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1.
Diabetes Care ; 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601636

RESUMO

OBJECTIVE: Maternal gestational diabetes mellitus (GDM) has been associated with adverse outcomes in the offspring. Growing evidence suggests that the epigenome may play a role, but most previous studies have been small and adjusted for few covariates. The current study meta-analyzed the association between maternal GDM and cord blood DNA methylation in the Pregnancy and Childhood Epigenetics (PACE) consortium. RESEARCH DESIGN AND METHODS: Seven pregnancy cohorts (3,677 mother-newborn pairs [317 with GDM]) contributed results from epigenome-wide association studies, using DNA methylation data acquired by the Infinium HumanMethylation450 BeadChip array. Associations between GDM and DNA methylation were examined using robust linear regression, with adjustment for potential confounders. Fixed-effects meta-analyses were performed using METAL. Differentially methylated regions (DMRs) were identified by taking the intersection of results obtained using two regional approaches: comb-p and DMRcate. RESULTS: Two DMRs were identified by both comb-p and DMRcate. Both regions were hypomethylated in newborns exposed to GDM in utero compared with control subjects. One DMR (chr 1: 248100345-248100614) was located in the OR2L13 promoter, and the other (chr 10: 135341870-135342620) was located in the gene body of CYP2E1. Individual CpG analyses did not reveal any differentially methylated loci based on a false discovery rate-adjusted P value threshold of 0.05. CONCLUSIONS: Maternal GDM was associated with lower cord blood methylation levels within two regions, including the promoter of OR2L13, a gene associated with autism spectrum disorder, and the gene body of CYP2E1, which is upregulated in type 1 and type 2 diabetes. Future studies are needed to understand whether these associations are causal and possible health consequences.

2.
Environ Health Perspect ; 127(5): 57012, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31148503

RESUMO

BACKGROUND: Prenatal exposure to air pollution has been associated with childhood respiratory disease and other adverse outcomes. Epigenetics is a suggested link between exposures and health outcomes. OBJECTIVES: We aimed to investigate associations between prenatal exposure to particulate matter (PM) with diameter [Formula: see text] ([Formula: see text]) or [Formula: see text] ([Formula: see text]) and DNA methylation in newborns and children. METHODS: We meta-analyzed associations between exposure to [Formula: see text] ([Formula: see text]) and [Formula: see text] ([Formula: see text]) at maternal home addresses during pregnancy and newborn DNA methylation assessed by Illumina Infinium HumanMethylation450K BeadChip in nine European and American studies, with replication in 688 independent newborns and look-up analyses in 2,118 older children. We used two approaches, one focusing on single cytosine-phosphate-guanine (CpG) sites and another on differentially methylated regions (DMRs). We also related PM exposures to blood mRNA expression. RESULTS: Six CpGs were significantly associated [false discovery rate (FDR) [Formula: see text]] with prenatal [Formula: see text] and 14 with [Formula: see text] exposure. Two of the [Formula: see text] CpGs mapped to FAM13A (cg00905156) and NOTCH4 (cg06849931) previously associated with lung function and asthma. Although these associations did not replicate in the smaller newborn sample, both CpGs were significant ([Formula: see text]) in 7- to 9-y-olds. For cg06849931, however, the direction of the association was inconsistent. Concurrent [Formula: see text] exposure was associated with a significantly higher NOTCH4 expression at age 16 y. We also identified several DMRs associated with either prenatal [Formula: see text] and or [Formula: see text] exposure, of which two [Formula: see text] DMRs, including H19 and MARCH11, replicated in newborns. CONCLUSIONS: Several differentially methylated CpGs and DMRs associated with prenatal PM exposure were identified in newborns, with annotation to genes previously implicated in lung-related outcomes. https://doi.org/10.1289/EHP4522.

3.
Nat Commun ; 10(1): 1893, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015461

RESUMO

Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (PBonferroni < 1.06 x 10-7). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10-74) and BMI in pregnancy (3/914, p = 1.13x10-3), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.


Assuntos
Peso ao Nascer/genética , DNA/metabolismo , Epigênese Genética , Genoma Humano , Adolescente , Adulto , Índice de Massa Corporal , Criança , Ilhas de CpG , DNA/genética , Metilação de DNA , Feminino , Desenvolvimento Fetal/genética , Feto , Ácido Fólico/sangue , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Fumar/efeitos adversos , Fumar/sangue , Fumar/genética
4.
Hum Mol Genet ; 26(20): 4067-4085, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-29016858

RESUMO

Pre-pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later in life. Individual studies have shown that epigenetic modifications such as DNA methylation could contribute. Within the Pregnancy and Childhood Epigenetics (PACE) Consortium, we meta-analysed the association between pre-pregnancy maternal BMI and methylation at over 450,000 sites in newborn blood DNA, across 19 cohorts (9,340 mother-newborn pairs). We attempted to infer causality by comparing the effects of maternal versus paternal BMI and incorporating genetic variation. In four additional cohorts (1,817 mother-child pairs), we meta-analysed the association between maternal BMI at the start of pregnancy and blood methylation in adolescents. In newborns, maternal BMI was associated with small (<0.2% per BMI unit (1 kg/m2), P < 1.06 × 10-7) methylation variation at 9,044 sites throughout the genome. Adjustment for estimated cell proportions greatly attenuated the number of significant CpGs to 104, including 86 sites common to the unadjusted model. At 72/86 sites, the direction of the association was the same in newborns and adolescents, suggesting persistence of signals. However, we found evidence for acausal intrauterine effect of maternal BMI on newborn methylation at just 8/86 sites. In conclusion, this well-powered analysis identified robust associations between maternal adiposity and variations in newborn blood DNA methylation, but these small effects may be better explained by genetic or lifestyle factors than a causal intrauterine mechanism. This highlights the need for large-scale collaborative approaches and the application of causal inference techniques in epigenetic epidemiology.


Assuntos
Herança Materna/genética , Obesidade/complicações , Resultado da Gravidez/genética , Adulto , Índice de Massa Corporal , Estudos de Coortes , Metilação de DNA/genética , Epigênese Genética/genética , Epigenômica/métodos , Feminino , Humanos , Recém-Nascido , Masculino , Herança Materna/fisiologia , Mães , Gravidez/fisiologia , Resultado da Gravidez/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo
5.
Environ Mol Mutagen ; 58(6): 398-410, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28556291

RESUMO

Epigenetic changes such as DNA methylation may be a molecular mechanism through which environmental exposures affect health. Phthalates are known endocrine disruptors with ubiquitous exposures in the general population including pregnant women, and they have been linked with a number of adverse health outcomes. We examined the association between in utero phthalate exposure and altered patterns of cord blood DNA methylation in 336 Mexican-American newborns. Concentrations of 11 phthalate metabolites were analyzed in maternal urine samples collected at 13 and 26 weeks gestation as a measure of fetal exposure. DNA methylation was assessed using the Infinium HumanMethylation 450K BeadChip adjusting for cord blood cell composition. To identify differentially methylated regions (DMRs) that may be more informative than individual CpG sites, we used two different approaches, DMRcate and comb-p. Regional assessment by both methods identified 27 distinct DMRs, the majority of which were in relation to multiple phthalate metabolites. Most of the significant DMRs (67%) were observed for later pregnancy (26 weeks gestation). Further, 51% of the significant DMRs were associated with the di-(2-ethylhexyl) phthalate metabolites. Five individual CpG sites were associated with phthalate metabolite concentrations after multiple comparisons adjustment (FDR), all showing hypermethylation. Genes with DMRs were involved in inflammatory response (IRAK4 and ESM1), cancer (BRCA1 and LASP1), endocrine function (CNPY1), and male fertility (IFT140, TESC, and PRDM8). These results on differential DNA methylation in newborns with prenatal phthalate exposure provide new insights and targets to explore mechanism of adverse effects of phthalates on human health. Environ. Mol. Mutagen. 58:398-410, 2017. © 2017 Wiley Periodicals, Inc.


Assuntos
Metilação de DNA/genética , Sangue Fetal/metabolismo , Exposição Materna , Ácidos Ftálicos/toxicidade , Efeitos Tardios da Exposição Pré-Natal/genética , Ilhas de CpG/genética , Metilação de DNA/efeitos dos fármacos , Demografia , Feminino , Sangue Fetal/efeitos dos fármacos , Humanos , Recém-Nascido , Masculino , Metaboloma/efeitos dos fármacos , Gravidez
6.
Environ Health Perspect ; 125(4): 511-526, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28362264

RESUMO

BACKGROUND: Characterization of the epigenome is a primary interest for children's environmental health researchers studying the environmental influences on human populations, particularly those studying the role of pregnancy and early-life exposures on later-in-life health outcomes. OBJECTIVES: Our objective was to consider the state of the science in environmental epigenetics research and to focus on DNA methylation and the collective observations of many studies being conducted within the Children's Environmental Health and Disease Prevention Research Centers, as they relate to the Developmental Origins of Health and Disease (DOHaD) hypothesis. METHODS: We address the current laboratory and statistical tools available for epigenetic analyses, discuss methods for validation and interpretation of findings, particularly when magnitudes of effect are small, question the functional relevance of findings, and discuss the future for environmental epigenetics research. DISCUSSION: A common finding in environmental epigenetic studies is the small-magnitude epigenetic effect sizes that result from such exposures. Although it is reasonable and necessary that we question the relevance of such small effects, we present examples in which small effects persist and have been replicated across populations and across time. We encourage a critical discourse on the interpretation of such small changes and further research on their functional relevance for children's health. CONCLUSION: The dynamic nature of the epigenome will require an emphasis on future longitudinal studies in which the epigenome is profiled over time, over changing environmental exposures, and over generations to better understand the multiple ways in which the epigenome may respond to environmental stimuli.


Assuntos
Exposição Ambiental , Saúde Ambiental , Epigenômica , Criança , Saúde da Criança , Bem-Estar da Criança , Metilação de DNA , Epigênese Genética , Feminino , Processos Grupais , Humanos , Estudos Longitudinais , Gravidez , Pesquisa
7.
Artigo em Inglês | MEDLINE | ID: mdl-28149326

RESUMO

BACKGROUND: Genetic data are known to harbor information about human demographics, and genotyping data are commonly used for capturing ancestry information by leveraging genome-wide differences between populations. In contrast, it is not clear to what extent population structure is captured by whole-genome DNA methylation data. RESULTS: We demonstrate, using three large-cohort 450K methylation array data sets, that ancestry information signal is mirrored in genome-wide DNA methylation data and that it can be further isolated more effectively by leveraging the correlation structure of CpGs with cis-located SNPs. Based on these insights, we propose a method, EPISTRUCTURE, for the inference of ancestry from methylation data, without the need for genotype data. CONCLUSIONS: EPISTRUCTURE can be used to infer ancestry information of individuals based on their methylation data in the absence of corresponding genetic data. Although genetic data are often collected in epigenetic studies of large cohorts, these are typically not made publicly available, making the application of EPISTRUCTURE especially useful for anyone working on public data. Implementation of EPISTRUCTURE is available in GLINT, our recently released toolset for DNA methylation analysis at: http://glint-epigenetics.readthedocs.io.


Assuntos
Epigenômica/métodos , Interface Usuário-Computador , Algoritmos , Ilhas de CpG , Metilação de DNA , Bases de Dados Genéticas , Genoma Humano , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Internet , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal
8.
BMC Med Genet ; 18(1): 7, 2017 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-28122515

RESUMO

BACKGROUND: To examine methylation of the peroxisome proliferator-activated receptor γ (PPARγ) gene and its relationship with child weight status, at birth and 9 years. METHODS: We measured PPARγ methylation across 23 CpG sites using the Infinium Illumina 450 k array for children from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) cohort at birth (N = 373) and 9 years (N = 245). RESULTS: Methylation level correlation patterns across the 23 PPARγ CpG sites were conserved between birth and 9-year ages. We found high inter-CpG correlations between sites 1-3 (methylation block 1) and also between sites 18-23 (methylation block 2) for both time points, although these patterns were less pronounced at 9 years. Additionally, sites 1-3 (north shore) had the highest intra-CpG correlations over time (r = 0.24, 0.42, and 0.3; P = 0.002, P < 0.001, P < 0.001, respectively). PPARγ methylation levels tended to increase with age, and the largest differences were observed for north shore sites (7.4%). Adjusting for sex, both site 1 and site 20 (gene body) methylation at birth was significantly and inversely associated with birth weight (ß = -0.13, P = 0.033; ß = -0.09, P = 0.025, respectively). Similarly, we found that site 1 and site 20 methylation at 9 years was significantly and inversely associated with 9-year BMI z-score (ß = -0.41, P = 0.015; ß = -0.23, P = 0.045, respectively). CONCLUSION: Our results indicate that PPARγ methylation is highly organized and conserved over time, and highlight the potential functional importance of north shore sites, adding to a better understanding of regional human methylome patterns. Overall, our results suggest that PPARγ methylation may be associated with child body size.


Assuntos
Peso ao Nascer/genética , Metilação de DNA , PPAR gama/genética , Índice de Massa Corporal , Criança , Ilhas de CpG , Humanos , Recém-Nascido , Estudos Longitudinais
9.
Circ Cardiovasc Genet ; 9(5): 436-447, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27651444

RESUMO

BACKGROUND: DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders. METHODS AND RESULTS: To comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15 907 blood-derived DNA samples from participants in 16 cohorts (including 2433 current, 6518 former, and 6956 never smokers). Comparing current versus never smokers, 2623 cytosine-phosphate-guanine sites (CpGs), annotated to 1405 genes, were statistically significantly differentially methylated at Bonferroni threshold of P<1×10-7 (18 760 CpGs at false discovery rate <0.05). Genes annotated to these CpGs were enriched for associations with several smoking-related traits in genome-wide studies including pulmonary function, cancers, inflammatory diseases, and heart disease. Comparing former versus never smokers, 185 of the CpGs that differed between current and never smokers were significant P<1×10-7 (2623 CpGs at false discovery rate <0.05), indicating a pattern of persistent altered methylation, with attenuation, after smoking cessation. Transcriptomic integration identified effects on gene expression at many differentially methylated CpGs. CONCLUSIONS: Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years after smoking cessation. Many of the differentially methylated genes were novel genes with respect to biological effects of smoking and might represent therapeutic targets for prevention or treatment of tobacco-related diseases. Methylation at these sites could also serve as sensitive and stable biomarkers of lifetime exposure to tobacco smoke.


Assuntos
Metilação de DNA , Epigênese Genética , Fumar/efeitos adversos , Fumar/genética , Transcriptoma , Idoso , Estudos de Casos e Controles , Ilhas de CpG , Feminino , Perfilação da Expressão Gênica/métodos , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Leucócitos/química , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Fumar/etnologia , Abandono do Hábito de Fumar , Prevenção do Hábito de Fumar , Fatores de Tempo
10.
Am J Hum Genet ; 98(4): 680-96, 2016 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-27040690

RESUMO

Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 × 10(-16)). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.


Assuntos
Metilação de DNA , Epigênese Genética , Fumar/efeitos adversos , Asma/etiologia , Asma/genética , Criança , Pré-Escolar , Mapeamento Cromossômico , Fenda Labial/etiologia , Fenda Labial/genética , Fissura Palatina/etiologia , Fissura Palatina/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudos de Associação Genética , Humanos , Lactente , Recém-Nascido , Gravidez
11.
Environ Res ; 148: 55-62, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27019040

RESUMO

Phthalates are frequently used in personal care products and plasticizers and phthalate exposure is ubiquitous in the US population. Exposure to phthalates during critical periods in utero has been associated with a variety of adverse health outcomes but the biological mechanisms linking these exposures with disease are not well characterized. In this study, we examined the relationship of in utero phthalate exposure with repetitive element DNA methylation, an epigenetic marker of genome instability, in children from the longitudinal birth cohort CHAMACOS. Methylation of Alu and long interspersed nucleotide elements (LINE-1) was determined using pyrosequencing of bisulfite-treated DNA isolated from whole blood samples collected from newborns and 9 year old children (n=355). Concentrations of eleven phthalate metabolites were measured in urine collected from pregnant mothers at 13 and 26 weeks gestation. We found a consistent inverse association between prenatal concentrations of monoethyl phthalate, the most frequently detected urinary metabolite, with cord blood methylation of Alu repeats (ß(95%CI): -0.14 (-0.28,0.00) and -0.16 (-0.31, -0.02)) for early and late pregnancy, respectively, and a similar but weaker association with LINE-1 methylation. Additionally, increases in urinary concentrations of di-(2-ethylhexyl) phthalate metabolites during late pregnancy were associated with lower levels of methylation of Alu repeats in 9 year old blood (significant p-values ranged from 0.003 to 0.03). Our findings suggest that prenatal exposure to some phthalates may influence differences in repetitive element methylation, highlighting epigenetics as a plausible biological mechanism through which phthalates may affect health.


Assuntos
Elementos Alu , Metilação de DNA , Poluentes Ambientais , Elementos Nucleotídeos Longos e Dispersos , Exposição Materna , Ácidos Ftálicos , Adolescente , Adulto , Biomarcadores , Criança , Poluentes Ambientais/urina , Epigênese Genética , Feminino , Sangue Fetal/metabolismo , Humanos , Recém-Nascido , Masculino , Troca Materno-Fetal , Americanos Mexicanos , Pessoa de Meia-Idade , Ácidos Ftálicos/urina , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Adulto Jovem
12.
BMC Genomics ; 16: 911, 2015 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-26553366

RESUMO

BACKGROUND: DNA methylation is an important epigenetic mark that can potentially link early life exposures to adverse health outcomes later in life. Host factors like sex and age strongly influence biological variation of DNA methylation, but characterization of these relationships is still limited, particularly in young children. METHODS: In a sample of 111 Mexican-American subjects (58 girls , 53 boys), we interrogated DNA methylation differences by sex at birth using the 450 K BeadChip in umbilical cord blood specimens, adjusting for cell composition. RESULTS: We observed that ~3% of CpG sites were differentially methylated between girls and boys at birth (FDR P < 0.05). Of those CpGs, 3031 were located on autosomes, and 82.8% of those were hypermethylated in girls compared to boys. Beyond individual CpGs, we found 3604 sex-associated differentially methylated regions (DMRs) where the majority (75.8%) had higher methylation in girls. Using pathway analysis, we found that sex-associated autosomal CpGs were significantly enriched for gene ontology terms related to nervous system development and behavior. Among hits in our study, 35.9% had been previously reported as sex-associated CpG sites in other published human studies. Further, for replicated hits, the direction of the association with methylation was highly concordant (98.5-100%) with previous studies. CONCLUSIONS: To our knowledge, this is the first reported epigenome-wide analysis by sex at birth that examined DMRs and adjusted for confounding by cell composition. We confirmed previously reported trends that methylation profiles are sex-specific even in autosomal genes, and also identified novel sex-associated CpGs in our methylome-wide analysis immediately after birth, a critical yet relatively unstudied developmental window.


Assuntos
Metilação de DNA/genética , Ilhas de CpG/genética , Epigênese Genética/genética , Epigenômica , Feminino , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Masculino
13.
Environ Mol Mutagen ; 56(9): 751-8, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26332589

RESUMO

Confounding by cellular heterogeneity has become a major concern for epigenome-wide association studies (EWAS) in peripheral blood samples from population and clinical studies. Adjusting for white blood cell percentage estimates produced by the minfi implementation of the Houseman algorithm (minfi) during statistical analysis is now an established method to account for this bias in adults. However, minfi has not been benchmarked against white blood cell counts in children that may differ substantially from the reference dataset used in its estimation. We compared estimates of white blood cell type percentages produced by two methods, minfi and differential cell count (DCC), in a birth cohort at two time points (birth and 12 years of age). We found that both minfi and DCC had similar trends as children aged, and neither count method differed by sex among newborns (P > 0.10). However, minfi estimates did not correlate well with DCC in samples from newborns (ρ = -0.05 for granulocytes; ρ = -0.03 for lymphocytes). In older children, correlation improved substantially (ρ = 0.77 for granulocytes; ρ = 0.75 for lymphocytes), likely due to increasing similarity with minfi's adult reference data as children aged. Our findings suggest that the minfi method may provide suitable estimates of white blood cell composition for samples from adults and older children, but may not currently be appropriate for EWAS involving newborns or young children.


Assuntos
Contagem de Células Sanguíneas/métodos , Células Sanguíneas/citologia , Células Sanguíneas/fisiologia , Fatores Etários , Criança , Estudos de Coortes , Metilação de DNA , Epigênese Genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Contagem de Leucócitos/métodos , Estudos Longitudinais , Masculino , Valores de Referência
14.
Mutagenesis ; 30(3): 411-20, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25589532

RESUMO

Epigenetic control of gene expression in children remains poorly understood, but new technologies can help elucidate the relationship between expression and DNA methylation. Here, we utilized the nCounter Analysis System to characterise the expression of 60 genes in 69 9-year-old children from a cohort with a high prevalence of obesity. nCounter expression levels ranged broadly (from 3 to over 10000 messenger RNA counts) and were divided into four categories: high (>2000 counts), moderate (200-1000 counts), low (100-200 counts) and marginal (<100 counts). For a subset of five genes (ADIPOR1, PPARG1, GSTM1, PON1 and ACACA) from different expression level categories, we validated nCounter data using reverse transcription-polymerase chain reaction (RT-PCR), and expanded RT-PCR analysis of ADIPOR1 to include 180 children. Expression data from the two methodologies were correlated for all five genes included in the validation experiment, with estimates ranging from r s = 0.26 (P = 0.02) to r s = 0.88 (P < 5×10(-6)). ADIPOR1 and PPARG1 nCounter expression levels were negatively correlated (r = -0.60, P < 5×10(-5)), and this relationship was stronger in overweight children (r = -0.73, P < 5×10(-5)) than in normal weight children (r = -0.42, P = 0.016). Using methylation data from the Infinium HumanMethylation450 BeadChip (n = 180), we found eight CpG sites in ADIPOR1 and PPARG where methylation level was associated with expression by RT-PCR (P < 0.05). Hypomethylation of PPARG gene body site cg10499651 was associated with increased expression as measured by both RT-PCR and nCounter (P < 0.05). We found no statistically significant relationships between either expression or methylation of ADIPOR1 and PPARG and body mass index or waist circumference. In addition to demonstrating the validity of expression data derived from nCounter, our results illustrate the use of new technologies in assessing epigenetic effects on expression in children.


Assuntos
Metilação de DNA , Epigênese Genética , Expressão Gênica , Obesidade/genética , Criança , Ilhas de CpG , Feminino , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Humanos , Masculino , PPAR gama/genética , PPAR gama/metabolismo , Receptores de Adiponectina/genética , Receptores de Adiponectina/metabolismo
15.
Environ Epigenet ; 1(1)2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26913202

RESUMO

Recent genome- and epigenome-wide studies demonstrate that the DNA methylation is controlled in part by genetics, highlighting the importance of integrating genetic and epigenetic data. To better understand molecular mechanisms affecting gene expression, we used the candidate susceptibility gene paraoxonase 1 (PON1) as a model to assess associations of PON1 genetic polymorphisms with DNA methylation and arylesterase activity, a marker of PON1 expression. PON1 has been associated with susceptibility to obesity, cardiovascular disease, and pesticide exposure. In this study, we assessed DNA methylation in 18 CpG sites located along PON1 shores, shelves, and its CpG island in blood specimens collected from newborns and 9-year-old children participating (n = 449) in the CHAMACOS birth cohort study. The promoter polymorphism, PON1-108 , was strongly associated with methylation, particularly for CpG sites located near the CpG island (P << 0.0005). Among newborns, these relationships were even more pronounced after adjusting for blood cell composition. We also observed significant decreases in arylesterase activity with increased methylation at the same nine CpG sites at both ages. Using causal mediation analysis, we found statistically significant indirect effects of methylation (ß(95% confidence interval): 6.9(1.5, 12.4)) providing evidence that DNA methylation mediates the relationship between PON1-108 genotype and PON1 expression. Our findings show that integration of genetic, epigenetic, and expression data can shed light on the functional mechanisms involving genetic and epigenetic regulation of candidate susceptibility genes like PON1.

16.
Reprod Toxicol ; 50: 19-26, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25305053

RESUMO

Low birth weight is associated with exposure to air pollution during pregnancy. The purpose of this study was to evaluate whether null polymorphisms of Glutathione S-transferases (GSTs), specifically GSTM1 and GSTT1 genes in infants or mothers, modify the association between high exposures to household air pollution (HAP) from cooking fires and birth weight. Pregnant women in rural Guatemala were randomized to receive a chimney stove or continue to use open fires for cooking. Newborns were measured within 48 h of birth. 132 mother-infant pairs provided infant genotypes (n=130) and/or maternal genotypes (n=116). Maternal null GSTM1 was associated with a 144 g (95% CI, -291, 1) and combined maternal/infant null GSTT1 was associated with a 155 g (95% CI, -303, -8) decrease in birth weight. Although there was a trend toward higher birth weights with increasing number of expressed GST genes, the effect modification by chimney stove use was not demonstrated.


Assuntos
Poluição do Ar/efeitos adversos , Peso ao Nascer , Glutationa Transferase/genética , Exposição Materna/efeitos adversos , Feminino , Humanos , Recém-Nascido , Gravidez
17.
Mutagenesis ; 29(5): 367-77, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25084778

RESUMO

In Central America, the traditional temazcales or wood-fired steam baths, commonly used by many Native American populations, are often heated by wood fires with little ventilation, and this use results in high wood smoke exposure. Urinary mutagenicity has been previously employed as a non-invasive biomarker of human exposure to combustion emissions. This study examined the urinary mutagenicity in 19 indigenous Mayan families from the highlands of Guatemala who regularly use temazcales (N = 32), as well as control (unexposed) individuals from the same population (N = 9). Urine samples collected before and after temazcal exposure were enzymatically deconjugated and extracted using solid-phase extraction. The creatinine-adjusted mutagenic potency of urine extracts was assessed using the plate-incorporation version of the Salmonella mutagenicity assay with strain YG1041 in the presence of exogenous metabolic activation. The post-exposure mutagenic potency of urine extracts were, on average, 1.7-fold higher than pre-exposure samples (P < 0.005) and also significantly more mutagenic than the control samples (P < 0.05). Exhaled carbon monoxide (CO) was ~10 times higher following temazcal use (P < 0.0001), and both CO level and time spent in temazcal were positively associated with urinary mutagenic potency (i.e. P < 0.0001 and P = 0.01, respectively). Thus, the wood smoke exposure associated with temazcal use contributes to increased excretion of conjugated mutagenic metabolites. Moreover, urinary mutagenic potency is correlated with other metrics of exposure (i.e. exhaled CO, duration of exposure). Since urinary mutagenicity is a biomarker associated with genetic damage, temazcal use may therefore be expected to contribute to an increased risk of DNA damage and mutation, effects associated with the initiation of cancer.


Assuntos
Biomarcadores/urina , Exposição Ambiental/efeitos adversos , Mutagênicos/toxicidade , Fumaça/efeitos adversos , Madeira/química , Adolescente , Adulto , Idoso , Monóxido de Carbono/análise , Criança , Pré-Escolar , Exposição Ambiental/análise , Feminino , Guatemala , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Testes de Mutagenicidade , Inquéritos e Questionários , Madeira/toxicidade , Adulto Jovem
18.
Environ Mol Mutagen ; 55(3): 209-22, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24375655

RESUMO

Epigenetic changes such as DNA methylation may be a molecular mechanism through which environmental exposures affect health. Methylation of Alu and long interspersed nucleotide elements (LINE-1) is a well-established measure of DNA methylation often used in epidemiologic studies. Yet, few studies have examined the effects of host factors on LINE-1 and Alu methylation in children. We characterized the relationship of age, sex, and prenatal exposure to persistent organic pollutants (POPs), dichlorodiphenyl trichloroethane (DDT), dichlorodiphenyldichloroethylene (DDE), and polybrominated diphenyl ethers (PBDEs), with DNA methylation in a birth cohort of Mexican-American children participating in the CHAMACOS study. We measured Alu and LINE-1 methylation by pyrosequencing bisulfite-treated DNA isolated from whole blood samples collected from newborns and nine-year old children (n = 358). POPs were measured in maternal serum during late pregnancy. Levels of DNA methylation were lower in nine-year olds compared to newborns and were higher in boys compared to girls. Higher prenatal DDT/E exposure was associated with lower Alu methylation at birth, particularly after adjusting for cell type composition (P = 0.02 for o,p' -DDT). Associations of POPs with LINE-1 methylation were only identified after examining the co-exposure of DDT/E with PBDEs simultaneously. Our data suggest that repeat element methylation can be an informative marker of epigenetic differences by age and sex and that prenatal exposure to POPs may be linked to hypomethylation in fetal blood. Accounting for co-exposure to different types of chemicals and adjusting for blood cell types may increase sensitivity of epigenetic analyses for epidemiological studies.


Assuntos
Metilação de DNA , Poluentes Ambientais/toxicidade , Compostos Orgânicos/toxicidade , Fatores Etários , Elementos Alu , Contagem de Células , Criança , Estudos de Coortes , DDT/toxicidade , Diclorodifenil Dicloroetileno/toxicidade , Epigênese Genética , Feminino , Sangue Fetal , Éteres Difenil Halogenados/toxicidade , Humanos , Recém-Nascido , Elementos Nucleotídeos Longos e Dispersos , Masculino , Exposição Materna , Americanos Mexicanos , Gravidez , Fatores Sexuais
19.
PLoS One ; 8(10): e77964, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24205046

RESUMO

OBJECTIVES: To address molecular mechanisms underlying obesity development, we examined patterns of critical metabolism-related hormones, adiponectin and leptin (adipokines), over childhood. SUBJECTS AND DESIGN: Plasma adiponectin and leptin were measured in 80 Mexican-American children at birth and again at 2, 5, and 9 years from the ongoing prospective cohort followed by the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS). We used a mixture modeling approach to identify patterns in adipokine trajectories from birth to 9 years. RESULTS: Leptin was positively related to child body size within all ages, however adiponectin had inverse and weaker associations with BMI at 2, 5, and 9 years. Correlations between adipokine levels over the 0-2, 2-5, and 5-9-year periods increased for both leptin (r = 0.06, 0.31 and 0.62) and adiponectin (r = 0.25, 0.41 and 0.46). Our mixture modeling approach identified three trajectory clusters for both leptin (1L [slowly-rising], 2L [rapidly-rising], and 3L [stable]) and adiponectin (1A [steep-dropping and rebounding], 2A [moderately-dropping], and 3A [stable]). While leptin groups were most separated over the 2-9-year period, adiponectin trajectories displayed greatest heterogeneity from birth to 2 years. Children in the rapidly-rising 2L group had highest BMI and waist circumference at 9 years. Further, children with greater birth weight had increased odds of belonging to this high risk group (OR = 1.21 95% CI 1.03, 1.43, compared to stable group 3L). Children whose mothers consumed more sugar-sweetened beverages during pregnancy were at risk of being in the steep-dropping 1A group (OR = 1.08, 95% CI 1.01, 1.17, compared to stable group 3A). CONCLUSION: Our results highlight developmental differences in leptin and adiponectin over the childhood period. Leptin closely reflects child body size however factors affecting adiponectin and long-term consequences of its changes over infancy need to be further explored.


Assuntos
Adiponectina/sangue , Leptina/sangue , Americanos Mexicanos/estatística & dados numéricos , Obesidade/sangue , Adolescente , Adulto , Índice de Massa Corporal , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Gravidez , Estudos Prospectivos , Inquéritos e Questionários , Adulto Jovem
20.
Epigenetics ; 8(11): 1141-52, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23959097

RESUMO

Analysis of epigenetic mechanisms, particularly DNA methylation, is of increasing interest for epidemiologic studies examining disease etiology and impacts of environmental exposures. The Infinium HumanMethylation450 BeadChip(®) (450K), which interrogates over 480,000 CpG sites and is relatively cost effective, has become a popular tool to characterize the DNA methylome. For large-scale studies, minimizing technical variability and potential bias is paramount. The goal of this paper was to evaluate the performance of several existing and novel color channel normalizations designed to reduce technical variability and batch effects in 450K analysis from a large population study. Comparative assessment of 10 normalization procedures included the GenomeStudio(®) Illumina procedure, the lumi smooth quantile approach, and the newly proposed All Sample Mean Normalization (ASMN). We also examined the performance of normalizations in combination with correction for the two types of Infinium chemistry utilized on the 450K array. We observed that the performance of the GenomeStudio(®) normalization procedure was highly variable and dependent on the quality of the first sample analyzed in an experiment, which is used as a reference in this procedure. While the lumi normalization was able to decrease batch variability, it increased variation among technical replicates, potentially reducing biologically meaningful findings. The proposed ASMN procedure performed consistently well, both at reducing batch effects and improving replicate comparability. In summary, the ASMN procedure can improve existing color channel normalization, especially for large epidemiologic studies, and can be successfully implemented to enhance a 450K DNA methylation data pipeline.


Assuntos
Ilhas de CpG , Metilação de DNA , Análise de Sequência com Séries de Oligonucleotídeos/normas , Criança , Epigênese Genética , Genética Populacional , Humanos , Estudos Longitudinais , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Controle de Qualidade , Software
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