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1.
Artigo em Inglês | MEDLINE | ID: mdl-33068447

RESUMO

We would like to thank Owora et al. for their interest in our systematic review of childhood asthma prediction models1 and welcome their subsequent analyses and recommendations for future research in this field. In their letter, Owora et al. rightly highlight that prediction models can be classified as either diagnostic or prognostic models, with diagnostic models predicting the presence of a disease of interest at the time of prediction whilst prognostic models predict the presence of the disease of interest at a future time-point.

2.
Environ Health Perspect ; 128(6): 67003, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32484729

RESUMO

BACKGROUND: Few epigenome-wide association studies (EWAS) on air pollutants exist, and none have been done on transportation noise exposures, which also contribute to environmental burden of disease. OBJECTIVE: We performed mutually independent EWAS on transportation noise and air pollution exposures. METHODS: We used data from two time points of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) from 1,389 participants contributing 2,542 observations. We applied multiexposure linear mixed-effects regressions with participant-level random intercept to identify significant Cytosine-phosphate-Guanine (CpG) sites and differentially methylated regions (DMRs) in relation to 1-y average aircraft, railway, and road traffic day-evening-night noise (Lden); nitrogen dioxide (NO2); and particulate matter (PM) with aerodynamic diameter <2.5µm (PM2.5). We performed candidate (CpG-based; cross-systemic phenotypes, combined into "allostatic load") and agnostic (DMR-based) pathway enrichment tests, and replicated previously reported air pollution EWAS signals. RESULTS: We found no statistically significant CpGs at false discovery rate <0.05. However, 14, 48, 183, 8, and 71 DMRs independently associated with aircraft, railway, and road traffic Lden; NO2; and PM2.5, respectively, with minimally overlapping signals. Transportation Lden and air pollutants tendentially associated with decreased and increased methylation, respectively. We observed significant enrichment of candidate DNA methylation related to C-reactive protein and body mass index (aircraft, road traffic Lden, and PM2.5), renal function and "allostatic load" (all exposures). Agnostic functional networks related to cellular immunity, gene expression, cell growth/proliferation, cardiovascular, auditory, embryonic, and neurological systems development were enriched. We replicated increased methylation in cg08500171 (NO2) and decreased methylation in cg17629796 (PM2.5). CONCLUSIONS: Mutually independent DNA methylation was associated with source-specific transportation noise and air pollution exposures, with distinct and shared enrichments for pathways related to inflammation, cellular development, and immune responses. These findings contribute in clarifying the pathways linking these exposures and age-related diseases but need further confirmation in the context of mediation analyses. https://doi.org/10.1289/EHP6174.

3.
BMC Pulm Med ; 20(1): 171, 2020 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-32546146

RESUMO

BACKGROUND: Low lung function has been associated with increased body mass index (BMI). The aim of this study was to investigate whether the effect of BMI on lung function is mediated by DNA methylation. METHODS: We used individual data from 285,495 participants in four population-based cohorts: the European Community Respiratory Health Survey, the Northern Finland Birth Cohort 1966, the Swiss Study on Air Pollution and Lung Disease in Adults, and the UK Biobank. We carried out Mendelian randomisation (MR) analyses in two steps using a two-sample approach with SNPs as instrumental variables (IVs) in each step. In step 1 MR, we estimated the causal effect of BMI on peripheral blood DNA methylation (measured at genome-wide level) using 95 BMI-associated SNPs as IVs. In step 2 MR, we estimated the causal effect of DNA methylation on FEV1, FVC, and FEV1/FVC using two SNPs acting as methQTLs occurring close (in cis) to CpGs identified in the first step. These analyses were conducted after exclusion of weak IVs (F statistic < 10) and MR estimates were derived using the Wald ratio, with standard error from the delta method. Individuals whose data were used in step 1 were not included in step 2. RESULTS: In step 1, we found that BMI might have a small causal effect on DNA methylation levels (less than 1% change in methylation per 1 kg/m2 increase in BMI) at two CpGs (cg09046979 and cg12580248). In step 2, we found no evidence of a causal effect of DNA methylation at cg09046979 on lung function. We could not estimate the causal effect of DNA methylation at cg12580248 on lung function as we could not find publicly available data on the association of this CpG with SNPs. CONCLUSIONS: To our knowledge, this is the first paper to report the use of a two-step MR approach to assess the role of DNA methylation in mediating the effect of a non-genetic factor on lung function. Our findings do not support a mediating effect of DNA methylation in the association of lung function with BMI.

4.
Artigo em Inglês | MEDLINE | ID: mdl-32443666

RESUMO

Several small studies have shown associations between breastfeeding and genome-wide DNA methylation (DNAm). We performed a comprehensive Epigenome-Wide Association Study (EWAS) to identify associations between breastfeeding and DNAm patterns in childhood. We analysed DNAm data from the Isle of Wight Birth Cohort at birth, 10, 18 and 26 years. The feeding method was categorized as breastfeeding duration >3 months and >6 months, and exclusive breastfeeding duration >3 months. EWASs using robust linear regression were performed to identify differentially methylated positions (DMPs) in breastfed and non-breastfed children at age 10 (false discovery rate of 5%). Differentially methylated regions (DMRs) were identified using comb-p. The persistence of significant associations was evaluated in neonates and individuals at 18 and 26 years. Two DMPs, in genes SNX25 and LINC00840, were significantly associated with breastfeeding duration >6 months at 10 years and was replicated for >3 months of exclusive breastfeeding. Additionally, a significant DMR spanning the gene FDFT1 was identified in 10-year-old children who were exposed to a breastfeeding duration >3 months. None of these signals persisted to 18 or 26 years. This study lends further support for a suggestive role of DNAm in the known benefits of breastfeeding on a child's future health.


Assuntos
Aleitamento Materno , Epigênese Genética , Epigenoma , Adolescente , Criança , Metilação de DNA , Feminino , Seguimentos , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Fatores de Tempo , Adulto Jovem
5.
Respir Res ; 21(1): 80, 2020 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-32264874

RESUMO

BACKGROUND: Adolescence is a significant period for the gender-dependent development of lung function. Prior studies have shown that DNA methylation (DNA-M) is associated with lung function and DNA-M at some cytosine-phosphate-guanine dinucleotide sites (CpGs) changes over time. This study examined whether changes of DNA-M at lung-function-related CpGs are associated with changes in lung function during adolescence for each gender, and if so, the biological significance of the detected CpGs. METHODS: Genome-scale DNA-M was measured in peripheral blood samples at ages 10 (n = 330) and 18 years (n = 476) from the Isle of Wight (IOW) birth cohort in United Kingdom, using Illumina Infinium arrays (450 K and EPIC). Spirometry was conducted at both ages. A training and testing method was used to screen 402,714 CpGs for their potential associations with lung function. Linear regressions were applied to assess the association of changes in lung function with changes of DNA-M at those CpGs potentially related to lung function. Adolescence-related and personal and family-related confounders were included in the model. The analyses were stratified by gender. Multiple testing was adjusted by controlling false discovery rate of 0.05. Findings were further examined in two independent birth cohorts, the Avon Longitudinal Study of Children and Parents (ALSPAC) and the Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE) cohort. Pathway analyses were performed on genes to which the identified CpGs were mapped. RESULTS: For females, 42 CpGs showed statistically significant associations with change in FEV1/FVC, but none for change in FEV1 or FVC. No CpGs were identified for males. In replication analyses, 16 and 21 of the 42 CpGs showed the same direction of associations among the females in the ALSPAC and BAMSE cohorts, respectively, with 11 CpGs overlapping across all the three cohorts. Through pathway analyses, significant biological processes were identified that have previously been related to lung function development. CONCLUSIONS: The detected 11 CpGs in all three cohorts have the potential to serve as the candidate epigenetic markers for changes in lung function during adolescence in females.

6.
Genome Med ; 12(1): 25, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32114984

RESUMO

BACKGROUND: Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. METHODS: We performed meta-analysis of Illumina's HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4-18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. RESULTS: We identified 8899 CpGs in cord blood that were associated with gestational age (range 27-42 weeks), at Bonferroni significance, P < 1.06 × 10- 7, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. CONCLUSIONS: We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.

7.
Pediatr Allergy Immunol ; 31(6): 616-627, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32181536

RESUMO

BACKGROUND: The inability to objectively diagnose childhood asthma before age five often results in both under-treatment and over-treatment of asthma in preschool children. Prediction tools for estimating a child's risk of developing asthma by school-age could assist physicians in early asthma care for preschool children. This review aimed to systematically identify and critically appraise studies which either developed novel or updated existing prediction models for predicting school-age asthma. METHODS: Three databases (MEDLINE, Embase and Web of Science Core Collection) were searched up to July 2019 to identify studies utilizing information from children ≤5 years of age to predict asthma in school-age children (6-13 years). Validation studies were evaluated as a secondary objective. RESULTS: Twenty-four studies describing the development of 26 predictive models published between 2000 and 2019 were identified. Models were either regression-based (n = 21) or utilized machine learning approaches (n = 5). Nine studies conducted validations of six regression-based models. Fifteen (out of 21) models required additional clinical tests. Overall model performance, assessed by area under the receiver operating curve (AUC), ranged between 0.66 and 0.87. Models demonstrated moderate ability to either rule in or rule out asthma development, but not both. Where external validation was performed, models demonstrated modest generalizability (AUC range: 0.62-0.83). CONCLUSION: Existing prediction models demonstrated moderate predictive performance, often with modest generalizability when independently validated. Limitations of traditional methods have shown to impair predictive accuracy and resolution. Exploration of novel methods such as machine learning approaches may address these limitations for future school-age asthma prediction.

8.
Aging (Albany NY) ; 12(1): 518-542, 2020 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-31926111

RESUMO

Lung function, strongly associated with morbidity and mortality, decreases with age. This study examines whether poor adult lung function is associated with age accelerations (AAs). DNA methylation (DNAm) based AAs, lifespan predictors (GrimAge and plasminogen activator inhibitor 1-PAI1) and their related age-adjusted measures were estimated from peripheral blood at two time points (8-to-11 years apart) in adults from two cohorts: SAPALDIA (n=987) and ECRHS (n=509). Within each cohort and stratified by gender (except for estimators from GrimAge and PAI1), AAs were used as predictors in multivariate linear regression with cross-sectional lung function parameters, and in covariate-adjusted mixed linear regression with longitudinal change in lung function and meta-analysed.AAs were found cross-sectionally associated with lower mean FEV1 (Forced Expiratory Volume in one second) (AA-residuals:P-value=4x10-4; Intrinsic Epigenetic AA:P-value=2x10-4) in females at the follow-up time point only, and the same trend was observed for FVC (Forced Vital Capacity). Both lifespan and plasma level predictors were observed strongly associated with lung function decline and the decline was stronger in the follow-up time points (strongest association between FEV1 and DNAmAge GrimAge:P-value=1.25x10-17).This study suggests that DNAm based lifespan and plasma level predictors can be utilised as important factors to assess lung health in adults.

9.
Epigenetics ; 15(5): 454-461, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31818188

RESUMO

DNA methylation (DNAm) in blood (umbilical cord blood and capillary blood collected after birth on Guthrie cards) during the perinatal period is being increasingly studied with the aim of identifying epigenetic markers of in utero environmental exposures or later disease development. However, the comparability in DNAm between these two sources is unknown. To this end, DNAm from the cord blood and capillary blood of 34 subjects in the Isle of Wight 3rd Generation Birth Cohort (68 samples) were included to assess the comparability. Differences in average DNAm (overall agreement), correlations in DNAm, and intra-class correlation coefficients (ICC) in DNAm between the two sources, at each of the 430,742 CpG sites, were evaluated. The results showed that a high proportion (70.1%) of the CpGs DNAm agreed between cord blood and neonatal blood on Guthrie cards. A small portion of CpGs showed high correlation (correlation ≥0.5) or high ICC (ICC ≥0.5) in DNAm of the whole genome. This proportion increased dramatically in differentially methylated regions (DMRs) that are associated with exposure to maternal smoking, between the two sources.

10.
Clin Epigenetics ; 11(1): 176, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31791392

RESUMO

BACKGROUND: Adolescence is a period characterized by major biological development, which may be associated with changes in DNA methylation (DNA-M). However, it is unknown to what extent DNA-M varies from pre- to post-adolescence, whether the pattern of changes is different between females and males, and how adolescence-related factors are associated with changes in DNA-M. METHODS: Genome-scale DNA-M at ages 10 and 18 years in whole blood of 325 subjects (n = 140 females) in the Isle of Wight (IOW) birth cohort was analyzed using Illumina Infinium arrays (450K and EPIC). Linear mixed models were used to examine DNA-M changes between pre- and post-adolescence and whether the changes were gender-specific. Adolescence-related factors and environmental exposure factors were assessed on their association with DNA-M changes. Replication of findings was attempted in the comparable Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. RESULTS: In the IOW cohort, after controlling for technical variation and cell compositions at both pre- and post-adolescence, 15,532 cytosine-phosphate-guanine (CpG) sites (of 400,825 CpGs, 3.88%) showed statistically significant DNA-M changes from pre-adolescence to post-adolescence invariant to gender (false discovery rate (FDR) = 0.05). Of these 15,532 CpGs, 10,212 CpGs (66%) were replicated in the ALSPAC cohort. Pathway analysis using Ingenuity Pathway Analysis (IPA) identified significant biological pathways related to growth and development of the reproductive system, emphasizing the importance of this period of transition on epigenetic state of genes. In addition, in IOW, we identified 1179 CpGs with gender-specific DNA-M changes. In the IOW cohort, body mass index (BMI) at age 10 years, age of growth spurt, nonsteroidal drugs use, and current smoking status showed statistically significant associations with DNA-M changes at 15 CpGs on 14 genes such as the AHRR gene. For BMI at age 10 years, the association was gender-specific. Findings on current smoking status were replicated in the ALSPAC cohort. CONCLUSION: Adolescent transition is associated with changes in DNA-M at more than 15K CpGs. Identified pathways emphasize the importance of this period of transition on epigenetic state of genes relevant to cell growth and immune system development.

11.
Clin Epigenetics ; 11(1): 190, 2019 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-31829238

RESUMO

BACKGROUND: A subset of individuals affected by imprinting disorders displays multi-locus imprinting disturbances (MLID). MLID has been associated with maternal-effect variants that alter the maintenance of methylation at germline-derived differentially methylated regions (gDMRs) in early embryogenesis. Pedigrees of individuals with MLID also include siblings with healthy phenotype. However, it is unknown if these healthy individuals have MLID themselves or if their methylation patterns differ from those associated with imprinting disorders, and in general, if MLID affects the clinical phenotype. METHODS: We have investigated gDMR methylation by locus-specific and whole-genome analyses in a family with multiple pregnancy losses, a child with Beckwith-Wiedemann syndrome (BWS) and a further child with no clinical diagnosis of imprinting disorder or other pathologies. RESULTS: We detected MLID with different methylation profiles in the BWS-affected and healthy siblings. Whole-exome sequencing demonstrated the presence of novel loss-of-function variants of NLRP5 in compound heterozygosity in the mother. The methylation profiles of the two siblings were compared with those of other cases with MLID and control groups by principal component analysis and unsupervised hierarchical clustering, but while their patterns were clearly separated from those of controls, we were unable to cluster those associated with specific clinical phenotypes among the MLID cases. CONCLUSION: The identification of two novel maternal-effect variants of NLRP5 associated with poly-abortivity and MLID adds further evidence to the role of this gene in the maintenance of genomic imprinting in early embryos. Furthermore, our results demonstrate that within these pedigrees, MLID can also be present in the progeny with healthy phenotype, indicating that some sort of compensation occurs between altered imprinted loci in these individuals. The analysis of larger cohorts of patients with MLID is needed to formulate more accurate epigenotype-phenotype correlations.

12.
Epigenomics ; 11(13): 1487-1500, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31536415

RESUMO

Aim: Cigarette smoking influences DNA methylation genome wide, in newborns from pregnancy exposure and in adults from personal smoking. Whether a unique methylation signature exists for in utero exposure in newborns is unknown. Materials & methods: We separately meta-analyzed newborn blood DNA methylation (assessed using Illumina450k Beadchip), in relation to sustained maternal smoking during pregnancy (9 cohorts, 5648 newborns, 897 exposed) and adult blood methylation and personal smoking (16 cohorts, 15907 participants, 2433 current smokers). Results & conclusion: Comparing meta-analyses, we identified numerous signatures specific to newborns along with many shared between newborns and adults. Unique smoking-associated genes in newborns were enriched in xenobiotic metabolism pathways. Our findings may provide insights into specific health impacts of prenatal exposure on offspring.

13.
Clin Epigenetics ; 11(1): 128, 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31464656

RESUMO

BACKGROUND: Breastfeeding is protective against many long-term diseases, yet the mechanisms involved are unknown. Leptin gene (LEP) is reported to be associated with body mass index (BMI). On the other hand, breastfeeding duration has been found to be associated with DNA methylation (DNAm) of the LEP gene. Therefore, epigenetic regulation of LEP may represent the mechanism underlying the protective effect of breastfeeding duration against obesity. METHODS: In the Isle of Wight Birth Cohort, peripheral blood DNAm at 23 cytosine-phosphate-guanine sites (CpGs) in the LEP locus in 10-year-old (n = 297) samples and 16 CpGs in 18-year-old (n = 305) samples, were generated using the Illumina Infinium MethylationEPIC and HumanMethylation450 Beadchips respectively and tested for association with breastfeeding duration (total and exclusive) using linear regression. To explore the association between breastfeeding durations and genome-wide DNAm, epigenome-wide association studies (EWASs) and differential methylation region (DMR) analyses were performed. BMI trajectories spanning the first 18 years of life were used as the outcome to test the association with breastfeeding duration (exposure) using multi-nominal logistic regression. Mediation analysis was performed for significant CpG sites. RESULTS: Both total and exclusive breastfeeding duration were associated with DNAm at four LEP CpG sites at 10 years (P value < 0.05), and not at 18 years. Though no association was observed between breastfeeding duration and genome-wide DNAm, DMR analyses identified five significant differentially methylated regions (Sidak adjusted P value < 0.05). Breastfeeding duration was also associated with the early transient overweight trajectory. Furthermore, DNAm of LEP was associated with this trajectory at one CpG site and early persistent obesity at another, though mediation analysis was not significant. CONCLUSIONS: Breastfeeding duration is associated with LEP methylation at age 10 years and BMI trajectory. LEP DNAm is also significantly associated with BMI trajectories throughout childhood, though sample sizes were small. However, mediation analysis did not demonstrate that DNAm of LEP explained the protective effect of breastfeeding against childhood obesity.

14.
Artigo em Inglês | MEDLINE | ID: mdl-31367216

RESUMO

Background: To identify novel epigenetic markers of adolescent asthma and replicate findings in an independent cohort, then explore whether such markers are detectable at birth, predictive of early-life wheeze, and associated with gene expression in cord blood. Methods: We performed epigenome-wide screening with recursive random forest feature selection and internal validation in the IOW birth cohort. We then tested whether we could replicate these findings in the independent cohort ALSPAC and followed-up our top finding with children of the IOW cohort. Results: We identified 10 CpG sites associated with adolescent asthma at a 5% false discovery rate (IOW, n = 370), five of which exhibited evidence of associations in the replication study (ALSPAC, n = 720). One site, cg16658191, within HK1 displayed particularly strong associations after cellular heterogeneity adjustments in both cohorts (ORIOW = 0.17, 95% CI 0.04-0.57) (ORALSPAC = 0.57, 95% CI 0.38-0.87). Additionally, higher expression of HK1 (OR = 3.81, 95% CI 1.41-11.77) in cord blood was predictive of wheezing in infancy (n = 82). Conclusion: We identified novel associations between asthma and wheeze with methylation at cg16658191 and the expression of HK1, which may serve as markers of, predictors of, and potentially etiologic factors involved in asthma and early life wheeze.

15.
Clin Epigenetics ; 11(1): 97, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31262328

RESUMO

BACKGROUND: Maternal smoking during pregnancy is associated with adverse offspring health outcomes across their life course. We hypothesize that DNA methylation is a potential mediator of this relationship. METHODS: We examined the association of prenatal maternal smoking with offspring blood DNA methylation in 2821 individuals (age 16 to 48 years) from five prospective birth cohort studies and perform Mendelian randomization and mediation analyses to assess whether methylation markers have causal effects on disease outcomes in the offspring. RESULTS: We identify 69 differentially methylated CpGs in 36 genomic regions (P value < 1 × 10-7) associated with exposure to maternal smoking in adolescents and adults. Mendelian randomization analyses provided evidence for a causal role of four maternal smoking-related CpG sites on an increased risk of inflammatory bowel disease or schizophrenia. Further mediation analyses showed some evidence of cg25189904 in GNG12 gene mediating the effect of exposure to maternal smoking on schizophrenia-related outcomes. CONCLUSIONS: DNA methylation may represent a biological mechanism through which maternal smoking is associated with increased risk of psychiatric morbidity in the exposed offspring.

16.
Genes Nutr ; 14: 20, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31244960

RESUMO

Background: Evidence suggests that prenatal exposure to n-3 long-chain polyunsaturated fatty acids (LCPUFA) reduces the incidence of allergic disease in children. LCPUFAs are produced from dietary precursors catalyzed by desaturases and elongases encoded by the FADS1/2 and ELOVL5 genes. DNA methylation regulates gene activity and fatty acid supplementation could alter DNA methylation (DNA-M) at these genes. We investigated whether DNA-M and expression of the FADS1/2 and ELOVL5 genes were associated with allergy in children and gestational fish intake. We studied 170 participants from the Isle of Wight 3rd Generation Cohort, UK. Phenotype data and exposure was assessed by questionnaires. Genome-wide DNA-M in cord blood samples was quantified using the Illumina Infinium HumanMethylation450 and EPIC Beadchips. Five SNPs (single-nucleotide polymorphisms) in the FADS gene cluster and one SNP in ELOVL5 were genotyped in offspring. FADS gene expression in offspring cord blood was determined. Results: Gestational fish intake was significantly associated with increased methylation of cg12517394 (P = 0.049), which positively correlated with FADS1 mRNA levels (P = 0.021). ELOVL5 rs2397142 was significantly associated with eczema (P = 0.011) and methylation at cg11748354 and cg24524396 (P < 0.001 and P = 0.036, respectively). Gestational fish intake was strongly associated with elevated DNA-M at cg11748354 and cg24524396 (P = 0.029 and P = 0.002, respectively) and reduced ELOVL5 mRNA expression (P = 0.028). Conclusion: The association between induced FADS1/2 and ELOVL5 DNA-M and reduced gene expression due to gestational fish intake provide a mechanistic explanation of the previously observed association between maternal LCPUFA intake and allergy development in early childhood.

17.
Hypertension ; 74(2): 375-383, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31230546

RESUMO

Hypertensive disorders of pregnancy (HDP) are associated with low birth weight, shorter gestational age, and increased risk of maternal and offspring cardiovascular diseases later in life. The mechanisms involved are poorly understood, but epigenetic regulation of gene expression may play a part. We performed meta-analyses in the Pregnancy and Childhood Epigenetics Consortium to test the association between either maternal HDP (10 cohorts; n=5242 [cases=476]) or preeclampsia (3 cohorts; n=2219 [cases=135]) and epigenome-wide DNA methylation in cord blood using the Illumina HumanMethylation450 BeadChip. In models adjusted for confounders, and with Bonferroni correction, HDP and preeclampsia were associated with DNA methylation at 43 and 26 CpG sites, respectively. HDP was associated with higher methylation at 27 (63%) of the 43 sites, and across all 43 sites, the mean absolute difference in methylation was between 0.6% and 2.6%. Epigenome-wide associations of HDP with offspring DNA methylation were modestly consistent with the equivalent epigenome-wide associations of preeclampsia with offspring DNA methylation (R2=0.26). In longitudinal analyses conducted in 1 study (n=108 HDP cases; 550 controls), there were similar changes in DNA methylation in offspring of those with and without HDP up to adolescence. Pathway analysis suggested that genes located at/near HDP-associated sites may be involved in developmental, embryogenesis, or neurological pathways. HDP is associated with offspring DNA methylation with potential relevance to development.


Assuntos
Metilação de DNA/genética , Proteínas de Ligação a DNA/genética , Estudo de Associação Genômica Ampla , Hipertensão Induzida pela Gravidez/genética , Recém-Nascido Prematuro , Resultado da Gravidez , Adulto , Estudos de Coortes , Epigênese Genética , Feminino , Sangue Fetal , Idade Gestacional , Humanos , Hipertensão Induzida pela Gravidez/diagnóstico , Recém-Nascido , Gravidez
18.
J Allergy Clin Immunol ; 144(2): 624-625, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31213285
19.
Genome Res ; 29(7): 1057-1066, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31160375

RESUMO

Germline mutations in fundamental epigenetic regulatory molecules including DNA methyltransferase 3 alpha (DNMT3A) are commonly associated with growth disorders, whereas somatic mutations are often associated with malignancy. We profiled genome-wide DNA methylation patterns in DNMT3A c.2312G > A; p.(Arg771Gln) carriers in a large Amish sibship with Tatton-Brown-Rahman syndrome (TBRS), their mosaic father, and 15 TBRS patients with distinct pathogenic de novo DNMT3A variants. This defined widespread DNA hypomethylation at specific genomic sites enriched at locations annotated as genes involved in morphogenesis, development, differentiation, and malignancy predisposition pathways. TBRS patients also displayed highly accelerated DNA methylation aging. These findings were most marked in a carrier of the AML-associated driver mutation p.Arg882Cys. Our studies additionally defined phenotype-related accelerated and decelerated epigenetic aging in two histone methyltransferase disorders: NSD1 Sotos syndrome overgrowth disorder and KMT2D Kabuki syndrome growth impairment. Together, our findings provide fundamental new insights into aberrant epigenetic mechanisms, the role of epigenetic machinery maintenance, and determinants of biological aging in these growth disorders.


Assuntos
Envelhecimento/genética , DNA (Citosina-5-)-Metiltransferases/genética , Epigênese Genética , Transtornos do Crescimento/genética , Mutação , Anormalidades Múltiplas/genética , Adolescente , Adulto , Amish/genética , Criança , Metilação de DNA , Face/anormalidades , Doenças Hematológicas/genética , Humanos , Deficiência Intelectual/genética , Leucemia Mieloide Aguda/genética , Masculino , Metiltransferases , Morfogênese/genética , Síndrome , Doenças Vestibulares/genética , Adulto Jovem
20.
Eur Respir J ; 54(1)2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31073081

RESUMO

Previous reports link differential DNA methylation (DNAme) to environmental exposures that are associated with lung function. Direct evidence on lung function DNAme is, however, limited. We undertook an agnostic epigenome-wide association study (EWAS) on pre-bronchodilation lung function and its change in adults.In a discovery-replication EWAS design, DNAme in blood and spirometry were measured twice, 6-15 years apart, in the same participants of three adult population-based discovery cohorts (n=2043). Associated DNAme markers (p<5×10-7) were tested in seven replication cohorts (adult: n=3327; childhood: n=420). Technical bias-adjusted residuals of a regression of the normalised absolute ß-values on control probe-derived principle components were regressed on level and change of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and their ratio (FEV1/FVC) in the covariate-adjusted discovery EWAS. Inverse-variance-weighted meta-analyses were performed on results from discovery and replication samples in all participants and never-smokers.EWAS signals were enriched for smoking-related DNAme. We replicated 57 lung function DNAme markers in adult, but not childhood samples, all previously associated with smoking. Markers not previously associated with smoking failed replication. cg05575921 (AHRR (aryl hydrocarbon receptor repressor)) showed the statistically most significant association with cross-sectional lung function (FEV1/FVC: pdiscovery=3.96×10-21 and pcombined=7.22×10-50). A score combining 10 DNAme markers previously reported to mediate the effect of smoking on lung function was associated with lung function (FEV1/FVC: p=2.65×10-20).Our results reveal that lung function-associated methylation signals in adults are predominantly smoking related, and possibly of clinical utility in identifying poor lung function and accelerated decline. Larger studies with more repeat time-points are needed to identify lung function DNAme in never-smokers and in children.

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