/MS-MS). Associations were investigated with multiple linear regressions with tertiles of dietary intake measures (main exposures) and z-standardized plasma SAAs (outcomes). RESULTS: Intake of total SAAs and total proteins was positively associated with plasma tCys and cystathionine. Associations were stronger in women and in those with normal body weight. Higher intake of cysteine and plant proteins was associated with lower plasma tHcy and higher cystathionine. Higher methionine intake was associated with lower plasma tGSH, whereas cysteine intake was positively associated with tGSH. Higher intake of methionine and animal proteins was associated with higher plasma taurine. Better diet quality was consistently related to lower plasma tHcy concentrations, but it was not associated with the other SAAs. CONCLUSION: Targeted dietary modifications might be effective in modifying plasma concentrations of tCys, tHcy, and cystathionine, which have been associated with obesity and cardiometabolic disorders.

Alcohol consumption and microvascular dysfunction: a J-shaped association: The Maastricht Study.

BACKGROUND: Microvascular dysfunction (MVD) is an important contributor to major clinical disease such as stroke, dementia, depression, retinopathy, and chronic kidney disease. Alcohol consumption may be a determinant of MVD. OBJECTIVE: Main objectives were (1) to study whether alcohol consumption was associated with MVD as assessed in the brain, retina, skin, kidney and in the blood; and (2) to investigate whether associations differed by history of cardiovascular disease or sex. DESIGN: We used cross-sectional data from The Maastricht Study (N = 3,120 participants, 50.9% men, mean age 60 years, and 27.5% with type 2 diabetes [the latter oversampled by design]). We used regression analyses to study the association between total alcohol (per unit and in the categories, i.e. none, light, moderate, high) and MVD, where all measures of MVD were combined into a total MVD composite score (expressed in SD). We adjusted all associations for potential confounders; and tested for interaction by sex, and history of cardiovascular disease. Additionally we tested for interaction with glucose metabolism status. RESULTS: The association between total alcohol consumption and MVD was non-linear, i.e. J-shaped. Moderate versus light total alcohol consumption was significantly associated with less MVD, after full adjustment (beta [95% confidence interval], -0.10 [-0.19; -0.01]). The shape of the curve differed with sex (Pinteraction = 0.03), history of cardiovascular disease (Pinteraction < 0.001), and glucose metabolism status (Pinteraction = 0.02). CONCLUSIONS: The present cross-sectional, population-based study found evidence that alcohol consumption may have an effect on MVD. Hence, although increasing alcohol consumption cannot be recommended as a policy, this study suggests that prevention of MVD may be possible through dietary interventions.

Selection bias in follow-up studies of stem cell transplantation survivors: an experience within the Maastricht Observational study of late effects after Stem cell trAnsplantation (MOSA).

Hematopoietic stem cell transplantation is an important treatment for many malignant hematological and non-hematological diseases. Survivors of hematopoietic stem cell transplantation (HCT) are at risk of long-term health problems and reduced quality of life related to previous treatments. Many studies about these long-term effects have been conducted over the last decades. However, selection bias is a concern in long-term follow-up studies and little is known about the non-participating group. As part of the Maastricht Observational study of late effects after Stem cell trAnsplantation (MOSA), investigating long-term health effects by extensively phenotyping HCT survivors, we conducted a survey to characterise the non-participating group. This survey mostly focused on quality of life and physical complaints. The survey responders were generally older than the MOSA group, had more history of relapsed disease, and described their general health as bad or mediocre significantly more often than the MOSA group. Also, more deaths occurred in the group of non-participants between the start of study inclusion in 2015 and analysis of the survey results in 2021. This study suggests that a selection of higher functioning HCT survivors with a relatively better quality of life participated in this long-term follow-up study of stem cell transplantation survivors. These results could also impact the results of other long-term follow-up studies in cancer survivors, knowing that possibly an unhealthier population is missed in these studies and some long-term negative effects of treatments might be underestimated.Trial registration number: NL-48599.

Associations between plasma sulfur amino acids and specific fat depots in two independent cohorts: CODAM and The Maastricht Study.

PURPOSE: Sulfur amino acids (SAAs) have been associated with obesity and obesity-related metabolic diseases. We investigated whether plasma SAAs (methionine, total cysteine (tCys), total homocysteine, cystathionine and total glutathione) are related to specific fat depots. METHODS: We examined cross-sectional subsets from the CODAM cohort (n = 470, 61.3% men, median [IQR]: 67 [61, 71] years) and The Maastricht Study (DMS; n = 371, 53.4% men, 63 [55, 68] years), enriched with (pre)diabetic individuals. SAAs were measured in fasting EDTA plasma with LC-MS/MS. Outcomes comprised BMI, skinfolds, waist circumference (WC), dual-energy X-ray absorptiometry (DXA, DMS), body composition, abdominal subcutaneous and visceral adipose tissues (CODAM: ultrasound, DMS: MRI) and liver fat (estimated, in CODAM, or MRI-derived, in DMS, liver fat percentage and fatty liver disease). Associations were examined with linear or logistic regressions adjusted for relevant confounders with z-standardized primary exposures and outcomes. RESULTS: Methionine was associated with all measures of liver fat, e.g., fatty liver disease [CODAM: OR = 1.49 (95% CI 1.19, 1.88); DMS: OR = 1.51 (1.09, 2.14)], but not with other fat depots. tCys was associated with overall obesity, e.g., BMI [CODAM: ß = 0.19 (0.09, 0.28); DMS: ß = 0.24 (0.14, 0.34)]; peripheral adiposity, e.g., biceps and triceps skinfolds [CODAM: ß = 0.15 (0.08, 0.23); DMS: ß = 0.20 (0.12, 0.29)]; and central adiposity, e.g., WC [CODAM: ß = 0.16 (0.08, 0.25); DMS: ß = 0.17 (0.08, 0.27)]. Associations of tCys with VAT and liver fat were inconsistent. Other SAAs were not associated with body fat. CONCLUSION: Plasma concentrations of methionine and tCys showed distinct associations with different fat depots, with similar strengths in the two cohorts.

Assessing long-term effects after stem cell transplantation: design of the MOSA study.

OBJECTIVES: The MOSA study (Maastricht Observational study of late effects after Stem cell trAnsplantation) aims to study the prevalence of adverse health effects in hematopoietic stem cell transplantation (HCT) survivors compared to a matched cohort, representing the general population. STUDY DESIGN AND SETTING: The MOSA study is a matched cohort study, nested within a large prospective cohort, The Maastricht Study. Participants of The Maastricht Study serve as a reference group matched on age, gender, and education to compare MOSA participants to the general population. In both studies, the same study protocol and extensive phenotyping measurements are used. RESULTS: HCT Survivors: Five hundred and thirty nine survivors were invited of which, so far, 123 (23%) participants completed the study assessments. Data will be analyzed and published separately. Reference Group: For each MOSA participant, four reference cases were matched. After matching, both groups are comparable with respect to age, gender, and education. CONCLUSION: To our knowledge, this is the first study conducting such detailed phenotyping in HCT survivors. Comparison with a large reference group provides essential information about late effects of HCT and associated risk factors. This may improve screening and prevention strategies, potentially leading to a positive impact on morbidity, mortality, and quality of life.

Fructose Intake From Fruit Juice and Sugar-Sweetened Beverages Is Associated With Higher Intrahepatic Lipid Content: The Maastricht Study.

OBJECTIVE: Epidemiological evidence regarding the relationship between fructose intake and intrahepatic lipid (IHL) content is inconclusive. We, therefore, assessed the relationship between different sources of fructose and IHL at the population level. RESEARCH DESIGN AND METHODS: We used cross-sectional data from The Maastricht Study, a population-based cohort study (n = 3,981; mean ± SD age: 60 ± 9 years; 50% women). We assessed the relationship between fructose intake (assessed with a food-frequency questionnaire)-total and derived from fruit, fruit juice, and sugar-sweetened beverages (SSB)-and IHL (quantified with 3T Dixon MRI) with adjustment for age, sex, type 2 diabetes, education, smoking status, physical activity, and intakes of total energy, alcohol, saturated fat, protein, vitamin E, and dietary fiber. RESULTS: Energy-adjusted total fructose intake and energy-adjusted fructose from fruit were not associated with IHL in the fully adjusted models (P = 0.647 and P = 0.767). In contrast, energy-adjusted intake of fructose from fruit juice and SSB was associated with higher IHL in the fully adjusted models (P = 0.019 and P = 0.009). Individuals in the highest tertile of energy-adjusted intake of fructose from fruit juice and SSB had a 1.04-fold (95% CI 0.99; 1.11) and 1.09-fold (95% CI 1.03; 1.16) higher IHL, respectively, in comparison with the lowest tertile in the fully adjusted models. Finally, the association for fructose from fruit juice was stronger in individuals with type 2 diabetes (P for interaction = 0.071). CONCLUSIONS: Fructose from fruit juice and SSB is independently associated with higher IHL. These cross-sectional findings contribute to current knowledge in support of measures to reduce the intake of fructose-containing beverages as a means to prevent nonalcoholic fatty liver disease at the population level.

Sleep Apnea is Associated With Accelerated Vascular Aging: Results From 2 European Community-Based Cohort Studies.

Background The mechanisms underlying the association between obstructive sleep apnea (OSA) and cardiovascular disease may include accelerated vascular aging. The aim was to compare the magnitude of vascular aging in patients with high versus low risk of OSA. Methods and Results In 2 community-based studies, the PPS3 (Paris Prospective Study 3) and the Maastricht Study, high risk of OSA was determined with the Berlin questionnaire (a screening questionnaire for OSA). We assessed carotid artery properties (carotid intima-media thickness, Young's elastic modulus, carotid-femoral pulse wave velocity, carotid pulse wave velocity, carotid diameter using high precision ultrasound echography), and carotid-femoral pulse wave velocity (in the Maastricht Study only). Regression coefficients were estimated on pooled data using multivariate linear regression. A total of 8615 participants without prior cardiovascular disease were included (6840 from PPS3, 62% men, mean age 59.5±6.2 years, and 1775 from the Maastricht Study, 51% men, 58.9±8.1 years). Overall, high risk of OSA prevalence was 16.8% (n=1150) in PPS3 and 23.8% (n=423) in the Maastricht Study. A high risk of OSA was associated with greater carotid intima-media thickness (ß=0.21; 0.17-0.26), Young's elastic modulus (ß=0.21; 0.17-0.25), carotid-femoral pulse wave velocity (ß=0.24; 0.14-0.34), carotid pulse wave velocity (ß=0.31; 0.26-0.35), and carotid diameter (ß=0.43; 0.38-0.48), after adjustment for age, sex, total cholesterol, smoking, education level, diabetes mellitus, heart rate, and study site. Consistent associations were observed after additional adjustments for mean blood pressure, body mass index, or antihypertensive medications. Conclusions These data lend support for accelerated vascular aging in individuals with high risk of OSA. This may, at least in part, underlie the association between OSA and cardiovascular disease.

Sulfur amino acid restriction, energy metabolism and obesity: a study protocol of an 8-week randomized controlled dietary intervention with whole foods and amino acid supplements.

BACKGROUND: Dietary sulfur amino acid (SAA) restriction is an established animal model for increasing lifespan and improving metabolic health. Data from human studies are limited. In the study outlined in this protocol, we will evaluate if dietary SAA restriction can reduce body weight and improve resting energy expenditure (REE) and parameters related to metabolic health. METHOD/DESIGN: Men and women (calculated sample size = 60), aged 18-45 years, with body mass index of 27-35 kg/m2 will be included in a double-blind 8-week dietary intervention study. The participants will be randomized in a 1:1 manner to a diet with either low or high SAA. Both groups will receive an equal base diet consisting of low-SAA plant-based whole foods and an amino acid supplement free of SAA. Contrasting SAA contents will be achieved using capsules with or without methionine and cysteine (SAAhigh, total diet SAA ~ 50-60 mg/kg body weight/day; SAAlow, total diet SAA ~ 15-25 mg/kg body weight/day). The primary outcome is body weight change. Data and material collection will also include body composition (dual X-ray absorptiometry), resting energy expenditure (whole-room indirect calorimetry) and samples of blood, urine, feces and adipose tissue at baseline, at 4 weeks and at study completion. Measures will be taken to promote and monitor diet adherence. Data will be analyzed using linear mixed model regression to account for the repeated measures design and within-subject correlation. DISCUSSION: The strength of this study is the randomized double-blind design. A limitation is the restrictive nature of the diet which may lead to poor compliance. If this study reveals a beneficial effect of the SAAlow diet on body composition and metabolic health, it opens up for new strategies for prevention and treatment of overweight, obesity and its associated disorders. Trial registration ClinicalTrials.gov: NCT04701346, Registration date: January 8th, 2021.

Genome-wide identification of genes regulating DNA methylation using genetic anchors for causal inference.

BACKGROUND: DNA methylation is a key epigenetic modification in human development and disease, yet there is limited understanding of its highly coordinated regulation. Here, we identify 818 genes that affect DNA methylation patterns in blood using large-scale population genomics data. RESULTS: By employing genetic instruments as causal anchors, we establish directed associations between gene expression and distant DNA methylation levels, while ensuring specificity of the associations by correcting for linkage disequilibrium and pleiotropy among neighboring genes. The identified genes are enriched for transcription factors, of which many consistently increased or decreased DNA methylation levels at multiple CpG sites. In addition, we show that a substantial number of transcription factors affected DNA methylation at their experimentally determined binding sites. We also observe genes encoding proteins with heterogenous functions that have widespread effects on DNA methylation, e.g., NFKBIE, CDCA7(L), and NLRC5, and for several examples, we suggest plausible mechanisms underlying their effect on DNA methylation. CONCLUSION: We report hundreds of genes that affect DNA methylation and provide key insights in the principles underlying epigenetic regulation.

Metabolomics Profile in Depression: A Pooled Analysis of 230 Metabolic Markers in 5283 Cases With Depression and 10,145 Controls.

BACKGROUND: Depression has been associated with metabolic alterations, which adversely impact cardiometabolic health. Here, a comprehensive set of metabolic markers, predominantly lipids, was compared between depressed and nondepressed persons. METHODS: Nine Dutch cohorts were included, comprising 10,145 control subjects and 5283 persons with depression, established with diagnostic interviews or questionnaires. A proton nuclear magnetic resonance metabolomics platform provided 230 metabolite measures: 51 lipids, fatty acids, and low-molecular-weight metabolites; 98 lipid composition and particle concentration measures of lipoprotein subclasses; and 81 lipid and fatty acids ratios. For each metabolite measure, logistic regression analyses adjusted for gender, age, smoking, fasting status, and lipid-modifying medication were performed within cohort, followed by random-effects meta-analyses. RESULTS: Of the 51 lipids, fatty acids, and low-molecular-weight metabolites, 21 were significantly related to depression (false discovery rate q < .05). Higher levels of apolipoprotein B, very-low-density lipoprotein cholesterol, triglycerides, diglycerides, total and monounsaturated fatty acids, fatty acid chain length, glycoprotein acetyls, tyrosine, and isoleucine and lower levels of high-density lipoprotein cholesterol, acetate, and apolipoprotein A1 were associated with increased odds of depression. Analyses of lipid composition indicators confirmed a shift toward less high-density lipoprotein and more very-low-density lipoprotein and triglyceride particles in depression. Associations appeared generally consistent across gender, age, and body mass index strata and across cohorts with depressive diagnoses versus symptoms. CONCLUSIONS: This large-scale meta-analysis indicates a clear distinctive profile of circulating lipid metabolites associated with depression, potentially opening new prevention or treatment avenues for depression and its associated cardiometabolic comorbidity.

Association of dietary folate and vitamin B-12 intake with genome-wide DNA methylation in blood: a large-scale epigenome-wide association analysis in 5841 individuals.

BACKGROUND: Folate and vitamin B-12 are essential micronutrients involved in the donation of methyl groups in cellular metabolism. However, associations between intake of these nutrients and genome-wide DNA methylation levels have not been studied comprehensively in humans. OBJECTIVE: The aim of this study was to assess whether folate and/or vitamin B-12 intake are asssociated with genome-wide changes in DNA methylation in leukocytes. METHODS: A large-scale epigenome-wide association study of folate and vitamin B-12 intake was performed on DNA from 5841 participants from 10 cohorts using Illumina 450k arrays. Folate and vitamin B-12 intakes were calculated from food-frequency questionnaires (FFQs). Continuous and categorical (low compared with high intake) linear regression mixed models were applied per cohort, controlling for confounders. A meta-analysis was performed to identify significant differentially methylated positions (DMPs) and regions (DMRs), and a pathway analysis was performed on the DMR annotated genes. RESULTS: The categorical model resulted in 6 DMPs, which are all negatively associated with folate intake, annotated to FAM64A, WRAP73, FRMD8, CUX1, and LCN8 genes, which have a role in cellular processes including centrosome localization, cell proliferation, and tumorigenesis. Regional analysis showed 74 folate-associated DMRs, of which 73 were negatively associated with folate intake. The most significant folate-associated DMR was a 400-base pair (bp) spanning region annotated to the LGALS3BP gene. In the categorical model, vitamin B-12 intake was associated with 29 DMRs annotated to 48 genes, of which the most significant was a 1100-bp spanning region annotated to the calcium-binding tyrosine phosphorylation-regulated gene (CABYR). Vitamin B-12 intake was not associated with DMPs. CONCLUSIONS: We identified novel epigenetic loci that are associated with folate and vitamin B-12 intake. Interestingly, we found a negative association between folate and DNA methylation. Replication of these methylation loci is necessary in future studies.

Association of maternal prenatal smoking GFI1-locus and cardio-metabolic phenotypes in 18,212 adults.

BACKGROUND: DNA methylation at the GFI1-locus has been repeatedly associated with exposure to smoking from the foetal period onwards. We explored whether DNA methylation may be a mechanism that links exposure to maternal prenatal smoking with offspring's adult cardio-metabolic health. METHODS: We meta-analysed the association between DNA methylation at GFI1-locus with maternal prenatal smoking, adult own smoking, and cardio-metabolic phenotypes in 22 population-based studies from Europe, Australia, and USA (n = 18,212). DNA methylation at the GFI1-locus was measured in whole-blood. Multivariable regression models were fitted to examine its association with exposure to prenatal and own adult smoking. DNA methylation levels were analysed in relation to body mass index (BMI), waist circumference (WC), fasting glucose (FG), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), diastolic, and systolic blood pressure (BP). FINDINGS: Lower DNA methylation at three out of eight GFI1-CpGs was associated with exposure to maternal prenatal smoking, whereas, all eight CpGs were associated with adult own smoking. Lower DNA methylation at cg14179389, the strongest maternal prenatal smoking locus, was associated with increased WC and BP when adjusted for sex, age, and adult smoking with Bonferroni-corrected P < 0·012. In contrast, lower DNA methylation at cg09935388, the strongest adult own smoking locus, was associated with decreased BMI, WC, and BP (adjusted 1 × 10-7 < P < 0.01). Similarly, lower DNA methylation at cg12876356, cg18316974, cg09662411, and cg18146737 was associated with decreased BMI and WC (5 × 10-8 < P < 0.001). Lower DNA methylation at all the CpGs was consistently associated with higher TG levels. INTERPRETATION: Epigenetic changes at the GFI1 were linked to smoking exposure in-utero/in-adulthood and robustly associated with cardio-metabolic risk factors. FUND: European Union's Horizon 2020 research and innovation programme under grant agreement no. 633595 DynaHEALTH.

Genome-wide identification of directed gene networks using large-scale population genomics data.

Identification of causal drivers behind regulatory gene networks is crucial in understanding gene function. Here, we develop a method for the large-scale inference of gene-gene interactions in observational population genomics data that are both directed (using local genetic instruments as causal anchors, akin to Mendelian Randomization) and specific (by controlling for linkage disequilibrium and pleiotropy). Analysis of genotype and whole-blood RNA-sequencing data from 3072 individuals identified 49 genes as drivers of downstream transcriptional changes (Wald P < 7 × 10-10), among which transcription factors were overrepresented (Fisher's P = 3.3 × 10-7). Our analysis suggests new gene functions and targets, including for SENP7 (zinc-finger genes involved in retroviral repression) and BCL2A1 (target genes possibly involved in auditory dysfunction). Our work highlights the utility of population genomics data in deriving directed gene expression networks. A resource of trans-effects for all 6600 genes with a genetic instrument can be explored individually using a web-based browser.

Dietary intake of advanced glycation endproducts is associated with higher levels of advanced glycation endproducts in plasma and urine: The CODAM study.

BACKGROUND & AIMS: Advanced glycation endproducts (AGEs) are formed by the reaction between reducing sugars and proteins. AGEs in the body have been associated with several age-related diseases. High-heat treated and most processed foods are rich in AGEs. The aim of our study was to investigate whether dietary AGEs, are associated with plasma and urinary AGE levels. METHODS: In 450 participants of the Cohort on Diabetes and Atherosclerosis Maastricht study (CODAM study) we measured plasma and urine concentrations of the AGEs Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL) and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) using UPLC-MS/MS. We also estimated dietary intake of CML, CEL and MG-H1 with the use of a dietary AGE database and a food frequency questionnaire (FFQ). We used linear regression to investigate the association between standardized dietary AGE intake and standardized plasma or urinary AGE levels, after adjustment for age, sex, glucose metabolism status, waist circumference, kidney function, energy- and macro-nutrient intake, smoking status, physical activity, alcohol intake, LDL-cholesterol and markers of oxidative stress. RESULTS: We found that higher intake of dietary CML, CEL and MG-H1 was associated with significantly higher levels of free plasma and urinary CML, CEL and MG-H1 (ßCML = 0.253 (95% CI 0.086; 0.415), ßCEL = 0.194 (95% CI 0.040; 0.339), ßMG-H1 = 0.223 (95% CI 0.069; 0.373) for plasma and ßCML = 0.223 (95% CI 0.049; 0.393), ßCEL = 0.180 (95% CI 0.019; 0.332), ßMG-H1 = 0.196 (95% CI 0.037; 0.349) for urine, respectively). In addition, we observed non-significant associations of dietary AGEs with their corresponding protein bound plasma AGEs. CONCLUSION: We demonstrate that higher intake of dietary AGEs is associated with higher levels of AGEs in plasma and urine. Our findings may have important implications for those who ingest a diet rich in AGEs.