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1.
Artigo em Inglês | MEDLINE | ID: mdl-30201514

RESUMO

BACKGROUND: Asthma is a common but complex disease with racial/ethnic differences in prevalence, morbidity, and response to therapies. OBJECTIVE: We sought to perform an analysis of genetic ancestry to identify new loci that contribute to asthma susceptibility. METHODS: We leveraged the mixed ancestry of 3902 Latinos and performed an admixture mapping meta-analysis for asthma susceptibility. We replicated associations in an independent study of 3774 Latinos, performed targeted sequencing for fine mapping, and tested for disease correlations with gene expression in the whole blood of more than 500 subjects from 3 racial/ethnic groups. RESULTS: We identified a genome-wide significant admixture mapping peak at 18q21 in Latinos (P = 6.8 × 10-6), where Native American ancestry was associated with increased risk of asthma (odds ratio [OR], 1.20; 95% CI, 1.07-1.34; P = .002) and European ancestry was associated with protection (OR, 0.86; 95% CI, 0.77-0.96; P = .008). Our findings were replicated in an independent childhood asthma study in Latinos (P = 5.3 × 10-3, combined P = 2.6 × 10-7). Fine mapping of 18q21 in 1978 Latinos identified a significant association with multiple variants 5' of SMAD family member 2 (SMAD2) in Mexicans, whereas a single rare variant in the same window was the top association in Puerto Ricans. Low versus high SMAD2 blood expression was correlated with case status (13.4% lower expression; OR, 3.93; 95% CI, 2.12-7.28; P < .001). In addition, lower expression of SMAD2 was associated with more frequent exacerbations among Puerto Ricans with asthma. CONCLUSION: Ancestry at 18q21 was significantly associated with asthma in Latinos and implicated multiple ancestry-informative noncoding variants upstream of SMAD2 with asthma susceptibility. Furthermore, decreased SMAD2 expression in blood was strongly associated with increased asthma risk and increased exacerbations.

3.
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
4.
Epigenomics ; 9(3): 351-367, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28234021

RESUMO

Maternal smoking and micronutrient intake during pregnancy are two strong biological candidates for impacting the developing epigenome. The extent to which DNA methylation in offspring is modified by these intrauterine exposures has not been presented in parallel. In this review, we summarize human studies which have investigated genome-wide DNA methylation in the offspring in relation to maternal smoking and one-carbon micronutrient exposure during pregnancy. We contrast the primarily independent efforts for these two categories of exposure, and potential explanations for these differences. We emphasize methodological considerations such as power to detect methylation signals, exposure assessment, control of sources of variability, causal inference and the role of observed methylation changes in mediating downstream outcomes in the offspring.


Assuntos
Metilação de DNA/efeitos dos fármacos , Desenvolvimento Embrionário , Micronutrientes/genética , Fumar/genética , Epigenômica/métodos , Epigenômica/normas , Feminino , Estudo de Associação Genômica Ampla/métodos , Estudo de Associação Genômica Ampla/normas , Humanos , Micronutrientes/deficiência , Micronutrientes/farmacologia , Gravidez , Fumar/efeitos adversos
5.
Reprod Toxicol ; 68: 34-48, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27871864

RESUMO

The Developmental Origins of Health and Disease (DOHaD) scientific field investigates the influence of early life environmental stressors on later life health outcomes. Environmental chemical exposures are a particular focus area within this field. Although the DOHaD hypothesis originated in the 1990s, the data evaluating this hypothesis in environmental epidemiology has not been comprehensively summarized. We conducted a scoping literature review to describe the human evidence for the DOHaD hypothesis and to identify, 1) where there may be reasonable data to draw conclusions, and 2) areas warranting further research. Using PubMed and Web of Science we identified 425 publications through 2014 that met our criteria for evaluating the DOHaD hypothesis in environmental epidemiology. These publications covered 60 different chemicals. The majority of publications focused on neurological/cognitive outcomes, followed by cancer, and respiratory outcomes. We note areas ready for more detailed review, those requiring more data and ideas for future directions.


Assuntos
Exposição Ambiental/efeitos adversos , Poluentes Ambientais/toxicidade , Estudos Epidemiológicos , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Animais , Feminino , Humanos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia
6.
Environ Health Perspect ; 125(4): 760-766, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27323799

RESUMO

BACKGROUND: Maternal smoking during pregnancy, especially when sustained, leads to numerous adverse health outcomes in offspring. Pregnant women disproportionately underreport smoking and smokers tend to have lower follow-up rates to repeat questionnaires. Missing, incomplete, or inaccurate data on presence and duration of smoking in pregnancy impairs identification of novel health effects and limits adjustment for smoking in studies of other pregnancy exposures. An objective biomarker in newborns of maternal smoking during pregnancy would be valuable. OBJECTIVES: We developed a biomarker of sustained maternal smoking in pregnancy using common DNA methylation platforms. METHODS: Using a dimension reduction method, we developed and tested a numeric score in newborns to reflect sustained maternal smoking in pregnancy from data on cotinine, a short-term smoking biomarker measured mid-pregnancy, and Illumina450K cord blood DNA methylation from newborns in the Norwegian Mother and Child Cohort Study (MoBa). RESULTS: This score reliably predicted smoking status in the training set (n = 1,057; accuracy = 96%, sensitivity = 80%, specificity = 98%). Sensitivity (58%) was predictably lower in the much smaller test set (n = 221), but accuracy (91%) and specificity (97%) remained high. Reduced birth weight, a well-known effect of maternal smoking, was as strongly related to the score as to cotinine. A three-site score had lower, but acceptable, performance (accuracytrain = 82%, accuracytest = 83%). CONCLUSIONS: Our smoking methylation score represents a promising novel biomarker of sustained maternal smoking during pregnancy easily calculated with Illumina450K or IlluminaEPIC data. It may help identify novel health impacts and improve adjustment for smoking when studying other risk factors with more subtle effects.


Assuntos
Biomarcadores/sangue , Metilação de DNA , Exposição Materna/estatística & dados numéricos , Fumar/epidemiologia , Adulto , Peso ao Nascer , Estudos de Coortes , Cotinina/sangue , Feminino , Sangue Fetal/metabolismo , Humanos , Recém-Nascido , Gravidez , Efeitos Tardios da Exposição Pré-Natal
8.
BMC Genomics ; 17(1): 976, 2016 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-27887572

RESUMO

BACKGROUND: Children exposed to maternal smoking during pregnancy exhibit increased risk for many adverse health effects. Maternal smoking influences methylation in newborns at specific CpG sites (CpGs). Here, we extend evaluation of individual CpGs to gene-level and pathway-level analyses among 1062 participants in the Norwegian Mother and Child Cohort Study (MoBa) using the Illumina 450 K platform to measure methylation in newborn DNA and maternal smoking in pregnancy, assessed using the biomarker, plasma cotinine. We used novel implementations of bioinformatics tools to collapse epigenome-wide methylation data into gene- and pathway-level effects to test whether exposure to maternal smoking in utero differentially methylated CpGs in genes enriched in biologic pathways. Unlike most pathway analysis applications, our approach allows replication in an independent cohort. RESULTS: Data on 485,577 CpGs, mapping to a total of 20,199 genes, were used to create gene scores that were tested for association with maternal plasma cotinine levels using Sequence Kernel Association Test (SKAT), and 15 genes were found to be associated (q < 0.25). Six of these 15 genes (GFI1, MYO1G, CYP1A1, RUNX1, LCTL, and AHRR) contained individual CpGs that were differentially methylated with regards to cotinine levels (p < 1.06 × 10-7). Nine of the 15 genes (FCRLA, MIR641, SLC25A24, TRAK1, C1orf180, ITLN2, GLIS1, LRFN1, and MIR451) were associated with cotinine at the gene-level (q < 0.25) but had no genome-wide significant individual CpGs (p > 1.06 × 10-7). Pathway analyses using gene scores resulted in 51 significantly associated pathways, which we tested for replication in an independent cohort (q < 0.05). Of those 32 replicated in an independent cohort, which clustered into six groups. The largest cluster consisted of pathways related to cancer, cell cycle, ERα receptor signaling, and angiogenesis. The second cluster, organized into five smaller pathway groups, related to immune system function, such as T-cell regulation and other white blood cell related pathways. CONCLUSIONS: Here we use novel implementations of bioinformatics tools to determine biological pathways impacted through epigenetic changes in utero by maternal smoking in 1062 participants in the MoBa, and successfully replicate these findings in an independent cohort. The results provide new insight into biological mechanisms that may contribute to adverse health effects from exposure to tobacco smoke in utero.


Assuntos
Epigênese Genética , Regulação da Expressão Gênica , Exposição Materna , Efeitos Tardios da Exposição Pré-Natal , Transdução de Sinais , Fumar/efeitos adversos , Análise por Conglomerados , Ilhas de CpG , Metilação de DNA , Feminino , Humanos , Gravidez
9.
PLoS One ; 11(7): e0156361, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27383059

RESUMO

Offspring of older mothers are at increased risk of adverse birth outcomes, childhood cancers, type 1 diabetes, and neurodevelopmental disorders. The underlying biologic mechanisms for most of these associations remain obscure. One possibility is that maternal aging may produce lasting changes in the epigenetic features of a child's DNA. To test this, we explored the association of mothers' age at pregnancy with methylation in her offspring, using blood samples from 890 Norwegian newborns and measuring DNA methylation at more than 450,000 CpG sites across the genome. We examined replication of a maternal-age finding in an independent group of 1062 Norwegian newborns, and then in 200 US middle-aged women. Older maternal age was significantly associated with reduced methylation at four adjacent CpGs near the 2nd exon of KLHL35 in newborns (p-values ranging from 3x10-6 to 8x10-7). These associations were replicated in the independent set of newborns, and replicated again in women 40 to 60 years after their birth. This study provides the first example of parental age permanently affecting the epigenetic profile of offspring. While the specific functions of the affected gene are unknown, this finding opens the possibility that a mother's age at pregnancy could affect her child's health through epigenetic mechanisms.


Assuntos
Ilhas de CpG , Epigênese Genética , Idade Materna , Adulto , Peso ao Nascer/genética , Estudos de Coortes , Metilação de DNA , Feminino , Humanos , Recém-Nascido , Noruega , Gravidez , Adulto Jovem
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.
Nat Commun ; 7: 10577, 2016 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-26861414

RESUMO

Folate is vital for fetal development. Periconceptional folic acid supplementation and food fortification are recommended to prevent neural tube defects. Mechanisms whereby periconceptional folate influences normal development and disease are poorly understood: epigenetics may be involved. We examine the association between maternal plasma folate during pregnancy and epigenome-wide DNA methylation using Illumina's HumanMethyl450 Beadchip in 1,988 newborns from two European cohorts. Here we report the combined covariate-adjusted results using meta-analysis and employ pathway and gene expression analyses. Four-hundred forty-three CpGs (320 genes) are significantly associated with maternal plasma folate levels during pregnancy (false discovery rate 5%); 48 are significant after Bonferroni correction. Most genes are not known for folate biology, including APC2, GRM8, SLC16A12, OPCML, PRPH, LHX1, KLK4 and PRSS21. Some relate to birth defects other than neural tube defects, neurological functions or varied aspects of embryonic development. These findings may inform how maternal folate impacts the developing epigenome and health outcomes in offspring.


Assuntos
Metilação de DNA , Epigênese Genética , Ácido Fólico/sangue , Regulação da Expressão Gênica no Desenvolvimento , Adulto , Moléculas de Adesão Celular/genética , Proteínas do Citoesqueleto/genética , Feminino , Proteínas Ligadas por GPI/genética , Humanos , Recém-Nascido , Calicreínas/genética , Proteínas com Homeodomínio LIM/genética , Transportadores de Ácidos Monocarboxílicos/genética , Periferinas/genética , Gravidez , Serina Endopeptidases/genética , Fatores de Transcrição/genética
12.
BMC Res Notes ; 8: 321, 2015 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-26219460

RESUMO

BACKGROUND: Several epidemiologic studies indicate that maternal gestational weight gain (GWG) influences health outcomes in offspring. Any underlying mechanisms have, however, not been established. A recent study of 88 children based on the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort examined the methylation levels at 1,505 Cytosine-Guanine methylation (CpG) loci and found several to be significantly associated with maternal weight gain between weeks 0 and 18 of gestation. Since these results could not be replicated we wanted to examine associations between 0 and 18 week GWG and genome-wide methylation levels using the Infinium HumanMethylation450 BeadChip (450K) platform on a larger sample size, i.e. 729 newborns sampled from the Norwegian Mother and Child Cohort Study (MoBa). RESULTS: We found no CpG loci associated with 0-18 week GWG after adjusting for the set of covariates used in the ALSPAC study (i.e. child's sex and maternal age) and for multiple testing (q > 0.9, both 1,505 and 473,731 tests). Hence, none of the CpG loci linked with the genes found significantly associated with 0-18 week GWG in the ALSPAC study were significant in our study. CONCLUSIONS: The inconsistency in the results with the ALSPAC study with regards to the 0-18 week GWG model may arise for several reasons: sampling from different populations, dissimilar methylome coverage, sample size and/or false positive findings.


Assuntos
Metilação de DNA , Epigênese Genética , Ganho de Peso/fisiologia , Adulto , Peso ao Nascer , Ilhas de CpG , Feminino , Loci Gênicos , Idade Gestacional , Humanos , Recém-Nascido , Estudos Longitudinais , Masculino , Mães , Gravidez
13.
Genet Epidemiol ; 39(2): 53-64, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25537884

RESUMO

New high throughput technologies are now enabling simultaneous epigenetic profiling of DNA methylation at hundreds of thousands of CpGs across the genome. A problem of considerable practical interest is identification of large scale, global changes in methylation that are associated with environmental variables, clinical outcomes, or other experimental conditions. However, there has been little statistical research on methods for global methylation analysis using technologies with individual CpG resolution. To address this critical gap in the literature, we develop a new strategy for global analysis of methylation profiles using a functional regression approach wherein we approximate either the density or the cumulative distribution function (CDF) of the methylation values for each individual using B-spline basis functions. The spline coefficients for each individual are allowed to summarize the individual's overall methylation profile. We then test for association between the overall distribution and a continuous or dichotomous outcome variable using a variance component score test that naturally accommodates the correlation between spline coefficients. Simulations indicate that our proposed approach has desirable power while protecting type I error. The method was applied to detect methylation differences, both genome wide and at LINE1 elements, between the blood samples from rheumatoid arthritis patients and healthy controls and to detect the epigenetic changes of human hepatocarcinogenesis in the context of alcohol abuse and hepatitis C virus infection. A free implementation of our methods in the R language is available in the Global Analysis of Methylation Profiles (GAMP) package at http://research.fhcrc.org/wu/en.html.


Assuntos
Ilhas de CpG/genética , Metilação de DNA , Epigênese Genética/genética , Epigenômica , Alcoolismo/genética , Artrite Reumatoide/genética , Estudos de Casos e Controles , Genoma/genética , Hepatite C/genética , Humanos , Internet , Elementos Nucleotídeos Longos e Dispersos/genética , Modelos Genéticos , Software
14.
PLoS One ; 9(7): e100776, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24983941

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.


Assuntos
Cromossomos Humanos Par 11/genética , Regulação da Expressão Gênica , Loci Gênicos , Estudo de Associação Genômica Ampla , Respiração/genética , Adulto , Feminino , Humanos , Estudos Longitudinais , Masculino
15.
PLoS One ; 9(6): e99716, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24964093

RESUMO

BACKGROUND: Smoking while pregnant is associated with a myriad of negative health outcomes in the child. Some of the detrimental effects may be due to epigenetic modifications, although few studies have investigated this hypothesis in detail. OBJECTIVES: To characterize site-specific epigenetic modifications conferred by prenatal smoking exposure within asthmatic children. METHODS: Using Illumina HumanMethylation27 microarrays, we estimated the degree of methylation at 27,578 distinct DNA sequences located primarily in gene promoters using whole blood DNA samples from the Childhood Asthma Management Program (CAMP) subset of Asthma BRIDGE childhood asthmatics (n = 527) ages 5-12 with prenatal smoking exposure data available. Using beta-regression, we screened loci for differential methylation related to prenatal smoke exposure, adjusting for gender, age and clinical site, and accounting for multiple comparisons by FDR. RESULTS: Of 27,578 loci evaluated, 22,131 (80%) passed quality control assessment and were analyzed. Sixty-five children (12%) had a history of prenatal smoke exposure. At an FDR of 0.05, we identified 19 CpG loci significantly associated with prenatal smoke, of which two replicated in two independent populations. Exposure was associated with a 2% increase in mean CpG methylation in FRMD4A (p = 0.01) and Cllorf52 (p = 0.001) compared to no exposure. Four additional genes, XPNPEP1, PPEF2, SMPD3 and CRYGN, were nominally associated in at least one replication group. CONCLUSIONS: These data suggest that prenatal exposure to tobacco smoke is associated with reproducible epigenetic changes that persist well into childhood. However, the biological significance of these altered loci remains unknown.


Assuntos
Asma/genética , Ilhas de CpG , Metilação de DNA , Epigênese Genética , Efeitos Tardios da Exposição Pré-Natal , Fumar/efeitos adversos , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Gravidez
16.
Cancer Epidemiol Biomarkers Prev ; 23(6): 1007-17, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24740201

RESUMO

BACKGROUND: Maternal smoking in pregnancy is associated with adverse health outcomes in children, including cancers; underlying mechanisms may include epigenetic modifications. Using Illumina's 450K array, we previously identified differential DNA methylation related to maternal smoking during pregnancy at 26 CpG sites (CpGs) in 10 genes in newborn cord bloods from the Norwegian Mother and Child Cohort Study (MoBa). Whether these methylation signals in newborns reflect in utero exposure only or possibly epigenetic inheritance of smoking-related modifications is unclear. METHODS: We therefore evaluated the impact of the timing of mother's smoking (before or during pregnancy using cotinine measured at 18 weeks gestation), the father's smoking before conception, and the grandmother's smoking during her pregnancy with the mother on methylation at these 26 CpGs in 1,042 MoBa newborns. We used robust linear regression, adjusting for covariates, applying Bonferroni correction. RESULTS: The strongest and only statistically significant associations were observed for sustained smoking by the mother during pregnancy through at least gestational week 18 (P < 1.6 × 10(-5) for all 26 CpGs). We observed no statistically significant differential methylation due to smoking by the mother before pregnancy or that ceased by week 18, father's smoking before conception, or grandmother's smoking while pregnant with the mother. CONCLUSIONS: Differential methylation at these CpGs in newborns seems to reflect sustained in utero exposure rather than epigenetic inheritance. IMPACT: Smoking cessation in early pregnancy may negate effects on methylation. Analyses of maternal smoking during pregnancy and offspring health outcomes, including cancer, limited to ever smoking might miss true associations. Cancer Epidemiol Biomarkers Prev; 23(6); 1007-17. ©2014 AACR.


Assuntos
Metilação de DNA/genética , Epigênese Genética/genética , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/genética , Fumar/efeitos adversos , Adulto , Feminino , Humanos , Gravidez , Adulto Jovem
17.
Am J Epidemiol ; 179(7): 834-42, 2014 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-24561991

RESUMO

Although epigenetic regulation plays a critical role in embryonic development, few studies have examined the relationship of epigenome-wide methylation with fetal growth. Using the Infinium HumanMethylation450 BeadChip (Illumina, Inc., San Diego, California) in a substudy of 1,046 infants from the Norwegian Mother and Child Cohort Study (MoBa) enrolled between 1999 and 2008, we examined epigenome-wide cord blood DNA methylation in relation to birth weight. In multivariable-adjusted robust linear regression models, we identified differential methylation at 19 cytosine-guanine dinucleotides (CpGs) associated with either decreased (AT-rich interactive domain 5B (MRF1-like) (ARID5B), 2 CpGs) or increased (x-ray repair complementing defective repair in Chinese hamster cells 3 (XRCC3), 4 CpGs) birth weight. ARID5B knockout mice have less adipose tissue and significantly lower weight in the postnatal period. XRCC3 plays a key role in the maintenance of chromosome stability and the repair of DNA damage. Although there are fewer data on the other implicated genes, many of these genes have been shown to have roles in developmental processes. This constitutes the largest and most robust study of birth weight using an epigenome-wide methylation platform and offers potential insights into epigenetic mechanisms of fetal growth.


Assuntos
Peso ao Nascer/genética , Metilação de DNA/genética , Proteínas de Ligação a DNA/genética , Epigênese Genética , Sangue Fetal/química , Fatores de Transcrição/genética , Adolescente , Adulto , Composição de Bases/genética , Estudos de Coortes , Feminino , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Modelos Lineares , Masculino , Noruega , Gravidez , Adulto Jovem
18.
Epigenetics ; 9(2): 318-29, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24241353

RESUMO

The Illumina Infinium HumanMethylation450 BeadChip has emerged as one of the most popular platforms for genome wide profiling of DNA methylation. While the technology is wide-spread, systematic technical biases are believed to be present in the data. For example, this array incorporates two different chemical assays, i.e., Type I and Type II probes, which exhibit different technical characteristics and potentially complicate the computational and statistical analysis. Several normalization methods have been introduced recently to adjust for possible biases. However, there is considerable debate within the field on which normalization procedure should be used and indeed whether normalization is even necessary. Yet despite the importance of the question, there has been little comprehensive comparison of normalization methods. We sought to systematically compare several popular normalization approaches using the Norwegian Mother and Child Cohort Study (MoBa) methylation data set and the technical replicates analyzed with it as a case study. We assessed both the reproducibility between technical replicates following normalization and the effect of normalization on association analysis. Results indicate that the raw data are already highly reproducible, some normalization approaches can slightly improve reproducibility, but other normalization approaches may introduce more variability into the data. Results also suggest that differences in association analysis after applying different normalizations are not large when the signal is strong, but when the signal is more modest, different normalizations can yield very different numbers of findings that meet a weaker statistical significance threshold. Overall, our work provides useful, objective assessment of the effectiveness of key normalization methods.


Assuntos
Metilação de DNA , Análise de Sequência com Séries de Oligonucleotídeos/estatística & dados numéricos , Adulto , Ilhas de CpG , Humanos , Recém-Nascido , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Reprodutibilidade dos Testes , Software
19.
Environ Health Perspect ; 120(10): 1425-31, 2012 10.
Artigo em Inglês | MEDLINE | ID: mdl-22851337

RESUMO

BACKGROUND: Epigenetic modifications, such as DNA methylation, due to in utero exposures may play a critical role in early programming for childhood and adult illness. Maternal smoking is a major risk factor for multiple adverse health outcomes in children, but the underlying mechanisms are unclear. OBJECTIVE: We investigated epigenome-wide methylation in cord blood of newborns in relation to maternal smoking during pregnancy. METHODS: We examined maternal plasma cotinine (an objective biomarker of smoking) measured during pregnancy in relation to DNA methylation at 473,844 CpG sites (CpGs) in 1,062 newborn cord blood samples from the Norwegian Mother and Child Cohort Study (MoBa) using the Infinium HumanMethylation450 BeadChip (450K). RESULTS: We found differential DNA methylation at epigenome-wide statistical significance (p-value < 1.06 × 10-7) for 26 CpGs mapped to 10 genes. We replicated findings for CpGs in AHRR, CYP1A1, and GFI1 at strict Bonferroni-corrected statistical significance in a U.S. birth cohort. AHRR and CYP1A1 play a key role in the aryl hydrocarbon receptor signaling pathway, which mediates the detoxification of the components of tobacco smoke. GFI1 is involved in diverse developmental processes but has not previously been implicated in responses to tobacco smoke. CONCLUSIONS: We identified a set of genes with methylation changes present at birth in children whose mothers smoked during pregnancy. This is the first study of differential methylation across the genome in relation to maternal smoking during pregnancy using the 450K platform. Our findings implicate epigenetic mechanisms in the pathogenesis of the adverse health outcomes associated with this important in utero exposure.


Assuntos
Cotinina/sangue , Metilação de DNA , Epigênese Genética , Estudo de Associação Genômica Ampla , Exposição Materna , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Poluição por Fumaça de Tabaco/efeitos adversos , Adulto , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Biomarcadores/sangue , Cromatografia Líquida , Estudos de Coortes , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Sangue Fetal , Humanos , Recém-Nascido , Masculino , Noruega/epidemiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Espectrometria de Massas em Tandem , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Estados Unidos/epidemiologia
20.
Neurobiol Aging ; 33(10): 2528.e1-6, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22763023

RESUMO

Little is known about gene-environment interactions in Parkinson disease (PD). We examined potential interactions of smoking and caffeine intake with 10 genome-wide association studies single nucleotide polymorphisms (SNPs) at or near the SNCA, MAPT, LRRK2, and HLA loci among 584 PD patients and 1571 controls. The main effects of these SNPs and environmental exposures were consistent with previous reports. Family history of PD was associated with PD risk (odds ratio = 2.71, 95% confidence interval, 1.97-3.74), which was little affected by further adjustment for these SNPs and environmental exposures. Overall, we did not find significant interactions of either smoking or caffeine intake with these SNPs. However, with a combined smoking and caffeine intake exposure, we found a significant interaction with rs2896905 at SLC2A13, near LRRK2 (p uncorrected = 0.0008). Each A allele was associated with a 35% higher PD risk among never smokers with low caffeine intake, but with a 32% lower risk among smokers with high caffeine intake. This study provides preliminary evidence of a potential gene-environment interaction for PD, which should be investigated in future studies.


Assuntos
Interação Gene-Ambiente , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Doença de Parkinson/genética , Idade de Início , Idoso , Cafeína/administração & dosagem , Feminino , Loci Gênicos , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Proteínas Facilitadoras de Transporte de Glucose/genética , Humanos , Incidência , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/epidemiologia , Polimorfismo de Nucleotídeo Único , Proteínas Serina-Treonina Quinases/genética , Risco , Fumar/epidemiologia , Fumar/genética
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