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1.
Clin Epigenetics ; 11(1): 128, 2019 Aug 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.

2.
Clin Epigenetics ; 11(1): 97, 2019 Jul 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.

3.
Mol Ther Nucleic Acids ; 16: 770-777, 2019 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-31150930

RESUMO

The human proinsulin gene (INS) contains a thymine-to-adenine variant (rs689) located in the 3' splice site (3' ss) recognition motif of the first intron. The adenine at rs689 is strongly associated with type 1 diabetes. By weakening the polypyrimidine tract, the adenine allele reduces the efficiency of intron 1 splicing, which can be ameliorated by antisense oligonucleotides blocking a splicing silencer located upstream of the 3' ss. The silencer is surrounded by guanine-rich tracts that may form guanine quadruplexes (G4s) and modulate the accessibility of the silencer. Here, we employed thioflavin T (ThT) to monitor G4 formation in synthetic DNAs and RNAs derived from INS intron 1. We show that the antisense target is surrounded by ThT-positive segments in each direction, with oligoribonucleotides exhibiting consistently higher fluorescence than their DNA counterparts. The signal was reduced for ThT-positive oligonucleotides that were extended into the silencer, indicating that flanking G4s have a potential to mask target accessibility. Real-time monitoring of ThT fluorescence during INS transcription in vitro revealed a negative correlation with ex vivo splicing activities of corresponding INS constructs. Together, these results provide a better characterization of antisense targets in INS primary transcripts for restorative strategies designed to improve the INS splicing defect associated with type 1 diabetes.

4.
J Allergy Clin Immunol ; 144(2): 624-625, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31213285
5.
Hypertension ; 74(2): 375-383, 2019 Aug.
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.

6.
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.

7.
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
8.
Ann Am Thorac Soc ; 16(7): 868-876, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30888842

RESUMO

Rationale: Pooling data from multiple cohorts and extending the time frame across childhood should minimize study-specific effects, enabling better characterization of childhood wheezing. Objectives: To analyze wheezing patterns from early childhood to adolescence using combined data from five birth cohorts. Methods: We used latent class analysis to derive wheeze phenotypes among 7,719 participants from five birth cohorts with complete report of wheeze at five time periods. We tested the associations of derived phenotypes with late asthma outcomes and lung function, and investigated the uncertainty in phenotype assignment. Results: We identified five phenotypes: never/infrequent wheeze (52.1%), early onset preschool remitting (23.9%), early onset midchildhood remitting (9%), persistent (7.9%), and late-onset wheeze (7.1%). Compared with the never/infrequent wheeze, all phenotypes had higher odds of asthma and lower forced expiratory volume in 1 second and forced expiratory volume in 1 second/forced vital capacity in adolescence. The association with asthma was strongest for persistent wheeze (adjusted odds ratio, 56.54; 95% confidence interval, 43.75-73.06). We observed considerable within-class heterogeneity at the individual level, with 913 (12%) children having low membership probability (<0.60) of any phenotype. Class membership certainty was highest in persistent and never/infrequent, and lowest in late-onset wheeze (with 51% of participants having membership probabilities <0.80). Individual wheezing patterns were particularly heterogeneous in late-onset wheeze, whereas many children assigned to early onset preschool remitting class reported wheezing at later time points. Conclusions: All wheeze phenotypes had significantly diminished lung function in school-age children, suggesting that the notion that early life episodic wheeze has a benign prognosis may not be true for a proportion of transient wheezers. We observed considerable within-phenotype heterogeneity in individual wheezing patterns.

9.
Allergy ; 74(6): 1166-1175, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30762239

RESUMO

BACKGROUND: The presence of allergic sensitization has a major influence on the development and course of common childhood conditions such as asthma and rhinitis. The etiology of allergic sensitization is poorly understood, and its underlying biological mechanisms are not well established. Several studies showed that DNA methylation (DNAm) at some CpGs is associated with allergic sensitization. However, no studies have focused on the critical adolescence period. METHODS: We assessed the association of pre- and postadolescence genome-wide DNAm with allergic sensitization against indoor, outdoor and food allergens, using linear mixed models. We hypothesized that DNAm is associated with sensitization in general, and with poly-sensitization status, and these associations are age- and gender-specific. We tested these hypotheses in the IoW cohort (n = 376) and examined the findings in the BAMSE cohort (n = 267). RESULTS: Via linear mixed models, we identified 35 CpGs in IoW associated with allergic sensitization (at false discovery rate of 0.05), of which 33 were available in BAMSE and replicated with respect to the direction of associations with allergic sensitization. At the 35 CpGs except for cg19210306 on C13orf27, a reduction in methylation among atopic subjects was observed, most notably for cg21220721 and cg11699125 (ACOT7). DNAm at cg10159529 was strongly correlated with expression of IL5RA in peripheral blood (P-value = 6.76 × 10-20 ). Three CpGs (cg14121142, cg23842695, and cg26496795) were identified in IoW with age-specific association between DNAm and allergic sensitization. CONCLUSION: In adolescence, the status of allergic sensitization was associated with DNAm differentiation and at some CpGs the association is likely to be age-specific.

10.
Lancet Respir Med ; 7(1): 20-34, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30552067

RESUMO

BACKGROUND: Few genetic studies that focus on moderate-to-severe asthma exist. We aimed to identity novel genetic variants associated with moderate-to-severe asthma, see whether previously identified genetic variants for all types of asthma contribute to moderate-to-severe asthma, and provide novel mechanistic insights using expression analyses in patients with asthma. METHODS: In this genome-wide association study, we used a two-stage case-control design. In stage 1, we genotyped patient-level data from two UK cohorts (the Genetics of Asthma Severity and Phenotypes [GASP] initiative and the Unbiased BIOmarkers in PREDiction of respiratory disease outcomes [U-BIOPRED] project) and used data from the UK Biobank to collect patient-level genomic data for cases and controls of European ancestry in a 1:5 ratio. Cases were defined as having moderate-to-severe asthma if they were taking appropriate medication or had been diagnosed by a doctor. Controls were defined as not having asthma, rhinitis, eczema, allergy, emphysema, or chronic bronchitis as diagnosed by a doctor. For stage 2, an independent cohort of cases and controls (1:5) was selected from the UK Biobank only, with no overlap with stage 1 samples. In stage 1 we undertook a genome-wide association study of moderate-to-severe asthma, and in stage 2 we followed up independent variants that reached the significance threshold of p less than 1 × 10-6 in stage 1. We set genome-wide significance at p less than 5 × 10-8. For novel signals, we investigated their effect on all types of asthma (mild, moderate, and severe). For all signals meeting genome-wide significance, we investigated their effect on gene expression in patients with asthma and controls. FINDINGS: We included 5135 cases and 25 675 controls for stage 1, and 5414 cases and 21 471 controls for stage 2. We identified 24 genome-wide significant signals of association with moderate-to-severe asthma, including several signals in innate or adaptive immune-response genes. Three novel signals were identified: rs10905284 in GATA3 (coded allele A, odds ratio [OR] 0·90, 95% CI 0·88-0·93; p=1·76 × 10-10), rs11603634 in the MUC5AC region (coded allele G, OR 1·09, 1·06-1·12; p=2·32 × 10-8), and rs560026225 near KIAA1109 (coded allele GATT, OR 1·12, 1·08-1·16; p=3·06 × 10-9). The MUC5AC signal was not associated with asthma when analyses included mild asthma. The rs11603634 G allele was associated with increased expression of MUC5AC mRNA in bronchial epithelial brush samples via proxy SNP rs11602802; (p=2·50 × 10-5) and MUC5AC mRNA was increased in bronchial epithelial samples from patients with severe asthma (in two independent analyses, p=0·039 and p=0·022). INTERPRETATION: We found substantial shared genetic architecture between mild and moderate-to-severe asthma. We also report for the first time genetic variants associated with the risk of developing moderate-to-severe asthma that regulate mucin production. Finally, we identify candidate causal genes in these loci and provide increased insight into this difficult to treat population. FUNDING: Asthma UK, AirPROM, U-BIOPRED, UK Medical Research Council, and Rosetrees Trust.


Assuntos
Asma/genética , Fator de Transcrição GATA3/genética , Predisposição Genética para Doença , Mucina-5AC , Proteínas , Adulto , Idoso , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença
11.
Clin Exp Allergy ; 48(12): 1688-1697, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30311981

RESUMO

BACKGROUND: Cigarette smoke contains compounds similar to coal tar, an ancient remedy of eczema. Some studies have reported protective effects of maternal gestational smoking on offspring eczema; however, others have shown no or increased risks. Similarly, studies linking breastfeeding duration and eczema have demonstrated contradictory findings. No study has yet investigated combined effects of these two factors on eczema. OBJECTIVE: Since tobacco compounds can pass to offspring via breast milk, we investigated their combined effects on eczema development from childhood to adolescence. METHODS: We obtained information regarding gestational smoking, exclusive breastfeeding duration, and eczema at ages 1-or-2, 4, 10, and 18 years from the Isle of Wight (IOW) birth cohort, UK. Using generalized estimating equations, we assessed the interaction of gestational smoking and residual exclusive breastfeeding duration (Resid-BF-duration, obtained by regressing the latter on maternal smoking) on eczema over time adjusting for confounders. For the three transition periods of 1-or-2 to 4 years, 4-10, and 10-18 years, we estimated risks of persistent, incident, and remitting eczema associated with the interaction using repeated measurements. RESULTS: If the mother smoked during gestation, longer Resid-BF-duration was associated with a lower risk of eczema, compared to if she did not smoke. The risk ratios (95% CI) if the mother smoked during gestation and exclusively breastfed for at least 3, 9, 15, 21 weeks are 0.7 (0.6, 1.7), 0.6 (0. 4, 0.9), 0.5 (0.3, 0.8), and 0.4 (0.2, 0. 8), respectively. Additionally, in all three transition periods, the risk of persistent eczema was lower with longer Resid-BF-duration if the mother smoked during gestation. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest a protective effect of gestational smoking combined with longer duration of exclusive breastfeeding on early-onset persistent eczema. Future studies should examine underlying biological mechanisms. Prolonged breastfeeding should be encouraged even if the mother smoked during gestation.

12.
Int J Genomics ; 2018: 9093785, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30255030

RESUMO

Purpose: Airway epithelium acts as a protective barrier against the particles from the inhaled air. Damage to the epithelium may result in loss of the barrier function. Epithelial repair in response to injury requires complex mechanisms, such as microRNA, small noncoding molecules, to regulate the processes involved in wound repair. We aimed to establish if the microRNA gene expression profile is altered during the airway epithelial repair in differentiated cells. Methods: miRNA gene expression profile during the wound closure of differentiated normal human bronchial epithelium (NHBE) from one donor was analysed using quantitative real-time PCR. We have analysed the expression of 754 genes at five time points during a 48-hour period of epithelium repair using TaqMan Low Density Array. Results: We found out that 233 miRNA genes were expressed in normal human bronchial epithelium. Twenty miRNAs were differentially expressed during the wound repair process, but only one (miR-455-3p) showed significance after FDR adjustment (p = 0.02). Using STEM, we have identified two clusters of several miRNA genes with similar expression profile. Pathway enrichment analysis showed several significant signaling pathways altered during repair, mainly involved in cell cycle regulation, proliferation, migration, adhesion, and transcription regulation. Conclusions: miRNA expression profile is altered during airway epithelial repair of differentiated cells from one donor in response to mechanical injury in vitro, suggesting their potential role in wound repair.

13.
Respir Res ; 19(1): 156, 2018 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-30134983

RESUMO

BACKGROUND: The pathophysiological role of SERPINA1 in respiratory health may be more strongly determined by the regulation of its expression than by common genetic variants. A family based study of predominantly smoking adults found methylation at two Cytosine-phosphate-Guanine sites (CpGs) in SERPINA1 gene to be associated with chronic obstructive pulmonary disease risk. The objective of this study was to confirm the association of lung function with SERPINA1 methylation in general population samples by testing a comprehensive set of CpGs in the SERPINA gene cluster. We considered lung function level and decline in adult smokers from three European population-based cohorts and lung function level and growth in tobacco-smoke exposed children from a birth cohort. METHODS: DNA methylation using Illumina Infinium Human Methylation 450 k and EPIC beadchips and lung function were measured at two time points in 1076 SAPALDIA, ECRHS and NFBC adult cohort participants and 259 ALSPAC children. Associations of methylation at 119 CpG sites in the SERPINA gene cluster (PP4R4-SERPINA13P) with lung functions and circulating alpha-1-antitripsin (AAT) were assessed using multivariable cross-sectional and longitudinal regression models. RESULTS: Methylation at cg08257009 in the SERPINA gene cluster, located 32 kb downstream of SERPINA1, not annotated to a gene, was associated with FEV1/FVC at the Bonferroni corrected level in adults, but not in children. None of the methylation signals in the SERPINA1 gene showed associations with lung function after correcting for multiple testing. CONCLUSIONS: The results do not support a role of SERPINA1 gene methylation as determinant of lung function across the life course in the tobacco smoke exposed general population exposed.

14.
Eur Respir J ; 52(2)2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30093569

RESUMO

Evidence for a possible protective effect of maternal dietary antioxidant intake during pregnancy on childhood asthma and other atopic outcomes is conflicting, and associations with childhood lung function have been little studied.In the Avon Longitudinal Study of Parents and Children, we analysed associations between maternal intake of fruits, vegetables, vitamins C and E, carotene, zinc, and selenium in pregnancy and current doctor-diagnosed asthma, atopy and lung function in 8915 children at age 7-9 years. Potential modification of associations by maternal smoking and common maternal antioxidant gene polymorphisms was explored to strengthen causal inference.After controlling for confounders, positive associations were observed between maternal intake of zinc and childhood forced expiratory volume in 1 s and forced vital capacity (difference in age-, height- and sex-adjusted sd units per quartile increase in maternal dietary zinc intake ß 0.05 (95% CI 0.01-0.08); ptrend=0.01 and 0.05 (95% CI 0.02-0.09); ptrend=0.005, respectively). Weak evidence was found for an interaction between maternal zinc intake and maternal glutathione S-transferase GSTM1 genotype on childhood forced vital capacity (pinteraction=0.05); association among the GSTM1 null group ß 0.11 (95% CI 0.05-0.17); ptrend=0.001.Our results suggest that a higher maternal intake of zinc during pregnancy may be associated with better lung function in the offspring.

15.
Artigo em Inglês | MEDLINE | ID: mdl-29995435

RESUMO

RATIONALE: Puberty may influence lung function, but the precise role of pubertal height growth in lung development is unclear. OBJECTIVES: To examine associations of timing of puberty and peak velocity of pubertal height growth with lung function in adolescence and early-adulthood. METHODS: Longitudinal analyses of repeat height measurements from age 5-20 years for a British birth cohort with 4,772 males and 4,849 females were conducted to characterise height growth trajectories, and derive pubertal age and peak height velocity using the validated SuperImposition by Translation and Rotation (SITAR) model. Association of these estimates with pre-bronchodilator and post-bronchodilator spirometry measures: FEV1; FVC; FEV1/FVC; FEF25-75 at age 15 and 24 years were investigated using multivariable regression models adjusted for lung function at age 8 years, height and age at time of outcome measurements, and potential confounders. MEASUREMENTS AND MAIN RESULTS: Later pubertal age and greater peak velocity were associated with higher FEV1 and FVC at 24 years in both sexes. A 1-year advanced pubertal age was associated with a 263 ml higher FVC (95% confidence interval: 167, 360) for males (n=567), 100 ml (50, 150) for females (n=990). A 1-cm/year increase in peak velocity was associated with 145 ml (56, 234) and 50 ml (2, 99) increase in FVC for males and females respectively. No associations were found with FEV1/FVC. CONCLUSIONS: Later onset and greater peak velocity of height growth in puberty are associated with increased FEV1 and FVC in young adults but there was no evidence of dysanapsis of pubertal lung growth.

16.
J Allergy Clin Immunol ; 142(3): 765-772, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30040975

RESUMO

It has become clear that early life (including in utero exposures) is a key window of vulnerability during which environmental exposures can alter developmental trajectories and initiate allergic disease development. However, recent evidence suggests that there might be additional windows of vulnerability to environmental exposures in the parental generation before conception or even in previous generations. There is evidence suggesting that information of prior exposures can be transferred across generations, and experimental animal models suggest that such transmission can be conveyed through epigenetic mechanisms. Although the molecular mechanisms of intergenerational and transgenerationational epigenetic transmission have yet to be determined, the realization that environment before conception can alter the risks of allergic diseases has profound implications for the development of public health interventions to prevent disease. Future research in both experimental models and in multigenerational human cohorts is needed to better understand the role of intergenerational and transgenerational effects in patients with asthma and allergic disease. This will provide the knowledge basis for a new approach to efficient intervention strategies aimed at reducing the major public health challenge of these conditions.

18.
Int J Epidemiol ; 47(4): 1106-1117, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-29534228

RESUMO

Background: Mothers' smoking during pregnancy increases asthma risk in their offspring. There is some evidence that grandmothers' smoking may have a similar effect, and biological plausibility that fathers' smoking during adolescence may influence offspring's health through transmittable epigenetic changes in sperm precursor cells. We evaluated the three-generation associations of tobacco smoking with asthma. Methods: Between 2010 and 2013, at the European Community Respiratory Health Survey III clinical interview, 2233 mothers and 1964 fathers from 26 centres reported whether their offspring (aged ≤51 years) had ever had asthma and whether it had coexisted with nasal allergies or not. Mothers and fathers also provided information on their parents' (grandparents) and their own asthma, education and smoking history. Multilevel mediation models within a multicentre three-generation framework were fitted separately within the maternal (4666 offspring) and paternal (4192 offspring) lines. Results: Fathers' smoking before they were 15 [relative risk ratio (RRR) = 1.43, 95% confidence interval (CI): 1.01-2.01] and mothers' smoking during pregnancy (RRR = 1.27, 95% CI: 1.01-1.59) were associated with asthma without nasal allergies in their offspring. Grandmothers' smoking during pregnancy was associated with asthma in their daughters [odds ratio (OR) = 1.55, 95% CI: 1.17-2.06] and with asthma with nasal allergies in their grandchildren within the maternal line (RRR = 1.25, 95% CI: 1.02-1.55). Conclusions: Fathers' smoking during early adolescence and grandmothers' and mothers' smoking during pregnancy may independently increase asthma risk in offspring. Thus, risk factors for asthma should be sought in both parents and before conception. Funding: European Union (Horizon 2020, GA-633212).

19.
Int J Mol Sci ; 19(2)2018 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-29415463

RESUMO

To succeed, pregnancies need to initiate immune biases towards T helper 2 (Th2) responses, yet little is known about what establishes this bias. Using the Illumina 450 K platform, we explored changes in DNA methylation (DNAm) of Th1, Th2, Th17, and regulatory T cell pathway genes before and during pregnancy. Female participants were recruited at birth (1989), and followed through age 18 years and their pregnancy (2011-2015). Peripheral blood DNAm was measured in 245 girls at 18 years; from among these girls, the DNAm of 54 women was repeatedly measured in the first (weeks 8-21, n = 39) and second (weeks 22-38, n = 35) halves of pregnancy, respectively. M-values (logit-transformed ß-values of DNAm) were analyzed: First, with repeated measurement models, cytosine-phosphate-guanine sites (CpGs) of pathway genes in pregnancy and at age 18 (nonpregnant) were compared for changes (p ≤ 0.05). Second, we tested how many of the 348 pathway-related CpGs changed compared to 10 randomly selected subsets of all other CpGs and compared to 10 randomly selected subsets of other CD4+-related CpGs (348 in each subset). Contrasted to the nonpregnant state, 27.7% of Th1-related CpGs changed in the first and 36.1% in the second half of pregnancy. Among the Th2 pathway CpGs, proportions of changes were 35.1% (first) and 33.8% (second half). The methylation changes suggest involvement of both Th1 and Th2 pathway CpGs in the immune bias during pregnancy. Changes in regulatory T cell and Th17 pathways need further exploration.


Assuntos
Metilação de DNA , Regulação da Expressão Gênica , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Adolescente , Adulto , Alelos , Ilhas de CpG , Feminino , Perfilação da Expressão Gênica , Idade Gestacional , Humanos , Gravidez , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Células Th2/imunologia , Células Th2/metabolismo , Adulto Jovem
20.
J Invest Dermatol ; 138(1): 189-198, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28844940

RESUMO

Normal sun-exposed skin contains numerous epidermal patches that stain positive for p53 protein (p53 immunopositive patches, PIPs), which are considered potential early precursors of skin cancer. Although the TP53 gene is mutated in many PIPs, it is unclear whether PIPs contain any other cancer-related mutations. Here we report that PIPs, predominantly <3,000 p53 immunopositive cells in size, within normal chronically exposed skin contain mutations in multiple genes that are mutated in cutaneous squamous cell cancers. These mutations in the PIPs were not detected within the non-PIP epidermis of corresponding normal chronically exposed skin. Although some of these genetic alterations are clonal in the PIPs, many of the mutations are subclonal within these lesions. Similar mutations are seen in later precancers (actinic keratoses and Bowen's disease). Our results demonstrate that PIPs in chronically exposed skin contain multiple mutations in cancer-related genes. In addition, the results indicate that the clonal evolution of mutations that are seen within later precancerous lesions and in established malignancy can also occur in PIPs within normal human skin.

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