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1.
J Ren Nutr ; 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31668939

RESUMO

OBJECTIVES: This study aims to investigate the separate contributions of liver fat and visceral fat on microalbuminuria and impaired renal function, and second, to examine whether non-alcoholic fatty liver disease is causally related to microalbuminuria and/or impaired renal function. METHODS: Associations between visceral adipose tissue (VAT), hepatic triglyceride content (HTGC), and risk of microalbuminuria and renal function were studied cross-sectionally in the Netherlands Epidemiology of Obesity study. Mendelian randomization using GWAS meta-analysis data was performed to estimate the causal effect of non-alcoholic fatty liver disease (PNPLA3, LYPLAL1, NCAN, GCKR) on eGFR (Nmax 118,460), microalbuminuria (Nmax 54,116), and impaired renal function (Nmax 118,147). RESULTS: In total, 2,023 participants (mean age 55.5 ± 6.0 years, 53% women) were included of which 29% had fatty liver and 2.0% chronic kidney disease stage ≥3. In joint models, VAT was associated with a 2-fold increased risk of microalbuminuria which was mainly driven by the association in women (total population: per standard deviation [SD] = 55.4 cm2, odds ratio [OR] 2.02, 95% confidence interval [CI] 1.18-3.47; women: OR 2.83, 95% CI 1.44, 5.56), but HTGC was not (total population: per SD = 7.9%, OR 1.20, 95% CI 0.85, 1.70). No associations were found for VAT and HTGC with eGFR (VAT: per SD = 55.4 cm2, OR 1.25, 95% CI 0.83, 1.87; HTGC: per SD = 7.9%, OR 0.65, 95% CI 0.42, 0.99). No causal effect of NAFLD on microalbuminuria or impaired renal function was found. CONCLUSIONS: In observational analyses, visceral fat was associated with microalbuminuria in women. Liver fat was not associated with microalbuminuria or renal function, which was supported by Mendelian randomization. Visceral fat might be more important than liver fat in the etiology of microalbuminuria.

2.
Biol Psychiatry ; 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31635762

RESUMO

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.

3.
Cardiol Ther ; 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31621037

RESUMO

INTRODUCTION: We investigated improvement of electrocardiographic LVH detection by adding measures of adiposity and/or novel electrocardiographic measures. Left ventricular hypertrophy (LVH) is an important risk factor for adverse cardiovascular outcomes. Improvement of electrocardiographic criteria for LVH is desirable, since electrocardiography is widely used. METHODS: We included 1091 participants of the Netherlands Epidemiology of Obesity Study (NEO) who underwent cardiac magnetic resonance imaging (MRI). Performance of Sokolow-Lyon and Cornell voltage and product criteria was assessed. Stepwise regression analysis was performed with each conventional electrocardiographic criterion and age, sex, body mass index (BMI), waist circumference, and waist:hip ratio (p-entry < 0.05, p-removal > 0.10). T-wave abnormalities or the spatial QRS-T angle (SA) were added to the improved models. RESULTS: The study population had a mean (SD) age of 56 (6) years, BMI of 26.1 (4.0) kg/m2 and 46% were men. MRI-LVH was present in 10% of participants. The c-statistic for Sokolow-Lyon voltage was 0.58, R2 was 0.02 and sensitivity at 90% specificity was 16%, for Sokolow-Lyon product this was 0.62, 0.02, and 21%, for Cornell voltage 0.65, 0.04, and 28% and for Cornell product 0.67, 0.04, and 25%. Best performing models were obtained by addition of both BMI and SA (Sokolow-Lyon voltage: c-statistic 0.74, R2 0.11, sensitivity of 41% at 90% specificity; Sokolow-Lyon product: 0.75, 0.12, 42%; Cornell voltage: c-statistic 0.70, R2 0.08, sensitivity of 38% at 90% specificity; Cornell product: c-statistic 0.72, R2 0.08, sensitivity of 44% at 90% specificity). CONCLUSIONS: Electrocardiographic detection of LVH improved by adding BMI and SA to a model with conventional electrocardiographic criteria. This approach would require little extra effort and application in clinical practice is feasible. However, results should first be replicated in high-risk populations.

4.
Metabolomics ; 15(10): 139, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31587110

RESUMO

INTODUCTION: Excess visceral and liver fat are known risk factors for cardiometabolic disorders. Metabolomics might allow for easier quantification of these ectopic fat depots, instead of using invasive and costly tools such as MRI or approximations such as waist circumference. OBJECTIVE: We explored the potential use of plasma metabolites as biomarkers of visceral adipose tissue (VAT) and hepatic triglyceride content (HTGC). METHODS: We performed a cross-sectional analysis of a subset of the Netherlands Epidemiology of Obesity study. Plasma metabolite profiles were determined using the Biocrates AbsoluteIDQ p150 kit in 176 individuals with normal fasting plasma glucose. VAT was assessed with magnetic resonance imaging and HTGC with proton-MR spectroscopy. We used linear regression to investigate the associations of 190 metabolite variables with VAT and HTGC. RESULTS: After adjustment for age, sex, total body fat, currently used approximations of visceral and liver fat, and multiple testing, three metabolite ratios were associated with VAT. The strongest association was the lysophosphatidylcholines to total phosphatidylcholines (PCs) ratio [- 14.1 (95% CI - 21.7; - 6.6) cm2 VAT per SD of metabolite concentration]. Four individual metabolites were associated with HTGC, especially the diacyl PCs of which C32:1 was the strongest at a 1.31 (95% CI 1.14; 1.51) fold increased HTGC per SD of metabolite concentration. CONCLUSION: Metabolomics may be a useful tool to identify biomarkers of visceral fat and liver fat content that have added diagnostic value over current approximations. Replication studies are required to validate the diagnostic value of these metabolites.

5.
Psychoneuroendocrinology ; 110: 104429, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31526909

RESUMO

OBJECTIVE: We aimed to evaluate the association between measures of adiposity with depressive mood and specific depressive symptoms. METHODS: This study was performed in the Netherlands Epidemiology of Obesity (NEO) study, a population-based study that consists of 6671 middle-aged individuals. We examined the association between measures of overall adiposity (BMI and total body fat), and abdominal adiposity (waist circumference and visceral adipose tissue), with depressive mood severity subgroups and 30 depressive symptoms. Multinomial logistic regression was performed adjusting for potential confounding. RESULTS: Measures of adiposity were associated with depressive mood in a graded fashion. Total body fat showed the strongest association with mild (Odds Ratio (OR): 1.59 per standard deviation, 95% Confidence Interval (95% CI): 1.41-1.80) and moderate to very severe (OR: 1.97, 95% CI: 1.59-2.44) depressive mood. Regarding individual symptoms of depressive mood, total body fat was associated with most depressive symptoms (strongest associations for hyperphagia and fatigability). CONCLUSIONS: In the general population, overall and abdominal adiposity measures were associated with depressive mood. This association encompasses most of the depressive symptoms and appeared to be the strongest with specific ''atypical'' neurovegetative symptoms, which may be an indication of an alteration in the energy homeostasis.

6.
Diabetes ; 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31537524

RESUMO

Early phase insulin secretion is a determinant of postprandial glucose homeostasis. In this study, we aimed to identify novel genetic variants associated with the early phase insulin response to a liquid mixed meal by a genome-wide association study using a discovery and replication design embedded in the Netherlands Epidemiology of Obesity (NEO) study. The early phase insulin response was defined as the difference between the natural logarithm transformed insulin concentrations of the postprandial state at 30 minutes after a meal challenge and the fasting state (Δinsulin). After Bonferroni correction, rs505922 (Beta (MAF, P-value): -6.5% (0.32, 3.3x10-8)) located in the ABO gene reached genome-wide significant level (p-value<5 x10-8) and was also replicated successfully (Beta (MAF, P-value): -7.8% (0.32, 7.2x10-5)). The function of the ABO gene was assessed using in vitro shRNA mediated knock-down of gene expression in the murine pancreatic ß-cell line MIN6. Knocking down the ABO gene led to decreased insulin secretion in the murine pancreatic ß-cell line. These data indicate that the previously identified elevated risk of type 2 diabetes for carriers of the ABO rs505922:C allele may be caused by decreased early phase insulin secretion.

7.
Mol Nutr Food Res ; : e1900226, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31432628

RESUMO

SCOPE: Insulin resistance (IR) and inflammation are hallmarks of type 2 diabetes (T2D). The nod-like receptor pyrin domain containing-3 (NLRP3) inflammasome is a metabolic sensor activated by saturated fatty acids (SFA) initiating IL-1ß inflammation and IR. Interactions between SFA intake and NLRP3-related genetic variants may alter T2D risk factors. METHODS: Meta-analyses of six Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n = 19 005) tested interactions between SFA and NLRP3-related single-nucleotide polymorphisms (SNPs) and modulation of fasting insulin, fasting glucose, and homeostasis model assessment of insulin resistance. RESULTS: SFA interacted with rs12143966, wherein each 1% increase in SFA intake increased insulin by 0.0063 IU mL-1 (SE ± 0.002, p = 0.001) per each major (G) allele copy. rs4925663, interacted with SFA (ß ± SE = -0.0058 ± 0.002, p = 0.004) to increase insulin by 0.0058 IU mL-1 , per additional copy of the major (C) allele. Both associations are close to the significance threshold (p < 0.0001). rs4925663 causes a missense mutation affecting NLRP3 expression. CONCLUSION: Two NLRP3-related SNPs showed potential interaction with SFA to modulate fasting insulin. Greater dietary SFA intake accentuates T2D risk, which, subject to functional validation, may be further elaborated depending on NLRP3-related genetic variants.

8.
Int J Obes (Lond) ; 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31462693

RESUMO

BACKGROUND: It is unclear to what extent adherence to dietary guidelines may specifically affect visceral fat and liver fat. We aimed to study the association between the Dutch Healthy Diet Index (DHD-index) and total body fat, visceral adipose tissue (VAT) and hepatic triglyceride content (HTGC) in middle-aged men and women. DESIGN: In this cross-sectional study, VAT was assessed by magnetic resonance imaging (MRI) in 2580 participants, and HTGC by proton-MR spectroscopy in 2083 participants. Habitual dietary intake and physical activity were estimated by questionnaire. Adherence to the current Dutch dietary guidelines was estimated by the 2015 DHD-index score based on the thirteen components (vegetables, fruit, wholegrain products, legumes, nuts, dairy, fish, tea, liquid fats, red meat, processed meat, sweetened beverages, and alcohol). The DHD-index ranges between 0 and 130 with a higher score indicating a healthier diet. We used linear regression to examine associations of the DHD-index with VAT and HTGC, adjusted for age, smoking, education, ethnicity, basal metabolic rate, energy restricted diet, menopausal state, physical activity, total energy intake, and total body fat. We additionally excluded the components one by one to examine individual contributions to the associations. RESULTS: Included participants (43% men) had a mean (SD) age of 56 (6) years and DHD-index score of 71 (15). A 10-point higher DHD-index score was associated with 2.3 cm2 less visceral fat (95% CI; -3.5; -1.0 cm2) and less liver fat (0.94 times, 95% CI; 0.90; 0.98). Of all components, exclusion of dairy attenuated the associations with TBF and VAT. CONCLUSIONS: Adherence to the dietary guidelines as estimated by the DHD-index was associated with less total body fat, and with less visceral and liver fat after adjustment for total body fat. These findings might contribute to better understanding of the mechanisms underlying associations between dietary habits and cardiometabolic diseases.

9.
J Thromb Haemost ; 17(11): 1886-1897, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31325222

RESUMO

BACKGROUND: It is insufficiently understood if there is an association between diabetes and VT, and what the underlying mechanism would be. OBJECTIVES: We aimed to study the association between glucose concentrations with several coagulation factors in the general population. METHODS: This is a cross-sectional analysis of baseline measurements within 5778 participants of the Netherlands Epidemiology of Obesity (NEO) study, a population-based cohort study of individuals 45 to 65 years. Associations between fasting glucose and HbA1c concentrations, and postprandial glucose response and factor (F) VIII, FIX, FXI, and fibrinogen levels were examined using linear regression analyses and by calculating mean levels per category of glucose concentrations while adjusting for confounding factors. RESULTS: Per each mmol/L higher fasting glucose concentration we observed higher levels of fasting FVIII (5.33%, 95% CI: 4.00-6.65), FIX (6.19%, 95% CI: 5.15-7.23), and FXI (2.11%, 95% CI: 1.20-3.02). Results for fasting HbA1c and postprandial glucose response were similar. Participants with an impaired fasting glucose, high fasting glucose, and diabetes mellitus had higher mean levels of FVIII, FIX, and FXI than those with a normal glucose metabolism, with the highest differences in the levels of FVIII, FIX, and FXI between a high fasting glucose and a normal glucose metabolism. All associations attenuated after adjustment for total body fat, yet all of the above associations remained after adjustment for the confounding factors, except for fibrinogen when contrasted to glucose. CONCLUSION: Concentrations of fasting glucose and HbA1c and postprandial glucose response were positively associated with FVIII, FIX, and FXI, and to some extent also with fibrinogen.

10.
Sci Rep ; 9(1): 9996, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31292457

RESUMO

Cholesteryl ester transfer protein (CETP) is mainly expressed by Kupffer cells in the liver. A reduction of hepatic triglyceride content (HTGC) by pioglitazone or caloric restriction is accompanied by a decrease in circulating CETP. Since GLP-1 analogues also reduce HTGC, we assessed whether liraglutide decreases CETP. Furthermore, we investigated the association between HTGC and CETP in a population-based cohort. In a placebo-controlled trial, 50 patients with type 2 diabetes were randomly assigned to treatment with liraglutide or placebo added to standard care. In this trial and in 1,611 participants of the Netherlands Epidemiology of Obesity (NEO) study, we measured HTGC and circulating CETP by proton magnetic resonance spectroscopy and ELISA, respectively. The HTGC was decreased in the liraglutide group (-6.3%; 95%CI of difference [-9.5, -3.0]) but also in the placebo group (-4.0%; 95%CI[-6.0, -2.0]), without between-group differences. CETP was not decreased by liraglutide (-0.05 µg/mL; 95%CI[-0.13, 0.04]) or placebo (-0.04 µg/mL; 95%CI[-0.12, 0.04]). No association was present between HTGC and CETP at baseline (ß: 0.002 µg/mL per %TG, 95%CI[-0.005, 0.009]) and between the changes after treatment with liraglutide (ß: 0.003 µg/mL per %TG, 95%CI[-0.010, 0.017]) or placebo (ß: 0.006 µg/mL per %TG, 95%CI[-0.012,0.024]). Also, in the cohort n o association between HTGC and CETP was present (ß: -0.001 µg/mL per SD TG, 95%CI[-0.005, 0.003]). A reduction of HTGC after treatment with liraglutide or placebo does not decrease circulating CETP. Also, no association between HTGC and CETP was present in a large cohort. These findings indicate that circulating CETP is not determined by HTGC.Clinical Trial Registration: Clinicaltrials.gov (NCT01761318).

11.
Am J Kidney Dis ; 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31358312

RESUMO

RATIONALE & OBJECTIVE: Chronic kidney disease (CKD), defined as estimated glomerular filtration rate (eGFR)<60mL/min/1.73m2, is a risk factor for cardiovascular morbidity and mortality. Little is known about low birth weight and risk for CKD in middle-aged adults in the general population. We estimated the causal association between birth weight and eGFR in a Dutch cohort of middle-aged men and women. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 6,671 participants in the Netherlands Epidemiology of Obesity (NEO) Study. Replication study using data for 133,814 participants studied by the CKDGen consortium. EXPOSURE: Birth weight was self-reported and also based on an instrumental variable, 59 birth weight-associated genetic variants, derived from an independent data source. OUTCOME: eGFR at the age of 45 to 65 years. ANALYTICAL APPROACH: We assessed the association between self-reported birth weight and eGFR in the NEO Study using multivariable linear regression, adjusted for age, sex, education, smoking, and alcohol use. The effect of the instrument on eGFR was estimated using separate 2-sample Mendelian randomization analyses: one using individual data from the NEO cohort and one using summary data from the CKDGen consortium. RESULTS: At baseline, mean eGFR was 86±12.4 (SD) mL/min/1.73m2. After multivariable adjustment, self-reported birth weight was not associated with kidney function in middle age. Two-sample Mendelian randomization analysis showed that in the NEO cohort, for each 500-g lower birth weight defined using genetic variants, there was a 3.7 (95% CI, 0.5-6.9)-mL/min/1.73m2 lower eGFR at the age of 45 to 65 years. However, using CKDGen summary-level data, there was a smaller nonsignificant relationship between birth weight and eGFR. LIMITATIONS: Birth weight was self-reported. CONCLUSIONS: Lower birth weight defined using genetic variants was associated with lower eGFRs in Dutch middle-aged adults. However, this finding was not replicated within the CKDGen consortium.

12.
PLoS One ; 14(6): e0218549, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31220183

RESUMO

INTRODUCTION: It is crucial to understand the factors that introduce variability before applying metabolomics to clinical and biomarker research. OBJECTIVES: We quantified technical and biological variability of both fasting and postprandial metabolite concentrations measured using 1H NMR spectroscopy in plasma samples. METHODS: In the Netherlands Epidemiology of Obesity study (n = 6,671), 148 metabolite concentrations (101 metabolites belonging to lipoprotein subclasses) were measured under fasting and postprandial states (150 minutes after a mixed liquid meal). Technical variability was evaluated among 265 fasting and 851 postprandial samples, with the identical blood plasma sample being measured twice by the same laboratory protocol. Biological reproducibility was assessed by measuring 165 individuals twice across time for evaluation of short- (<6 months) and long-term (>3 years) biological variability. Intra-class coefficients (ICCs) were used to assess variability. The ICCs of the fasting metabolites were compared with the postprandial metabolites using two-sided paired Wilcoxon test separately for short- and long-term measurements. RESULTS: Both fasting and postprandial metabolite concentrations showed high technical reproducibility using 1H NMR spectroscopy (median ICC = 0.99). Postprandial metabolite concentrations revealed slightly higher ICC scores than fasting ones in short-term repeat measures (median ICC in postprandial and fasting metabolite concentrations 0.72 versus 0.67, Wilcoxon p-value = 8.0×10-14). Variability did not increase further in a long-term repeat measure, with median ICC in postprandial of 0.64 and in fasting metabolite concentrations 0.66. CONCLUSION: Technical reproducibility is excellent. Biological reproducibility of postprandial metabolite concentrations showed a less or equal variability than fasting metabolite concentrations over time.

13.
Am J Clin Nutr ; 110(2): 473-484, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31190057

RESUMO

BACKGROUND: Little is known about the contribution of genetic variation to food timing, and breakfast has been determined to exhibit the most heritable meal timing. As breakfast timing and skipping are not routinely measured in large cohort studies, alternative approaches include analyses of correlated traits. OBJECTIVES: The aim of this study was to elucidate breakfast skipping genetic variants through a proxy-phenotype genome-wide association study (GWAS) for breakfast cereal skipping, a commonly assessed correlated trait. METHODS: We leveraged the statistical power of the UK Biobank (n = 193,860) to identify genetic variants related to breakfast cereal skipping as a proxy-phenotype for breakfast skipping and applied several in silico approaches to investigate mechanistic functions and links to traits/diseases. Next, we attempted validation of our approach in smaller breakfast skipping GWAS from the TwinUK (n = 2,006) and the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (n = 11,963). RESULTS: In the UK Biobank, we identified 6 independent GWAS variants, including those implicated for caffeine (ARID3B/CYP1A1), carbohydrate metabolism (FGF21), schizophrenia (ZNF804A), and encoding enzymes important for N6-methyladenosine RNA transmethylation (METTL4, YWHAB, and YTHDF3), which regulates the pace of the circadian clock. Expression of identified genes was enriched in the cerebellum. Genome-wide correlation analyses indicated positive correlations with anthropometric traits. Through Mendelian randomization (MR), we observed causal links between genetically determined breakfast skipping and higher body mass index, more depressive symptoms, and smoking. In bidirectional MR, we demonstrated a causal link between being an evening person and skipping breakfast, but not vice versa. We observed association of our signals in an independent breakfast skipping GWAS in another British cohort (P = 0.032), TwinUK, but not in a meta-analysis of non-British cohorts from the CHARGE consortium (P = 0.095). CONCLUSIONS: Our proxy-phenotype GWAS identified 6 genetic variants for breakfast skipping, linking clock regulation with food timing and suggesting a possible beneficial role of regular breakfast intake as part of a healthy lifestyle.

14.
J Nutr ; 149(4): 649-658, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30949667

RESUMO

BACKGROUND: Fatty liver is the leading cause of chronic liver diseases and increases the risk of cardiovascular disease. Besides alcohol consumption, energy-containing nonalcoholic beverages may contribute to liver fat accumulation. OBJECTIVE: We aimed to study the consumption of alcoholic and nonalcoholic beverages and their mutual replacement in relation to hepatic triglyceride content (HTGC) in middle-aged men and women. METHODS: In this cross-sectional analysis, HTGC was assessed by proton magnetic resonance spectroscopy. Habitual consumption of alcoholic and nonalcoholic beverages was assessed using a validated food-frequency questionnaire. All beverages were converted to standard servings and to percentage of total energy intake (En%). We performed linear regression to examine the association of alcoholic and nonalcoholic beverages with HTGC, adjusted for age, sex, smoking, education, ethnicity, physical activity, total energy intake, and total body fat. We studied replacement of alcoholic beverages with nonalcoholic beverages per 1 serving/d and per 5 En%/d. RESULTS: After exclusion of individuals with missing values, 1966 participants (47% men) were analyzed, with a mean ± SD age of 55 ± 6 y, BMI of 26 ± 4 kg/m2, and HTGC of 5.7% ± 7.9%. Each extra alcoholic serving per day was associated with more liver fat (1.09 times; 95% CI: 1.05, 1.12). Replacing 5 En% of alcoholic beverages with milk was associated with less liver fat (0.89 times; 95% CI: 0.81, 0.98), whereas replacement with 5 En% of sugar-sweetened beverages was associated with liver fat to an extent similar to alcoholic beverages (1.00 times; 95% CI: 0.91, 1.09). CONCLUSION: In a population-based cohort, consumption of each extra daily alcoholic beverage was associated with more liver fat. In isocaloric replacement of alcoholic beverages, milk was associated with less liver fat, whereas sugar-sweetened beverages were equally associated with liver fat. This suggests that intake of alcohol and sugars may contribute to liver fat accumulation. This trial was registered at clinicaltrials.gov as NCT03410316.

15.
JAMA Neurol ; 76(6): 650-656, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30933216

RESUMO

Importance: Nine hereditary neurodegenerative diseases are known as polyglutamine diseases, including Huntington disease, 6 spinocerebellar ataxias (SCAs) (SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17), dentatorubral-pallidoluysion atrophy, and spinal bulbar muscular atrophy. Objective: To determine the prevalence of carriers of intermediate and pathological polyglutamine disease-associated alleles among the general population. Design, Setting, and Participants: This observational cross-sectional study included data from 5 large European population-based cohorts that were compiled between 1997 and 2012, and the analyses were conducted in 2018. In total, 16 547 DNA samples were obtained from participants of the 5 cohorts. Individuals with a lifetime diagnosis of major depression were excluded (n = 2351). In the remaining 14 196 participants without an established polyglutamine disease diagnosis, the CAG repeat size in both alleles of all 9 polyglutamine disease-associated genes (PDAGs) (ie, ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, HTT, ATN1, and AR) was determined. Exposure: The number of CAG repeats in the alleles of the 9 PDAGs. Main Outcomes and Measures: The number of individuals with alleles within the intermediate or pathological range per PDAG, as well as differences in sex, age, and body mass index between individuals carrying alleles within the normal or intermediate range and individuals carrying alleles within the pathological range of PDAGs. Results: In the 14 196 analyzed participants (age range, 18-99 years; 56.3% female), 10.7% had a CAG repeat number within the intermediate range of at least 1 PDAG. Moreover, up to 1.3% of the participants had a CAG repeat number within the disease-causing range, predominantly in the lower pathological range associated with elderly onset. No differences in sex, age, or body mass index were found between individuals with CAG repeat numbers within the pathological range and individuals with CAG repeat numbers within the normal or intermediate range. Conclusions and Relevance: These results indicate a high prevalence of individuals carrying intermediate and pathological ranges of polyglutamine disease-associated alleles among the general population. Therefore, a substantially larger proportion of individuals than previously estimated may be at risk of developing a polyglutamine disease later in life or bearing children with a de novo mutation.

16.
J Am Heart Assoc ; 8(9): e010810, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31017036

RESUMO

Background Identifying associations between serum metabolites and visceral adipose tissue ( VAT ) could provide novel biomarkers of VAT and insights into the pathogenesis of obesity-related diseases. We aimed to discover and replicate metabolites reflecting pathways related to VAT . Methods and Results Associations between fasting serum metabolites and VAT area (by computed tomography or magnetic resonance imaging) were assessed with cross-sectional linear regression of individual-level data from participants in MESA (Multi-Ethnic Study of Atherosclerosis; discovery, N=1103) and the NEO (Netherlands Epidemiology of Obesity) study (replication, N=2537). Untargeted 1H nuclear magnetic resonance metabolomics profiling of serum was performed in MESA, and metabolites were replicated in the NEO study using targeted 1H nuclear magnetic resonance spectroscopy. A total of 30 590 metabolomic spectral variables were evaluated. After adjustment for age, sex, race/ethnicity, socioeconomic status, smoking, physical activity, glucose/lipid-lowering medication, and body mass index, 2104 variables representing 24 nonlipid and 49 lipid/lipoprotein subclass metabolites remained significantly associated with VAT ( P=4.88×10-20-1.16×10-3). These included conventional metabolites, amino acids, acetylglycoproteins, intermediates of glucose and hepatic metabolism, organic acids, and subclasses of apolipoproteins, cholesterol, phospholipids, and triglycerides. Metabolites mapped to 31 biochemical pathways, including amino acid substrate use/metabolism and glycolysis/gluconeogenesis. In the replication cohort, acetylglycoproteins, branched-chain amino acids, lactate, glutamine (inversely), and atherogenic lipids remained associated with VAT ( P=1.90×10-35-8.46×10-7), with most associations remaining after additional adjustment for surrogates of VAT (glucose level, waist circumference, and serum triglycerides), reflecting novel independent associations. Conclusions We identified and replicated a metabolite panel associated with VAT in 2 community-based cohorts. These findings persisted after adjustment for body mass index and appear to define a metabolic signature of visceral adiposity.

17.
Am J Hum Genet ; 104(1): 112-138, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30595373

RESUMO

Mitochondria (MT), the major site of cellular energy production, are under dual genetic control by 37 mitochondrial DNA (mtDNA) genes and numerous nuclear genes (MT-nDNA). In the CHARGEmtDNA+ Consortium, we studied genetic associations of mtDNA and MT-nDNA associations with body mass index (BMI), waist-hip-ratio (WHR), glucose, insulin, HOMA-B, HOMA-IR, and HbA1c. This 45-cohort collaboration comprised 70,775 (insulin) to 170,202 (BMI) pan-ancestry individuals. Validation and imputation of mtDNA variants was followed by single-variant and gene-based association testing. We report two significant common variants, one in MT-ATP6 associated (p ≤ 5E-04) with WHR and one in the D-loop with glucose. Five rare variants in MT-ATP6, MT-ND5, and MT-ND6 associated with BMI, WHR, or insulin. Gene-based meta-analysis identified MT-ND3 associated with BMI (p ≤ 1E-03). We considered 2,282 MT-nDNA candidate gene associations compiled from online summary results for our traits (20 unique studies with 31 dataset consortia's genome-wide associations [GWASs]). Of these, 109 genes associated (p ≤ 1E-06) with at least 1 of our 7 traits. We assessed regulatory features of variants in the 109 genes, cis- and trans-gene expression regulation, and performed enrichment and protein-protein interactions analyses. Of the identified mtDNA and MT-nDNA genes, 79 associated with adipose measures, 49 with glucose/insulin, 13 with risk for type 2 diabetes, and 18 with cardiovascular disease, indicating for pleiotropic effects with health implications. Additionally, 21 genes related to cholesterol, suggesting additional important roles for the genes identified. Our results suggest that mtDNA and MT-nDNA genes and variants reported make important contributions to glucose and insulin metabolism, adipocyte regulation, diabetes, and cardiovascular disease.


Assuntos
DNA Mitocondrial/genética , Genes Mitocondriais/genética , Variação Genética/genética , Metabolismo/genética , Mitocôndrias/genética , Mitocôndrias/metabolismo , Adipócitos/metabolismo , Índice de Massa Corporal , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Estudos de Coortes , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Glucose/metabolismo , Hemoglobina A Glicada/metabolismo , Humanos , Insulina/metabolismo , Locos de Características Quantitativas , Relação Cintura-Quadril
18.
J Nutr ; 149(2): 304-313, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30657914

RESUMO

BACKGROUND: Visceral adipose tissue (VAT) and hepatic triglyceride content (HTGC) are major risk factors for cardiometabolic diseases. OBJECTIVE: We aimed to investigate the association of dietary intake of the main food groups with VAT and HTGC in middle-aged men and women. METHODS: We used data from the Netherlands Epidemiology of Obesity study, a population-based study including 6671 participants aged 45-65 y at baseline. In this cross-sectional analysis, VAT and HTGC were assessed by magnetic resonance imaging and spectroscopy, respectively, as the primary outcomes. Habitual intake of main food groups (dairy, meat, fish, fruits and vegetables, sweet snacks, and fats and oils) was estimated through the use of a food-frequency questionnaire. We examined associations of intake of different food groups with VAT and HTGC by linear regression analysis stratified by sex and adjusted for age, smoking, education, ethnicity, physical activity, basal metabolic rate, energy-restricted diet, menopausal state, and total energy intake. RESULTS: In women, a 100-g/d higher intake of dairy was associated with 2.0 cm2 less VAT (95% CI: -3.4, -0.7 cm2) and a 0.95-fold lower HTGC (95% CI: 0.90-, 0.99-fold). Moreover, a 100-g/d higher intake of fruit and vegetables was associated with 1.6 cm2 less VAT (95% CI: -2.9, -0.2 cm2) in women. Fruit and vegetables were negatively associated (0.95; 95% CI: 0.91, 1.00) with HTGC, and sweet snacks were positively associated (1.29; 95% CI: 1.03, 1.63). Patterns were weaker but similar in men. Fish intake was not associated with VAT or HTGC and plant-based fat and oil intake were only associated with VAT after adjustment for total body fat. CONCLUSIONS: Despite some variation in the strength of the associations between men and women, dietary intake of sweet snacks was positively associated with HTGC, and fruit and vegetable intake were negatively associated with visceral and liver fat content. Prospective studies are needed to confirm these results. The Netherlands Epidemiology of Obesity study is registered at clinicaltrials.gov with identifier NCT03410316.


Assuntos
Fígado Gorduroso/etiologia , Frutas , Gordura Intra-Abdominal , Lanches , Verduras , Adulto , Idoso , Estudos Transversais , Dieta , Feminino , Análise de Alimentos , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade
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