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1.
Clin Exp Allergy ; 54(5): 314-328, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38556721

RESUMO

BACKGROUND: Numerous children present with early wheeze symptoms, yet solely a subgroup develops childhood asthma. Early identification of children at risk is key for clinical monitoring, timely patient-tailored treatment, and preventing chronic, severe sequelae. For early prediction of childhood asthma, we aimed to define an integrated risk score combining established risk factors with genome-wide molecular markers at birth, complemented by subsequent clinical symptoms/diagnoses (wheezing, atopic dermatitis, food allergy). METHODS: Three longitudinal birth cohorts (PAULINA/PAULCHEN, n = 190 + 93 = 283, PASTURE, n = 1133) were used to predict childhood asthma (age 5-11) including epidemiological characteristics and molecular markers: genotype, DNA methylation and mRNA expression (RNASeq/NanoString). Apparent (ap) and optimism-corrected (oc) performance (AUC/R2) was assessed leveraging evidence from independent studies (Naïve-Bayes approach) combined with high-dimensional logistic regression models (LASSO). RESULTS: Asthma prediction with epidemiological characteristics at birth (maternal asthma, sex, farm environment) yielded an ocAUC = 0.65. Inclusion of molecular markers as predictors resulted in an improvement in apparent prediction performance, however, for optimism-corrected performance only a moderate increase was observed (upto ocAUC = 0.68). The greatest discriminate power was reached by adding the first symptoms/diagnosis (up to ocAUC = 0.76; increase of 0.08, p = .002). Longitudinal analysis of selected mRNA expression in PASTURE (cord blood, 1, 4.5, 6 years) showed that expression at age six had the strongest association with asthma and correlation of genes getting larger over time (r = .59, p < .001, 4.5-6 years). CONCLUSION: Applying epidemiological predictors alone showed moderate predictive abilities. Molecular markers from birth modestly improved prediction. Allergic symptoms/diagnoses enhanced the power of prediction, which is important for clinical practice and for the design of future studies with molecular markers.


Assuntos
Asma , Humanos , Asma/epidemiologia , Asma/genética , Asma/diagnóstico , Feminino , Masculino , Criança , Pré-Escolar , Fatores de Risco , Estudos Longitudinais , Metilação de DNA , Biomarcadores , Coorte de Nascimento
2.
Mol Psychiatry ; 28(9): 3874-3887, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37495887

RESUMO

Metabolome reflects the interplay of genome and exposome at molecular level and thus can provide deep insights into the pathogenesis of a complex disease like major depression. To identify metabolites associated with depression we performed a metabolome-wide association analysis in 13,596 participants from five European population-based cohorts characterized for depression, and circulating metabolites using ultra high-performance liquid chromatography/tandem accurate mass spectrometry (UHPLC/MS/MS) based Metabolon platform. We tested 806 metabolites covering a wide range of biochemical processes including those involved in lipid, amino-acid, energy, carbohydrate, xenobiotic and vitamin metabolism for their association with depression. In a conservative model adjusting for life style factors and cardiovascular and antidepressant medication use we identified 8 metabolites, including 6 novel, significantly associated with depression. In individuals with depression, increased levels of retinol (vitamin A), 1-palmitoyl-2-palmitoleoyl-GPC (16:0/16:1) (lecithin) and mannitol/sorbitol and lower levels of hippurate, 4-hydroxycoumarin, 2-aminooctanoate (alpha-aminocaprylic acid), 10-undecenoate (11:1n1) (undecylenic acid), 1-linoleoyl-GPA (18:2) (lysophosphatidic acid; LPA 18:2) are observed. These metabolites are either directly food derived or are products of host and gut microbial metabolism of food-derived products. Our Mendelian randomization analysis suggests that low hippurate levels may be in the causal pathway leading towards depression. Our findings highlight putative actionable targets for depression prevention that are easily modifiable through diet interventions.


Assuntos
Depressão , Espectrometria de Massas em Tandem , Humanos , Depressão/metabolismo , Dieta , Metaboloma/genética , Vitamina A/metabolismo , Hipuratos , Metabolômica/métodos
3.
Nature ; 541(7635): 81-86, 2017 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-28002404

RESUMO

Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation, a key regulator of gene expression and molecular phenotype. Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 × 10-7, range P = 9.2 × 10-8 to 6.0 × 10-46; n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 × 10-6, range P = 5.5 × 10-6 to 6.1 × 10-35, n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07-2.56); P = 1.1 × 10-54). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.


Assuntos
Adiposidade/genética , Índice de Massa Corporal , Metilação de DNA/genética , Diabetes Mellitus Tipo 2/genética , Epigênese Genética , Epigenômica , Estudo de Associação Genômica Ampla , Obesidade/genética , Tecido Adiposo/metabolismo , Povo Asiático/genética , Sangue/metabolismo , Estudos de Coortes , Diabetes Mellitus Tipo 2/complicações , Europa (Continente)/etnologia , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Índia/etnologia , Masculino , Obesidade/sangue , Obesidade/complicações , Sobrepeso/sangue , Sobrepeso/complicações , Sobrepeso/genética , População Branca/genética
4.
Mol Psychiatry ; 26(12): 7372-7383, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34088979

RESUMO

Depression constitutes a leading cause of disability worldwide. Despite extensive research on its interaction with psychobiological factors, associated pathways are far from being elucidated. Metabolomics, assessing the final products of complex biochemical reactions, has emerged as a valuable tool for exploring molecular pathways. We conducted a metabolome-wide association analysis to investigate the link between the serum metabolome and depressed mood (DM) in 1411 participants of the KORA (Cooperative Health Research in the Augsburg Region) F4 study (discovery cohort). Serum metabolomics data comprised 353 unique metabolites measured by Metabolon. We identified 72 (5.1%) KORA participants with DM. Linear regression tests were conducted modeling each metabolite value by DM status, adjusted for age, sex, body-mass index, antihypertensive, cardiovascular, antidiabetic, and thyroid gland hormone drugs, corticoids and antidepressants. Sensitivity analyses were performed in subcohorts stratified for sex, suicidal ideation, and use of antidepressants. We replicated our results in an independent sample of 968 participants of the SHIP-Trend (Study of Health in Pomerania) study including 52 (5.4%) individuals with DM (replication cohort). We found significantly lower laurylcarnitine levels in KORA F4 participants with DM after multiple testing correction according to Benjamini/Hochberg. This finding was replicated in the independent SHIP-Trend study. Laurylcarnitine remained significantly associated (p value < 0.05) with depression in samples stratified for sex, suicidal ideation, and antidepressant medication. Decreased blood laurylcarnitine levels in depressed individuals may point to impaired fatty acid oxidation and/or mitochondrial function in depressive disorders, possibly representing a novel therapeutic target.


Assuntos
Depressão , Metaboloma , Índice de Massa Corporal , Estudos de Coortes , Depressão/tratamento farmacológico , Humanos , Metabolômica
5.
Pediatr Allergy Immunol ; 33(2): e13721, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34919286

RESUMO

BACKGROUND: Childhood wheeze represents a first symptom of asthma. Early identification of children at risk for wheeze related to 17q12-21 variants and their underlying immunological mechanisms remain unknown. We aimed to assess the influence of 17q12-21 variants and mRNA expression at birth on the development of wheeze. METHODS: Children were classified as multitrigger/viral/no wheeze until six years of age. The PAULINA/PAULCHEN birth cohorts were genotyped (n = 216; GSA-chip). mRNA expression of 17q21 and innate/adaptive genes was measured (qRT-PCR) in cord blood mononuclear cells. Expression quantitative trait loci (eQTL) and mediation analyses were performed. Genetic variation of 17q12-21 asthma-single nucleotide polymorphisms (SNPs) was summarized as the first principal component (PC1) and used to classify single SNP effects on gene expression as (locus)-dependent/independent eQTL SNPs. RESULTS: Core region risk variants (IKZF3, ZPBP2, GSDMB, ORMDL3) were associated with multitrigger wheeze (OR: 3.05-5.43) and were locus-dependent eQTL SNPs with higher GSDMA, TLR2, TLR5, and lower TGFB1 expression. Increased risk of multitrigger wheeze with rs9303277 was in part mediated by TLR2 expression. Risk variants distal to the core region were mainly locus-independent eQTL SNPs with decreased CD209, CD86, TRAF6, RORA, and IL-9 expression. Distinct immune signatures in cord blood were associated either with multitrigger wheeze (increased innate genes, e.g., TLR2, IPS1, LY75) or viral wheeze (decreased NF-κB genes, e.g., TNFAIP3 and TNIP2). CONCLUSION: Locus-dependent eQTL SNPs (core region) associated with increased inflammatory genes (primarily TLR2) at birth and subsequent multitrigger wheeze indicate that early priming and imbalance may be crucial for asthma pathophysiology. Locus-independent eQTL SNPs (mainly distal region, rs1007654) may be involved in the initiation of dendritic cell activation/maturation (TRAF6) and interaction with T cells (CD209, CD86). Identifying potential mechanistic pathways at birth may point to critical key points during early immune development predisposing to asthma.


Assuntos
Asma , Sangue Fetal , Proteínas Adaptadoras de Transdução de Sinal/genética , Asma/epidemiologia , Asma/genética , Criança , Cromossomos Humanos Par 17 , Proteínas do Ovo , Predisposição Genética para Doença , Genótipo , Humanos , Recém-Nascido , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Proteínas Citotóxicas Formadoras de Poros , Sons Respiratórios/genética
6.
Eur J Epidemiol ; 37(8): 849-870, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35904671

RESUMO

The German government initiated the Network University Medicine (NUM) in early 2020 to improve national research activities on the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic. To this end, 36 German Academic Medical Centers started to collaborate on 13 projects, with the largest being the National Pandemic Cohort Network (NAPKON). The NAPKON's goal is creating the most comprehensive Coronavirus Disease 2019 (COVID-19) cohort in Germany. Within NAPKON, adult and pediatric patients are observed in three complementary cohort platforms (Cross-Sectoral, High-Resolution and Population-Based) from the initial infection until up to three years of follow-up. Study procedures comprise comprehensive clinical and imaging diagnostics, quality-of-life assessment, patient-reported outcomes and biosampling. The three cohort platforms build on four infrastructure core units (Interaction, Biosampling, Epidemiology, and Integration) and collaborations with NUM projects. Key components of the data capture, regulatory, and data privacy are based on the German Centre for Cardiovascular Research. By April 01, 2022, 34 university and 40 non-university hospitals have enrolled 5298 patients with local data quality reviews performed on 4727 (89%). 47% were female, the median age was 52 (IQR 36-62-) and 50 pediatric cases were included. 44% of patients were hospitalized, 15% admitted to an intensive care unit, and 12% of patients deceased while enrolled. 8845 visits with biosampling in 4349 patients were conducted by April 03, 2022. In this overview article, we summarize NAPKON's design, relevant milestones including first study population characteristics, and outline the potential of NAPKON for German and international research activities.Trial registration https://clinicaltrials.gov/ct2/show/NCT04768998 . https://clinicaltrials.gov/ct2/show/NCT04747366 . https://clinicaltrials.gov/ct2/show/NCT04679584.


Assuntos
COVID-19 , Pandemias , Adulto , COVID-19/epidemiologia , Criança , Ensaios Clínicos como Assunto , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Projetos de Pesquisa , SARS-CoV-2
7.
Proc Natl Acad Sci U S A ; 116(23): 11370-11379, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-31113877

RESUMO

Aging and psychosocial stress are associated with increased inflammation and disease risk, but the underlying molecular mechanisms are unclear. Because both aging and stress are also associated with lasting epigenetic changes, a plausible hypothesis is that stress along the lifespan could confer disease risk through epigenetic effects on molecules involved in inflammatory processes. Here, by combining large-scale analyses in human cohorts with experiments in cells, we report that FKBP5, a protein implicated in stress physiology, contributes to these relations. Across independent human cohorts (total n > 3,000), aging synergized with stress-related phenotypes, measured with childhood trauma and major depression questionnaires, to epigenetically up-regulate FKBP5 expression. These age/stress-related epigenetic effects were recapitulated in a cellular model of replicative senescence, whereby we exposed replicating human fibroblasts to stress (glucocorticoid) hormones. Unbiased genome-wide analyses in human blood linked higher FKBP5 mRNA with a proinflammatory profile and altered NF-κB-related gene networks. Accordingly, experiments in immune cells showed that higher FKBP5 promotes inflammation by strengthening the interactions of NF-κB regulatory kinases, whereas opposing FKBP5 either by genetic deletion (CRISPR/Cas9-mediated) or selective pharmacological inhibition prevented the effects on NF-κB. Further, the age/stress-related epigenetic signature enhanced FKBP5 response to NF-κB through a positive feedback loop and was present in individuals with a history of acute myocardial infarction, a disease state linked to peripheral inflammation. These findings suggest that aging/stress-driven FKBP5-NF-κB signaling mediates inflammation, potentially contributing to cardiovascular risk, and may thus point to novel biomarker and treatment possibilities.


Assuntos
Envelhecimento/genética , Doenças Cardiovasculares/genética , Epigênese Genética/genética , Inflamação/genética , NF-kappa B/genética , Estresse Psicológico/genética , Proteínas de Ligação a Tacrolimo/genética , Regulação para Cima/genética , Senescência Celular/genética , Pré-Escolar , Transtorno Depressivo Maior/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Fatores de Risco , Transdução de Sinais/genética
8.
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.


Assuntos
Cotinina/sangue , Metilação de DNA , DNA/sangue , Epigenômica/métodos , Fumar/efeitos adversos , Adulto , Área Sob a Curva , Biomarcadores/sangue , Feminino , Humanos , Masculino , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Fumar/genética , Abandono do Hábito de Fumar
9.
Hum Mol Genet ; 25(1): 191-201, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26546615

RESUMO

DNA methylation-based biomarkers of aging are highly correlated with actual age. Departures of methylation-estimated age from actual age can be used to define epigenetic measures of child development or age acceleration (AA) in adults. Very little is known about genetic or environmental determinants of these epigenetic measures of aging. We obtained DNA methylation profiles using Infinium HumanMethylation450 BeadChips across five time-points in 1018 mother-child pairs from the Avon Longitudinal Study of Parents and Children. Using the Horvath age estimation method, we calculated epigenetic age for these samples. AA was defined as the residuals from regressing epigenetic age on actual age. AA was tested for associations with cross-sectional clinical variables in children. We identified associations between AA and sex, birth weight, birth by caesarean section and several maternal characteristics in pregnancy, namely smoking, weight, BMI, selenium and cholesterol level. Offspring of non-drinkers had higher AA on average but this difference appeared to resolve during childhood. The associations between sex, birth weight and AA found in ARIES were replicated in an independent cohort (GOYA). In children, epigenetic AA measures are associated with several clinically relevant variables, and early life exposures appear to be associated with changes in AA during adolescence. Further research into epigenetic aging, including the use of causal inference methods, is required to better our understanding of aging.


Assuntos
Envelhecimento/genética , Metilação de DNA , Epigênese Genética , Peso ao Nascer , Criança , Estudos de Coortes , Humanos , Estudos Longitudinais , Mães
10.
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
11.
Pediatr Allergy Immunol ; 29(1): 34-41, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29047170

RESUMO

BACKGROUND: Allergic and non-allergic childhood asthma has been characterized by distinct immune mechanisms. While interferon regulating factor 1 (IRF-1) polymorphisms (SNPs) influence atopy risk, the effect of SNPs on asthma phenotype-specific immune mechanisms is unclear. We assessed whether IRF-1 SNPs modify distinct immune-regulatory pathways in allergic and non-allergic childhood asthma (AA/NA). METHODS: In the CLARA study, asthma was characterized by doctor's diagnosis and AA vs NA by positive or negative specific IgE. Children were genotyped for four tagging SNPs within IRF-1 (n = 172). mRNA expression was measured with qRT-PCR. Gene expression was analyzed depending on genetic variants within IRF-1 and phenotype including haplotype estimation and an allelic risk score. RESULTS: Carrying the risk alleles of IRF-1 in rs10035166, rs2706384, or rs2070721 was associated with increased risk for AA. Carrying the non-risk allele in rs17622656 was associated with lower risk for AA but not NA. In AA carrying the risk alleles, an increased pro-inflammatory expression of ICAM3, IRF-8, XBP-1, IFN-γ, RGS13, RORC, and TSC2 was observed. NOD2 expression was decreased in AA with risk alleles in rs2706384 and rs10035166 and with risk haplotype. Further, AA with risk haplotype showed increased IL-13 secretion. NA with risk allele in rs2070721 compared to non-risk allele in rs17622656 showed significantly upregulated calcium, innate, mTOR, neutrophil, and inflammatory-associated genes. CONCLUSION: IRF-1 polymorphisms influence the risk for childhood allergic asthma being associated with increased pro-inflammatory gene regulation. Thus, it is critical to implement IRF-1 genetics in immune assessment for childhood asthma phenotypes.


Assuntos
Asma/genética , Fator Regulador 1 de Interferon/genética , Adolescente , Criança , Pré-Escolar , Citocinas/metabolismo , Predisposição Genética para Doença , Genótipo , Humanos , Imunoglobulina E/sangue , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase em Tempo Real , Testes de Função Respiratória/métodos , Risco
12.
BMC Genomics ; 18(1): 805, 2017 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-29047347

RESUMO

BACKGROUND: The evidence for epigenome-wide associations between smoking and DNA methylation continues to grow through cross-sectional studies. However, few large-scale investigations have explored the associations using observations for individuals at multiple time-points. Here, through the use of the Illumina 450K BeadChip and data collected at two time-points separated by approximately 7 years, we investigate changes in methylation over time associated with quitting smoking or remaining a former smoker, and those associated with continued smoking. RESULTS: Our results indicate that after quitting smoking the most rapid reversion of altered methylation occurs within the first two decades, with reversion rates related to the initial differences in methylation. For 52 CpG sites, the change in methylation from baseline to follow-up is significantly different for former smokers relative to the change for never smokers (lowest p-value 3.61 x 10-39 for cg26703534, gene AHRR). Most of these sites' respective regions have been previously implicated in smoking-associated diseases. Despite the early rapid change, dynamism of methylation appears greater in former smokers vs never smokers even four decades after cessation. Furthermore, our study reveals the heterogeneous effect of continued smoking: the methylation levels of some loci further diverge between smokers and non-smokers, while others re-approach. Though intensity of smoking habit appears more significant than duration, results remain inconclusive. CONCLUSIONS: This study improves the understanding of the dynamic link between cigarette smoking and methylation, revealing the continued fluctuation of methylation levels decades after smoking cessation and demonstrating that continuing smoking can have an array of effects. The results can facilitate insights into the molecular mechanisms behind smoking-induced disturbed methylation, improving the possibility for development of biomarkers of past smoking behavior and increasing the understanding of the molecular path from exposure to disease.


Assuntos
Metilação de DNA , Fumar/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Fatores de Tempo
13.
Genome Med ; 14(1): 125, 2022 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-36344995

RESUMO

BACKGROUND: Molecular measurements of the genome, the transcriptome, and the epigenome, often termed multi-omics data, provide an in-depth view on biological systems and their integration is crucial for gaining insights in complex regulatory processes. These data can be used to explain disease related genetic variants by linking them to intermediate molecular traits (quantitative trait loci, QTL). Molecular networks regulating cellular processes leave footprints in QTL results as so-called trans-QTL hotspots. Reconstructing these networks is a complex endeavor and use of biological prior information can improve network inference. However, previous efforts were limited in the types of priors used or have only been applied to model systems. In this study, we reconstruct the regulatory networks underlying trans-QTL hotspots using human cohort data and data-driven prior information. METHODS: We devised a new strategy to integrate QTL with human population scale multi-omics data. State-of-the art network inference methods including BDgraph and glasso were applied to these data. Comprehensive prior information to guide network inference was manually curated from large-scale biological databases. The inference approach was extensively benchmarked using simulated data and cross-cohort replication analyses. Best performing methods were subsequently applied to real-world human cohort data. RESULTS: Our benchmarks showed that prior-based strategies outperform methods without prior information in simulated data and show better replication across datasets. Application of our approach to human cohort data highlighted two novel regulatory networks related to schizophrenia and lean body mass for which we generated novel functional hypotheses. CONCLUSIONS: We demonstrate that existing biological knowledge can improve the integrative analysis of networks underlying trans associations and generate novel hypotheses about regulatory mechanisms.


Assuntos
Locos de Características Quantitativas , Transcriptoma , Humanos , Redes Reguladoras de Genes
14.
Aging Cell ; 21(6): e13608, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35546478

RESUMO

DNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n = 15,013). During a mean follow-up of 10 years, there were 4314 deaths from all causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry-stratified meta-analysis of all-cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at p < 1 × 10-7 , of which 41 (EA) and 16 (AA) were also associated with CVD death, and 15 (EA) and 9 (AA) with cancer death. We built DNAm-based prediction models for all-cause mortality that predicted mortality risk after adjusting for clinical risk factors. The mortality prediction model trained by integrating DNAm with clinical risk factors showed an improvement in prediction of cancer death with 5% increase in the C-index in a replication cohort, compared with the model including clinical risk factors alone. Mendelian randomization identified 15 putatively causal CpGs in relation to longevity, CVD, or cancer risk. For example, cg06885782 (in KCNQ4) was positively associated with risk for prostate cancer (Beta = 1.2, PMR  = 4.1 × 10-4 ) and negatively associated with longevity (Beta = -1.9, PMR  = 0.02). Pathway analysis revealed that genes associated with mortality-related CpGs are enriched for immune- and cancer-related pathways. We identified replicable DNAm signatures of mortality and demonstrated the potential utility of CpGs as informative biomarkers for prediction of mortality risk.


Assuntos
Doenças Cardiovasculares , Neoplasias , Biomarcadores , Doenças Cardiovasculares/genética , Metilação de DNA/genética , Epigênese Genética , Epigenômica , Humanos , Masculino , Neoplasias/genética
15.
Clin Epigenetics ; 13(1): 198, 2021 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-34702360

RESUMO

BACKGROUND: Information on long-term alcohol consumption is relevant for medical and public health research, disease therapy, and other areas. Recently, DNA methylation-based inference of alcohol consumption from blood was reported with high accuracy, but these results were based on employing the same dataset for model training and testing, which can lead to accuracy overestimation. Moreover, only subsets of alcohol consumption categories were used, which makes it impossible to extrapolate such models to the general population. By using data from eight population-based European cohorts (N = 4677), we internally and externally validated the previously reported biomarkers and models for epigenetic inference of alcohol consumption from blood and developed new models comprising all data from all categories. RESULTS: By employing data from six European cohorts (N = 2883), we empirically tested the reproducibility of the previously suggested biomarkers and prediction models via ten-fold internal cross-validation. In contrast to previous findings, all seven models based on 144-CpGs yielded lower mean AUCs compared to the models with less CpGs. For instance, the 144-CpG heavy versus non-drinkers model gave an AUC of 0.78 ± 0.06, while the 5 and 23 CpG models achieved 0.83 ± 0.05, respectively. The transportability of the models was empirically tested via external validation in three independent European cohorts (N = 1794), revealing high AUC variance between datasets within models. For instance, the 144-CpG heavy versus non-drinkers model yielded AUCs ranging from 0.60 to 0.84 between datasets. The newly developed models that considered data from all categories showed low AUCs but gave low AUC variation in the external validation. For instance, the 144-CpG heavy and at-risk versus light and non-drinkers model achieved AUCs of 0.67 ± 0.02 in the internal cross-validation and 0.61-0.66 in the external validation datasets. CONCLUSIONS: The outcomes of our internal and external validation demonstrate that the previously reported prediction models suffer from both overfitting and accuracy overestimation. Our results show that the previously proposed biomarkers are not yet sufficient for accurate and robust inference of alcohol consumption from blood. Overall, our findings imply that DNA methylation prediction biomarkers and models need to be improved considerably before epigenetic inference of alcohol consumption from blood can be considered for practical applications.


Assuntos
Consumo de Bebidas Alcoólicas/sangue , Biomarcadores/análise , Epigênese Genética/genética , Consumo de Bebidas Alcoólicas/genética , Área Sob a Curva , Biomarcadores/sangue , Metilação de DNA , Epigênese Genética/fisiologia , Estudo de Associação Genômica Ampla/métodos , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Curva ROC , Reprodutibilidade dos Testes
16.
Clin Epigenetics ; 13(1): 121, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34078457

RESUMO

BACKGROUND: The difference between an individual's chronological and DNA methylation predicted age (DNAmAge), termed DNAmAge acceleration (DNAmAA), can capture life-long environmental exposures and age-related physiological changes reflected in methylation status. Several studies have linked DNAmAA to morbidity and mortality, yet its relationship with kidney function has not been assessed. We evaluated the associations between seven DNAm aging and lifespan predictors (as well as GrimAge components) and five kidney traits (estimated glomerular filtration rate [eGFR], urine albumin-to-creatinine ratio [uACR], serum urate, microalbuminuria and chronic kidney disease [CKD]) in up to 9688 European, African American and Hispanic/Latino individuals from seven population-based studies. RESULTS: We identified 23 significant associations in our large trans-ethnic meta-analysis (p < 1.43E-03 and consistent direction of effect across studies). Age acceleration measured by the Extrinsic and PhenoAge estimators, as well as Zhang's 10-CpG epigenetic mortality risk score (MRS), were associated with all parameters of poor kidney health (lower eGFR, prevalent CKD, higher uACR, microalbuminuria and higher serum urate). Six of these associations were independently observed in European and African American populations. MRS in particular was consistently associated with eGFR (ß = - 0.12, 95% CI = [- 0.16, - 0.08] change in log-transformed eGFR per unit increase in MRS, p = 4.39E-08), prevalent CKD (odds ratio (OR) = 1.78 [1.47, 2.16], p = 2.71E-09) and higher serum urate levels (ß = 0.12 [0.07, 0.16], p = 2.08E-06). The "first-generation" clocks (Hannum, Horvath) and GrimAge showed different patterns of association with the kidney traits. Three of the DNAm-estimated components of GrimAge, namely adrenomedullin, plasminogen-activation inhibition 1 and pack years, were positively associated with higher uACR, serum urate and microalbuminuria. CONCLUSION: DNAmAge acceleration and DNAm mortality predictors estimated in whole blood were associated with multiple kidney traits, including eGFR and CKD, in this multi-ethnic study. Epigenetic biomarkers which reflect the systemic effects of age-related mechanisms such as immunosenescence, inflammaging and oxidative stress may have important mechanistic or prognostic roles in kidney disease. Our study highlights new findings linking kidney disease to biological aging, and opportunities warranting future investigation into DNA methylation biomarkers for prognostic or risk stratification in kidney disease.


Assuntos
Senilidade Prematura/mortalidade , Mortalidade/tendências , Insuficiência Renal/sangue , Idoso , Senilidade Prematura/epidemiologia , Senilidade Prematura/genética , Metilação de DNA/genética , Metilação de DNA/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal/etiologia , Insuficiência Renal/mortalidade
17.
PLoS One ; 15(4): e0232073, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32343731

RESUMO

Lipoprotein(a) [Lp(a)] is a major cardiovascular risk factor, which is largely genetically determined by one major gene locus, the LPA gene. Many aspects of the transcriptional regulation of LPA are poorly understood and the role of epigenetics has not been addressed yet. Therefore, we conducted an epigenome-wide analysis of DNA methylation on Lp(a) levels in two population-based studies (total n = 2208). We identified a CpG site in the LPA promoter which was significantly associated with Lp(a) concentrations. Surprisingly, the identified CpG site was found to overlap the SNP rs76735376. We genotyped this SNP de-novo in three studies (total n = 7512). The minor allele of rs76735376 (1.1% minor allele frequency) was associated with increased Lp(a) values (p = 1.01e-59) and explained 3.5% of the variation of Lp(a). Statistical mediation analysis showed that the effect on Lp(a) is rather originating from the base change itself and is not mediated by DNA methylation levels. This finding is supported by eQTL data from 208 liver tissue samples from the GTEx project, which shows a significant association of the rs76735376 minor allele with increased LPA expression. To evaluate, whether the association signal at rs76735376 may actually be derived from a stronger eQTL signal in LD with this SNP, eQTL association results of all correlated SNPs (r2≥0.1) were integrated with genetic association results. This analysis pinpointed to rs10455872 as the potential trigger of the effect of rs76735376. Furthermore, both SNPs coincide with short apo(a) isoforms. Adjusting for both, rs10455872 and the apo(a) isoforms diminished the effect size of rs76735376 to 5.38 mg/dL (p = 0.0463). This indicates that the effect of rs76735376 can be explained by both an independent effect of the SNP and a strong correlation with rs10455872 and apo(a) isoforms.


Assuntos
Metilação de DNA , Estudo de Associação Genômica Ampla/métodos , Lipoproteína(a)/genética , Lipoproteína(a)/metabolismo , Fígado/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Ilhas de CpG , Epigênese Genética , Feminino , Regulação da Expressão Gênica , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Locos de Características Quantitativas , Sequenciamento Completo do Genoma
18.
Clin Epigenetics ; 12(1): 157, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-33092652

RESUMO

BACKGROUND: Tobacco smoking is a well-known modifiable risk factor for many chronic diseases, including cardiovascular disease (CVD). One of the proposed underlying mechanism linking smoking to disease is via epigenetic modifications, which could affect the expression of disease-associated genes. Here, we conducted a three-way association study to identify the relationship between smoking-related changes in DNA methylation and gene expression and their associations with cardio-metabolic traits. RESULTS: We selected 2549 CpG sites and 443 gene expression probes associated with current versus never smokers, from the largest epigenome-wide association study and transcriptome-wide association study to date. We examined three-way associations, including CpG versus gene expression, cardio-metabolic trait versus CpG, and cardio-metabolic trait versus gene expression, in the Rotterdam study. Subsequently, we replicated our findings in The Cooperative Health Research in the Region of Augsburg (KORA) study. After correction for multiple testing, we identified both cis- and trans-expression quantitative trait methylation (eQTM) associations in blood. Specifically, we found 1224 smoking-related CpGs associated with at least one of the 443 gene expression probes, and 200 smoking-related gene expression probes to be associated with at least one of the 2549 CpGs. Out of these, 109 CpGs and 27 genes were associated with at least one cardio-metabolic trait in the Rotterdam Study. We were able to replicate the associations with cardio-metabolic traits of 26 CpGs and 19 genes in the KORA study. Furthermore, we identified a three-way association of triglycerides with two CpGs and two genes (GZMA; CLDND1), and BMI with six CpGs and two genes (PID1; LRRN3). Finally, our results revealed the mediation effect of cg03636183 (F2RL3), cg06096336 (PSMD1), cg13708645 (KDM2B), and cg17287155 (AHRR) within the association between smoking and LRRN3 expression. CONCLUSIONS: Our study indicates that smoking-related changes in DNA methylation and gene expression are associated with cardio-metabolic risk factors. These findings may provide additional insights into the molecular mechanisms linking smoking to the development of CVD.


Assuntos
Doenças Cardiovasculares/genética , Epigenômica/métodos , Fumar/efeitos adversos , Triglicerídeos/genética , Idoso , Índice de Massa Corporal , Fatores de Risco Cardiometabólico , Doenças Cardiovasculares/epidemiologia , Estudos de Casos e Controles , Ilhas de CpG/genética , Metilação de DNA , Epigênese Genética , Feminino , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Fenótipo , Fumar/sangue , Fumar/genética , Transcriptoma
19.
Aging (Albany NY) ; 12(16): 16539-16554, 2020 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-32747609

RESUMO

Chronic obstructive pulmonary disease (COPD) is a frequent diagnosis in older individuals and contributor to global morbidity and mortality. Given the link between lung disease and aging, we need to understand how molecular indicators of aging relate to lung function and disease. Using data from the population-based KORA (Cooperative Health Research in the Region of Augsburg) surveys, we associated baseline epigenetic (DNA methylation) age acceleration with incident COPD and lung function. Models were adjusted for age, sex, smoking, height, weight, and baseline lung disease as appropriate. Associations were replicated in the Normative Aging Study. Of 770 KORA participants, 131 developed incident COPD over 7 years. Baseline accelerated epigenetic aging was significantly associated with incident COPD. The change in age acceleration (follow-up - baseline) was more strongly associated with COPD than baseline aging alone. The association between the change in age acceleration between baseline and follow-up and incident COPD replicated in the Normative Aging Study. Associations with spirometric lung function parameters were weaker than those with COPD, but a meta-analysis of both cohorts provide suggestive evidence of associations. Accelerated epigenetic aging, both baseline measures and changes over time, may be a risk factor for COPD and reduced lung function.


Assuntos
Envelhecimento/genética , Metilação de DNA , Epigênese Genética , Pulmão/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/genética , Adulto , Fatores Etários , Feminino , Predisposição Genética para Doença , Alemanha/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Medição de Risco , Fatores de Risco , Espirometria
20.
Aging (Albany NY) ; 11(7): 2045-2070, 2019 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-31009935

RESUMO

Differences in health status by socioeconomic position (SEP) tend to be more evident at older ages, suggesting the involvement of a biological mechanism responsive to the accumulation of deleterious exposures across the lifespan. DNA methylation (DNAm) has been proposed as a biomarker of biological aging that conserves memory of endogenous and exogenous stress during life.We examined the association of education level, as an indicator of SEP, and lifestyle-related variables with four biomarkers of age-dependent DNAm dysregulation: the total number of stochastic epigenetic mutations (SEMs) and three epigenetic clocks (Horvath, Hannum and Levine), in 18 cohorts spanning 12 countries.The four biological aging biomarkers were associated with education and different sets of risk factors independently, and the magnitude of the effects differed depending on the biomarker and the predictor. On average, the effect of low education on epigenetic aging was comparable with those of other lifestyle-related risk factors (obesity, alcohol intake), with the exception of smoking, which had a significantly stronger effect.Our study shows that low education is an independent predictor of accelerated biological (epigenetic) aging and that epigenetic clocks appear to be good candidates for disentangling the biological pathways underlying social inequalities in healthy aging and longevity.


Assuntos
Envelhecimento/genética , Envelhecimento/psicologia , Epigênese Genética , Estilo de Vida , Idoso , Estudos de Coortes , Metilação de DNA , Escolaridade , Feminino , Humanos , Masculino , Mutação , Fatores de Risco , Classe Social
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