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Article: Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels

Herder, Christian

Nature Communications, 7:10494

2016

Abstract: Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating ... ...

Institution	Deutsches Diabetes-Zentrum
Abstract	Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10−6 in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10−8) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
Language	English
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Database	Repository for Life Sciences

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Article: DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases

Herder, Christian

Genome biology, 17:255

2016

Abstract: BACKGROUND: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel ... ...

Institution	Deutsches Diabetes-Zentrum
Abstract	BACKGROUND: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation. RESULTS: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10–7) in the discovery panel of European ancestry and replicated (P < 2.29 × 10–4) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10–5), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10–3), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10–5). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants. CONCLUSION: We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.
Keywords	Coronary heart disease ; Body mass index ; C-reactive protein ; DNA methylation ; Diabetes ; Epigenome-wide association study ; Inflammation
Language	English
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Database	Repository for Life Sciences

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Article: A DNA methylation biomarker of alcohol consumption

Herder, Christian

Molecular psychiatry, 23:422-433

2016

Abstract: The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we ... ...

Institution	Deutsches Diabetes-Zentrum
Abstract	The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal=13 317; 54% women; mean age across cohorts 42–76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90–0.99) for current heavy alcohol intake (42 g per day in men and 28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1 × 10−7. Analysis of the monocyte-derived DNA (n=1251) identified 62 alcohol-related CpGs at P<1 × 10-7. In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption.
Keywords	Genetics
Language	English
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Article: Anxiety Associated Increased CpG Methylation in the Promoter of Asb1: A Translational Approach Evidenced by Epidemiological and Clinical Studies and a Murine Model

Roden, Michael / Herder, Christian

Neuropsychopharmacology, 43:342–353

2017

Abstract: Epigenetic regulation in anxiety is suggested, but evidence from large studies is needed. We conducted an epigenome-wide association study (EWAS) on anxiety in a population-based cohort and validated our finding in a clinical cohort as well as a murine ... ...

Institution	Deutsches Diabetes-Zentrum
Abstract	Epigenetic regulation in anxiety is suggested, but evidence from large studies is needed. We conducted an epigenome-wide association study (EWAS) on anxiety in a population-based cohort and validated our finding in a clinical cohort as well as a murine model. In the KORA cohort, participants (n=1522, age 32–72 years) were administered the Generalized Anxiety Disorder (GAD-7) instrument, whole blood DNA methylation was measured (Illumina 450K BeadChip), and circulating levels of hs-CRP and IL-18 were assessed in the association between anxiety and methylation. DNA methylation was measured using the same instrument in a study of patients with anxiety disorders recruited at the Max Planck Institute of Psychiatry (MPIP, 131 non-medicated cases and 169 controls). To expand our mechanistic understanding, these findings were reverse translated in a mouse model of acute social defeat stress. In the KORA study, participants were classified according to mild, moderate, or severe levels of anxiety (29.4%/6.0%/1.5%, respectively). Severe anxiety was associated with 48.5% increased methylation at a single CpG site (cg12701571) located in the promoter of the gene encoding Asb1 (β-coefficient=0.56 standard error (SE)=0.10, p (Bonferroni)=0.005), a protein hypothetically involved in regulation of cytokine signaling. An interaction between IL-18 and severe anxiety with methylation of this CpG cite showed a tendency towards significance in the total population (p=0.083) and a significant interaction among women (p=0.014). Methylation of the same CpG was positively associated with Panic and Agoraphobia scale (PAS) scores (β=0.005, SE=0.002, p=0.021, n=131) among cases in the MPIP study. In a murine model of acute social defeat stress, Asb1 gene expression was significantly upregulated in a tissue-specific manner (p=0.006), which correlated with upregulation of the neuroimmunomodulating cytokine interleukin 1 beta. Our findings suggest epigenetic regulation of the stress-responsive Asb1 gene in anxiety-related phenotypes. Further studies are necessary to elucidate the causal direction of this association and the potential role of Asb1-mediated immune dysregulation in anxiety disorders.
Language	English
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Article: Carbohydrates from Sources with a Higher Glycemic Index during Adolescence: Is Evening Rather than Morning Intake Relevant for Risk Markers of Type 2 Diabetes in Young Adulthood?

Herder, Christian / Roden, Michael

Nutrients, 9(6):591

2017

Abstract: BACKGROUND: This study investigated whether glycemic index (GI) or glycemic load (GL) of morning or evening intake and morning or evening carbohydrate intake from low- or higher-GI food sources (low-GI-CHO, higher-GI-CHO) during adolescence are relevant ... ...

Institution	Deutsches Diabetes-Zentrum
Abstract	BACKGROUND: This study investigated whether glycemic index (GI) or glycemic load (GL) of morning or evening intake and morning or evening carbohydrate intake from low- or higher-GI food sources (low-GI-CHO, higher-GI-CHO) during adolescence are relevant for risk markers of type 2 diabetes in young adulthood. METHODS: Analyses included DOrtmund Nutritional and Anthropometric Longitudinally Designed (DONALD) study participants who had provided at least two 3-day weighed dietary records (median: 7 records) during adolescence and one blood sample in young adulthood. Using multivariable linear regression analyses, estimated morning and evening GI, GL, low-GI-CHO (GI < 55) and higher-GI-CHO (GI ≥ 55) were related to insulin sensitivity (N = 252), hepatic steatosis index (HSI), fatty liver index (FLI) (both N = 253), and a pro-inflammatory-score (N = 249). RESULTS: Morning intakes during adolescence were not associated with any of the adult risk markers. A higher evening GI during adolescence was related to an increased HSI in young adulthood (p = 0.003). A higher consumption of higher-GI-CHO in the evening was associated with lower insulin sensitivity (p = 0.046) and an increased HSI (p = 0.006), while a higher evening intake of low-GI-CHO was related to a lower HSI (p = 0.009). Evening intakes were not related to FLI or the pro-inflammatory-score (all p > 0.1). CONCLUSION: Avoidance of large amounts of carbohydrates from higher-GI sources in the evening should be considered in preventive strategies to reduce the risk of type 2 diabetes in adulthood.
Keywords	adolescence ; glycaemic index ; glycaemic load ; daytime ; type 2 diabetes mellitus
Language	English
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Database	Repository for Life Sciences

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Article: An 8-week diet high in cereal fiber and coffee but free of red meat does not improve beta-cell function in patients with type 2 diabetes mellitus: a randomized controlled trial

Bierwagen, Alessandra / Herder, Christian / Roden, Michael / Szendroedi, Julia

Nutrition & metabolism, 15:90

2018

Abstract: BACKGROUND: Higher dietary intake of fibers and coffee, but lower red meat intake is associated with reduced risk for type 2 diabetes in epidemiological studies. We hypothesized that a calorie-restricted diet, which is high in fiber and coffee, but free ... ...

Institution	Deutsches Diabetes-Zentrum
Abstract	BACKGROUND: Higher dietary intake of fibers and coffee, but lower red meat intake is associated with reduced risk for type 2 diabetes in epidemiological studies. We hypothesized that a calorie-restricted diet, which is high in fiber and coffee, but free of red meat, improves beta-cell function in patients with T2D. METHODS: In a randomized parallel-group pilot trial, obese type 2 diabetes patients were randomly allocated to consume either a diet high in cereal fiber and coffee, but free of red meat (n = 17) (L-RISK) or a diet low in fiber, free of coffee but high in red meat (n = 20) (H-RISK) for 8 weeks. Insulin secretion was assessed from glucagon stimulation tests (GST) and mixed-meal tolerance tests (MMTT) before and after dietary intervention. RESULTS: Both diets resulted in comparable reduction of fasting concentrations of insulin (H-RISK -28% vs. L-RISK -32%, both p < 0.01), C-peptide (H-RISK -26% vs. L-RISK -30%, both p < 0.01) and blood glucose (H-RISK -6.8%, p < 0.05 vs. L-RISK -10%, p < 0.01). Gastric inhibitory peptide (GIP) secretion increased by 24% after 8 weeks in the L-RISK only (p < 0.01). However, GST and MMTT showed no differences in insulin secretion after intervention. CONCLUSIONS: Calorie restriction independent of the intake of fiber, coffee or meat failed to improve beta-cell function, but improved GIP secretion in obese patients with type 2 diabetes. TRIAL REGISTRATION: Registration at Clinicaltrials.gov, Identifier number: NCT01409330, Registered 4 August 2011 – Retrospectively registered.
Keywords	Coffee ; Calorie restriction ; Beta-cell function ; Dietary fiber ; Red meat
Language	English
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Article: Discovery and Fine-Mapping of Glycaemic and Obesity-Related Trait Loci Using High-Density Imputation

Herder, Christian / Roden, Michael

PLoS Genetics, 11(7):e1005230

2015

Abstract: Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic ...

Institution	Deutsches Diabetes-Zentrum
Abstract	Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.
Keywords	Body mass index ; Genome-wide association studies ; Genomic signal processing ; Obesity ; Molecular genetics ; Meta-analysis ; Quality control ; Quantitative trait loci
Language	English
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Article: Serum Chemerin Concentrations Associate with Beta-Cell Function, but Not with Insulin Resistance in Individuals with Non-Alcoholic Fatty Liver Disease (NAFLD)

Herder, Christian / Roden, Michael

PLOS ONE, 10(5):e0124935

2015

Abstract: The novel adipokine chemerin has been related to insulin-resistant states such as obesity and non alcoholic fatty liver disease (NAFLD). However, its association with insulin resistance and beta cell function remains controversial. The main objective was ...

Institution	Deutsches Diabetes-Zentrum
Abstract	The novel adipokine chemerin has been related to insulin-resistant states such as obesity and non alcoholic fatty liver disease (NAFLD). However, its association with insulin resistance and beta cell function remains controversial. The main objective was to examine whether serum chemerin levels associate with insulin sensitivity and beta cell function independently of body mass index (BMI), by studying consecutive outpatients of the hepatology clinics of a European university hospital. Individuals (n=196) with NAFLD were stratified into persons with normal glucose tolerance (NGT; n=110), impaired glucose tolerance (IGT; n=51) and type 2 diabetes (T2D; n=35) and the association between serum chemerin and measures of insulin sensitivity and beta cell function as assessed during fasting and during oral glucose tolerance test (OGTT) was measured. Our results showed that serum chemerin positively associated with BMI (P=0.0007) and C peptide during OGTT (P<0.004), but not with circulating glucose, insulin, lipids or liver enzymes (all P>0.18). No BMI independent relationships of chemerin with fasting and OGTT derived measures of insulin sensitivity were found (P>0.5). Chemerin associated positively with fasting beta cell function as well as the OGTT derived insulinogenic index IGI_cp and the adaptation index after adjustment for age, sex and BMI (P=0.002-0.007), and inversely with the insulin/C peptide ratio (P=0.007). Serum chemerin neither related to the insulinogenic index IGI_ins nor the disposition index. In conclusion, circulating chemerin is likely linked to enhanced beta cell function but not to insulin sensitivity in patients with NAFLD.
Keywords	Glucose tolerance ; Glucose tolerance tests ; Fatty liver ; Insulin ; Insulin resistance ; Insulin secretion ; Obesity ; Type 2 diabetes
Language	English
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Article: Differential Patterns and Determinants of Cardiac Autonomic Nerve Dysfunction during Endotoxemia and Oral Fat Load in Humans

Ziegler, Dan / Herder, Christian

PLOS ONE, 10(4):e0124242

2015

Abstract: The autonomic nervous system (ANS) plays an important role in regulating the metabolic homeostasis and controlling immune function. ANS alterations can be detected by reduced heart rate variability (HRV) in conditions like diabetes and sepsis. We ... ...

Institution	Deutsches Diabetes-Zentrum
Abstract	The autonomic nervous system (ANS) plays an important role in regulating the metabolic homeostasis and controlling immune function. ANS alterations can be detected by reduced heart rate variability (HRV) in conditions like diabetes and sepsis. We determined the effects of experimental conditions mimicking inflammation and hyperlipidemia on HRV and heart rate (HR) in relation to the immune, metabolic, and hormonal responses resulting from these interventions. Sixteen lean healthy subjects received intravenous (i.v.) low-dose endotoxin (lipopolysaccharide [LPS]), i.v. fat, oral fat, and i.v. glycerol (control) for 6 hours, during which immune, metabolic, hormonal, and five HRV parameters (pNN50, RMSSD, low-frequency (LF) and high-frequency (HF) power, and LF/HF ratio) were monitored and energy metabolism and insulin sensitivity (M-value) were assessed. LPS infusion induced an increase (AUC) in HR and LF/HF ratio and decline in pNN50 and RMSSD, while oral fat resulted in elevated HR and a transient (hours 1-2) decrease in pNN50, RMSSD, and HF power. During LPS infusion, ΔIL-1ra levels and ΔIL-1ra and ΔIL-1ß gene expression correlated positively with ΔLF/HF ratio and inversely with ΔRMSSD. During oral fat intake, ΔGLP-1 tended to correlate positively with ΔHR and inversely with ΔpNN50 and ΔRMSSD. Following LPS infusion, lipid oxidation correlated positively with HR and inversely with pNN50 and RMSSD, whereas HRV was not related to M-value. In conclusion, suppression of vagal tone and sympathetic predominance during endotoxemia are linked to anti-inflammatory processes and lipid oxidation but not to insulin resistance, while weaker HRV changes in relation to the GLP-1 response are noted during oral fat load.
Keywords	Cytokines ; Gene expression ; Glycerol ; Fats ; Heart rate ; Inflammation ; Oxidation ; Lipids
Language	English
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Article: Cell Specific eQTL Analysis without Sorting Cells

Herder, Christian / Roden, Michael

PLoS Genetics, 11(5):e1005223

2015

Abstract: The functional consequences of trait associated SNPs are often investigated using expression quantitative trait locus (eQTL) mapping. While trait-associated variants may operate in a cell-type specific manner, eQTL datasets for such cell-types may not ... ...

Institution	Deutsches Diabetes-Zentrum
Abstract	The functional consequences of trait associated SNPs are often investigated using expression quantitative trait locus (eQTL) mapping. While trait-associated variants may operate in a cell-type specific manner, eQTL datasets for such cell-types may not always be available. We performed a genome-environment interaction (GxE) meta-analysis on data from 5,683 samples to infer the cell type specificity of whole blood cis-eQTLs. We demonstrate that this method is able to predict neutrophil and lymphocyte specific cis-eQTLs and replicate these predictions in independent cell-type specific datasets. Finally, we show that SNPs associated with Crohn’s disease preferentially affect gene expression within neutrophils, including the archetypal NOD2 locus.
Keywords	Blood ; Gene expression ; Gene mapping ; Genome-wide association studies ; Monocytes ; Meta-analysis ; Neutrophils ; Principal component analysis
Language	English
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