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1.
EMBO J ; : e101982, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31633821

RESUMO

Cellular senescence has been shown to contribute to skin ageing. However, the role of melanocytes in the process is understudied. Our data show that melanocytes are the only epidermal cell type to express the senescence marker p16INK4A during human skin ageing. Aged melanocytes also display additional markers of senescence such as reduced HMGB1 and dysfunctional telomeres, without detectable telomere shortening. Additionally, senescent melanocyte SASP induces telomere dysfunction in paracrine manner and limits proliferation of surrounding cells via activation of CXCR3-dependent mitochondrial ROS. Finally, senescent melanocytes impair basal keratinocyte proliferation and contribute to epidermal atrophy in vitro using 3D human epidermal equivalents. Crucially, clearance of senescent melanocytes using the senolytic drug ABT737 or treatment with mitochondria-targeted antioxidant MitoQ suppressed this effect. In conclusion, our study provides proof-of-concept evidence that senescent melanocytes affect keratinocyte function and act as drivers of human skin ageing.

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.
Eur J Epidemiol ; 34(11): 1055-1074, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31494793

RESUMO

Inferring a person's smoking habit and history from blood is relevant for complementing or replacing self-reports in epidemiological and public health research, and for forensic applications. However, a finite DNA methylation marker set and a validated statistical model based on a large dataset are not yet available. Employing 14 epigenome-wide association studies for marker discovery, and using data from six population-based cohorts (N = 3764) for model building, we identified 13 CpGs most suitable for inferring smoking versus non-smoking status from blood with a cumulative Area Under the Curve (AUC) of 0.901. Internal fivefold cross-validation yielded an average AUC of 0.897 ± 0.137, while external model validation in an independent population-based cohort (N = 1608) achieved an AUC of 0.911. These 13 CpGs also provided accurate inference of current (average AUCcrossvalidation 0.925 ± 0.021, AUCexternalvalidation0.914), former (0.766 ± 0.023, 0.699) and never smoking (0.830 ± 0.019, 0.781) status, allowed inferring pack-years in current smokers (10 pack-years 0.800 ± 0.068, 0.796; 15 pack-years 0.767 ± 0.102, 0.752) and inferring smoking cessation time in former smokers (5 years 0.774 ± 0.024, 0.760; 10 years 0.766 ± 0.033, 0.764; 15 years 0.767 ± 0.020, 0.754). Model application to children revealed highly accurate inference of the true non-smoking status (6 years of age: accuracy 0.994, N = 355; 10 years: 0.994, N = 309), suggesting prenatal and passive smoking exposure having no impact on model applications in adults. The finite set of DNA methylation markers allow accurate inference of smoking habit, with comparable accuracy as plasma cotinine use, and smoking history from blood, which we envision becoming useful in epidemiology and public health research, and in medical and forensic applications.

4.
Nat Commun ; 10(1): 3669, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31413261

RESUMO

Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.

5.
Commun Biol ; 2: 285, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396565

RESUMO

Brain lobar volumes are heritable but genetic studies are limited. We performed genome-wide association studies of frontal, occipital, parietal and temporal lobe volumes in 16,016 individuals, and replicated our findings in 8,789 individuals. We identified six genetic loci associated with specific lobar volumes independent of intracranial volume. Two loci, associated with occipital (6q22.32) and temporal lobe volume (12q14.3), were previously reported to associate with intracranial and hippocampal volume, respectively. We identified four loci previously unknown to affect brain volumes: 3q24 for parietal lobe volume, and 1q22, 4p16.3 and 14q23.1 for occipital lobe volume. The associated variants were located in regions enriched for histone modifications (DAAM1 and THBS3), or close to genes causing Mendelian brain-related diseases (ZIC4 and FGFRL1). No genetic overlap between lobar volumes and neurological or psychiatric diseases was observed. Our findings reveal part of the complex genetics underlying brain development and suggest a role for regulatory regions in determining brain volumes.

6.
Sci Rep ; 9(1): 11623, 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31406173

RESUMO

Telomere shortening has been associated with multiple age-related diseases such as cardiovascular disease, diabetes, and dementia. However, the biological mechanisms responsible for these associations remain largely unknown. In order to gain insight into the metabolic processes driving the association of leukocyte telomere length (LTL) with age-related diseases, we investigated the association between LTL and serum metabolite levels in 7,853 individuals from seven independent cohorts. LTL was determined by quantitative polymerase chain reaction and the levels of 131 serum metabolites were measured with mass spectrometry in biological samples from the same blood draw. With partial correlation analysis, we identified six metabolites that were significantly associated with LTL after adjustment for multiple testing: lysophosphatidylcholine acyl C17:0 (lysoPC a C17:0, p-value = 7.1 × 10-6), methionine (p-value = 9.2 × 10-5), tyrosine (p-value = 2.1 × 10-4), phosphatidylcholine diacyl C32:1 (PC aa C32:1, p-value = 2.4 × 10-4), hydroxypropionylcarnitine (C3-OH, p-value = 2.6 × 10-4), and phosphatidylcholine acyl-alkyl C38:4 (PC ae C38:4, p-value = 9.0 × 10-4). Pathway analysis showed that the three phosphatidylcholines and methionine are involved in homocysteine metabolism and we found supporting evidence for an association of lipid metabolism with LTL. In conclusion, we found longer LTL associated with higher levels of lysoPC a C17:0 and PC ae C38:4, and with lower levels of methionine, tyrosine, PC aa C32:1, and C3-OH. These metabolites have been implicated in inflammation, oxidative stress, homocysteine metabolism, and in cardiovascular disease and diabetes, two major drivers of morbidity and mortality.

7.
Sci Rep ; 9(1): 12370, 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31451722

RESUMO

In the past few years, the gut microbiome has been shown to play an important role in various disorders including in particular cardiovascular diseases. Especially the metabolite trimethylamine-N-oxide (TMAO), which is produced by gut microbial metabolism, has repeatedly been associated with an increased risk for cardiovascular events. Here we report a fast liquid chromatography tandem mass spectrometry (LC-MS/MS) method that can analyze the five most important gut metabolites with regards to TMAO in three minutes. Fast liquid chromatography is unconventionally used in this method as an on-line cleanup step to remove the most important ion suppressors leaving the gut metabolites in a cleaned flow through fraction, also known as negative chromatography. We compared different blood matrix types to recommend best sampling practices and found citrated plasma samples demonstrated lower concentrations for all analytes and choline concentrations were significantly higher in serum samples. We demonstrated the applicability of our method by investigating the effect of a standardized liquid meal (SLM) after overnight fasting of 25 healthy individuals on the gut metabolite levels. The SLM did not significantly change the levels of gut metabolites in serum.

8.
Nat Commun ; 10(1): 3346, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31431621

RESUMO

Predicting longer-term mortality risk requires collection of clinical data, which is often cumbersome. Therefore, we use a well-standardized metabolomics platform to identify metabolic predictors of long-term mortality in the circulation of 44,168 individuals (age at baseline 18-109), of whom 5512 died during follow-up. We apply a stepwise (forward-backward) procedure based on meta-analysis results and identify 14 circulating biomarkers independently associating with all-cause mortality. Overall, these associations are similar in men and women and across different age strata. We subsequently show that the prediction accuracy of 5- and 10-year mortality based on a model containing the identified biomarkers and sex (C-statistic = 0.837 and 0.830, respectively) is better than that of a model containing conventional risk factors for mortality (C-statistic = 0.772 and 0.790, respectively). The use of the identified metabolic profile as a predictor of mortality or surrogate endpoint in clinical studies needs further investigation.

9.
Neurology ; 92(16): e1899-e1911, 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30944236

RESUMO

OBJECTIVE: To identify a plasma metabolomic biomarker signature for migraine. METHODS: Plasma samples from 8 Dutch cohorts (n = 10,153: 2,800 migraine patients and 7,353 controls) were profiled on a 1H-NMR-based metabolomics platform, to quantify 146 individual metabolites (e.g., lipids, fatty acids, and lipoproteins) and 79 metabolite ratios. Metabolite measures associated with migraine were obtained after single-metabolite logistic regression combined with a random-effects meta-analysis performed in a nonstratified and sex-stratified manner. Next, a global test analysis was performed to identify sets of related metabolites associated with migraine. The Holm procedure was applied to control the family-wise error rate at 5% in single-metabolite and global test analyses. RESULTS: Decreases in the level of apolipoprotein A1 (ß -0.10; 95% confidence interval [CI] -0.16, -0.05; adjusted p = 0.029) and free cholesterol to total lipid ratio present in small high-density lipoprotein subspecies (HDL) (ß -0.10; 95% CI -0.15, -0.05; adjusted p = 0.029) were associated with migraine status. In addition, only in male participants, a decreased level of omega-3 fatty acids (ß -0.24; 95% CI -0.36, -0.12; adjusted p = 0.033) was associated with migraine. Global test analysis further supported that HDL traits (but not other lipoproteins) were associated with migraine status. CONCLUSIONS: Metabolic profiling of plasma yielded alterations in HDL metabolism in migraine patients and decreased omega-3 fatty acids only in male migraineurs.

10.
Metabolomics ; 15(2): 23, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30830468

RESUMO

BACKGROUND: We aimed to identify novel metabolite and lipid signatures connected with the metabolic syndrome in a Dutch middle-aged population. METHODS: 115 individuals with a metabolic syndrome score ranging from 0 to 5 [50 cases of the metabolic syndrome (score ≥ 3) and 65 controls] were enrolled from the Leiden Longevity Study, and LC/GC-MS metabolomics and lipidomics profiling were performed on fasting plasma samples. Data were analysed with principal component analysis and orthogonal projections to latent structures (OPLS) to study metabolite/lipid signatures associated with the metabolic syndrome. In addition, univariate analyses were done with linear regression, adjusted for age and sex, for the study of individual metabolites/lipids in relation to the metabolic syndrome. RESULTS: Data was available on 103 metabolites and 223 lipids. In the OPLS model with metabolic syndrome score (Y-variable), 9 metabolites were negatively correlated and 26 metabolites (mostly acylcarnitines, amino acids and keto acids) were positively correlated with the metabolic syndrome score. In addition, a total of 100 lipids (mainly triacylglycerides) were positively correlated and 10 lipids from different lipid classes were negatively correlated with the metabolic syndrome score. In the univariate analyses, the metabolic syndrome (score) was associated with multiple individual metabolites (e.g., valeryl carnitine, pyruvic acid, lactic acid, alanine) and lipids [e.g., diglyceride(34:1), diglyceride(36:2)]. CONCLUSION: In this first study on metabolomics/lipidomics of the metabolic syndrome, we identified multiple novel metabolite and lipid signatures, from different chemical classes, that were connected to the metabolic syndrome and are of interest to cardiometabolic disease biology.

11.
Nat Commun ; 10(1): 35, 2019 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-30617297

RESUMO

Survival to extreme ages clusters within families. However, identifying genetic loci conferring longevity and low morbidity in such longevous families is challenging. There is debate concerning the survival percentile that best isolates the genetic component in longevity. Here, we use three-generational mortality data from two large datasets, UPDB (US) and LINKS (Netherlands). We study 20,360 unselected families containing index persons, their parents, siblings, spouses, and children, comprising 314,819 individuals. Our analyses provide strong evidence that longevity is transmitted as a quantitative genetic trait among survivors up to the top 10% of their birth cohort. We subsequently show a survival advantage, mounting to 31%, for individuals with top 10% surviving first and second-degree relatives in both databases and across generations, even in the presence of non-longevous parents. To guide future genetic studies, we suggest to base case selection on top 10% survivors of their birth cohort with equally long-lived family members.


Assuntos
Longevidade/genética , Característica Quantitativa Herdável , Estudos de Coortes , Feminino , Humanos , Masculino , Linhagem
12.
Nat Commun ; 9(1): 4455, 2018 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-30367059

RESUMO

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.

14.
J Clin Endocrinol Metab ; 103(12): 4569-4579, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30113659

RESUMO

Objective: We studied whether blood metabolomic measures in people with type 2 diabetes (T2D) are associated with insufficient glycemic control and whether this association is influenced differentially by various diabetes drugs. We then tested whether the same metabolomic profiles were associated with the initiation of insulin therapy. Methods: A total of 162 metabolomic measures were analyzed using a nuclear magnetic resonance-based method in people with T2D from four cohort studies (n = 2641) and one replication cohort (n = 395). Linear and logistic regression analyses with adjustment for potential confounders, followed by meta-analyses, were performed to analyze associations with hemoglobin A1c levels, six glucose-lowering drug categories, and insulin initiation during a 7-year follow-up period (n = 698). Results: After Bonferroni correction, 26 measures were associated with insufficient glycemic control (HbA1c >53 mmol/mol). The strongest association was with glutamine (OR, 0.66; 95% CI, 0.61 to 0.73; P = 7.6 × 10-19). In addition, compared with treatment-naive patients, 31 metabolomic measures were associated with glucose-lowering drug use (representing various metabolite categories; P ≤ 3.1 × 10-4 for all). In drug-stratified analyses, associations with insufficient glycemic control were only mildly affected by different glucose-lowering drugs. Five of the 26 metabolomic measures (apolipoprotein A1 and medium high-density lipoprotein subclasses) were also associated with insulin initiation during follow-up in both discovery and replication. The strongest association was observed for medium high-density lipoprotein cholesteryl ester (OR, 0.54; 95% CI, 0.42 to 0.71; P = 4.5 × 10-6). Conclusion: Blood metabolomic measures were associated with present and future glycemic control and might thus provide relevant cues to identify those at increased risk of treatment failure.

15.
Artigo em Inglês | MEDLINE | ID: mdl-29867770

RESUMO

Background: It is well known that adiposity is a risk factor for insulin resistance and type 2 diabetes mellitus. In the present study, we aimed to investigate the associations of measures of adiposity with indices of glycemia and of glycemic variability over a 72-h period in non-diabetic older adults. Methods: This cross-sectional study was conducted in non-diabetic individuals from the Active and Healthy Aging Study (N = 228), Switchbox (N = 116), and the Growing Old Together Study (N = 94). Body mass index (BMI) and waist circumference were measured, and indices of glycemia and glycemic variability were derived from continuous glucose monitoring (CGM) using the Mini-Med® CGM system. Associations between adiposity and CGM were studied separately for the three cohorts, and derived estimates were subsequently meta-analyzed. Results: After meta-analyzing the results from the separate cohorts, individuals with a higher BMI had higher levels of glycemia. Individuals with BMI between 30 and 35 kg/m2 had 0.28 mmol/L [95% confidence interval (CI): 0.12-0.44] higher 72 h-mean glucose concentration, 0.26 mmol/L (0.10-0.42) higher diurnal glucose (6:00 a.m. to 0:00 a.m.), and 0.39 mmol/L (0.19; 0.59) higher nocturnal glucose (3:00 a.m. to 6:00 a.m.) than participants with a normal weight (BMI 18.5-25 kg/m2). However, no associations were observed between higher BMI and glycemic variability. Results for glycemia and glycemic variability were similarly observed for a high waist circumference. Conclusion: High adiposity associates with constant higher mean glucose levels over the day in non-diabetic older adults.

17.
J Gerontol A Biol Sci Med Sci ; 73(10): 1295-1302, 2018 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-29596573

RESUMO

Members of longevous families live longer than individuals from similar birth cohorts and delay/escape age-related diseases. Insight into this familial component of longevity can provide important knowledge about mechanisms protecting against age-related diseases. This familial component of longevity was studied in the Leiden Longevity Study which consists of 944 longevous siblings (participants), their parents (N = 842), siblings (N = 2,302), and spouses (N = 809). Family longevity scores were estimated to explore whether human longevity is transmitted preferentially through the maternal or paternal line. Standardized mortality ratios (SMRs) were estimated to investigate whether longevous siblings have a survival advantage compared with longevous singletons and we investigated whether parents of longevous siblings harbor a life-long sustained survival advantage compared with the general Dutch population by estimating lifetime SMRs (L-SMRs). We found that sibships with long-lived mothers and non-long-lived fathers had 0.41 (p = .024) less observed deaths than sibships with long-lived fathers and non-long-lived mothers and 0.48 (p = .008) less observed deaths than sibships with both parents non-long lived. Participants had 18.6 per cent less deaths compared with matched singletons and parents had a life-long sustained survival advantage (L-SMR = 0.510 and 0.688). In conclusion, genetic longevity studies may incorporate the maternal transmission pattern and genes influencing the entire life-course of individuals.

18.
Front Immunol ; 9: 277, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29535710

RESUMO

Immunoglobulin G (IgG), a glycoprotein secreted by plasma B-cells, plays a major role in the human adaptive immune response and are associated with a wide range of diseases. Glycosylation of the Fc binding region of IgGs, responsible for the antibody's effector function, is essential for prompting a proper immune response. This study focuses on the general genetic impact on IgG glycosylation as well as corresponding subclass specificities. To identify genetic loci involved in IgG glycosylation, we performed a genome-wide association study (GWAS) on liquid chromatography electrospray mass spectrometry (LC-ESI-MS)-measured IgG glycopeptides of 1,823 individuals in the Cooperative Health Research in the Augsburg Region (KORA F4) study cohort. In addition, we performed GWAS on subclass-specific ratios of IgG glycans to gain power in identifying genetic factors underlying single enzymatic steps in the glycosylation pathways. We replicated our findings in 1,836 individuals from the Leiden Longevity Study (LLS). We were able to show subclass-specific genetic influences on single IgG glycan structures. The replicated results indicate that, in addition to genes encoding for glycosyltransferases (i.e., ST6GAL1, B4GALT1, FUT8, and MGAT3), other genetic loci have strong influences on the IgG glycosylation patterns. A novel locus on chromosome 1, harboring RUNX3, which encodes for a transcription factor of the runt domain-containing family, is associated with decreased galactosylation. Interestingly, members of the RUNX family are cross-regulated, and RUNX3 is involved in both IgA class switching and B-cell maturation as well as T-cell differentiation and apoptosis. Besides the involvement of glycosyltransferases in IgG glycosylation, we suggest that, due to the impact of variants within RUNX3, potentially mechanisms involved in B-cell activation and T-cell differentiation during the immune response as well as cell migration and invasion involve IgG glycosylation.

19.
Diabetologia ; 61(1): 117-129, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28936587

RESUMO

AIMS/HYPOTHESIS: Circulating metabolites have been shown to reflect metabolic changes during the development of type 2 diabetes. In this study we examined the association of metabolite levels and pairwise metabolite ratios with insulin responses after glucose, glucagon-like peptide-1 (GLP-1) and arginine stimulation. We then investigated if the identified metabolite ratios were associated with measures of OGTT-derived beta cell function and with prevalent and incident type 2 diabetes. METHODS: We measured the levels of 188 metabolites in plasma samples from 130 healthy members of twin families (from the Netherlands Twin Register) at five time points during a modified 3 h hyperglycaemic clamp with glucose, GLP-1 and arginine stimulation. We validated our results in cohorts with OGTT data (n = 340) and epidemiological case-control studies of prevalent (n = 4925) and incident (n = 4277) diabetes. The data were analysed using regression models with adjustment for potential confounders. RESULTS: There were dynamic changes in metabolite levels in response to the different secretagogues. Furthermore, several fasting pairwise metabolite ratios were associated with one or multiple clamp-derived measures of insulin secretion (all p < 9.2 × 10-7). These associations were significantly stronger compared with the individual metabolite components. One of the ratios, valine to phosphatidylcholine acyl-alkyl C32:2 (PC ae C32:2), in addition showed a directionally consistent positive association with OGTT-derived measures of insulin secretion and resistance (p ≤ 5.4 × 10-3) and prevalent type 2 diabetes (ORVal_PC ae C32:2 2.64 [ß 0.97 ± 0.09], p = 1.0 × 10-27). Furthermore, Val_PC ae C32:2 predicted incident diabetes independent of established risk factors in two epidemiological cohort studies (HRVal_PC ae C32:2 1.57 [ß 0.45 ± 0.06]; p = 1.3 × 10-15), leading to modest improvements in the receiver operating characteristics when added to a model containing a set of established risk factors in both cohorts (increases from 0.780 to 0.801 and from 0.862 to 0.865 respectively, when added to the model containing traditional risk factors + glucose). CONCLUSIONS/INTERPRETATION: In this study we have shown that the Val_PC ae C32:2 metabolite ratio is associated with an increased risk of type 2 diabetes and measures of insulin secretion and resistance. The observed effects were stronger than that of the individual metabolites and independent of known risk factors.


Assuntos
Biomarcadores/sangue , Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Arginina/metabolismo , Glicemia/metabolismo , Feminino , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Glucose/metabolismo , Teste de Tolerância a Glucose , Humanos , Insulina/metabolismo , Masculino , Fatores de Risco
20.
Biochim Biophys Acta Gen Subj ; 1862(3): 637-648, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29055820

RESUMO

BACKGROUND: Glycosylation is one of the most common post-translation modifications with large influences on protein structure and function. The effector function of immunoglobulin G (IgG) alters between pro- and anti-inflammatory, based on its glycosylation. IgG glycan synthesis is highly complex and dynamic. METHODS: With the use of two different analytical methods for assessing IgG glycosylation, we aim to elucidate the link between DNA methylation and glycosylation of IgG by means of epigenome-wide association studies. In total, 3000 individuals from 4 cohorts were analyzed. RESULTS: The overlap of the results from the two glycan measurement panels yielded DNA methylation of 7 CpG-sites on 5 genomic locations to be associated with IgG glycosylation: cg25189904 (chr.1, GNG12); cg05951221, cg21566642 and cg01940273 (chr.2, ALPPL2); cg05575921 (chr.5, AHRR); cg06126421 (6p21.33); and cg03636183 (chr.19, F2RL3). Mediation analyses with respect to smoking revealed that the effect of smoking on IgG glycosylation may be at least partially mediated via DNA methylation levels at these 7 CpG-sites. CONCLUSION: Our results suggest the presence of an indirect link between DNA methylation and IgG glycosylation that may in part capture environmental exposures. GENERAL SIGNIFICANCE: An epigenome-wide analysis conducted in four population-based cohorts revealed an association between DNA methylation and IgG glycosylation patterns. Presumably, DNA methylation mediates the effect of smoking on IgG glycosylation.


Assuntos
Metilação de DNA , Imunoglobulina G/química , Processamento de Proteína Pós-Traducional , Fumar/efeitos adversos , Mapeamento Cromossômico , Estudos de Coortes , Ilhas de CpG , Epigenômica/métodos , Europa (Continente) , Glicosilação , Humanos , Imunoglobulina G/metabolismo , Estudos Multicêntricos como Assunto , Polissacarídeos/análise , Estudos em Gêmeos como Assunto
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