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1.
Hum Mol Genet ; 31(21): 3694-3714, 2022 10 28.
Artículo en Inglés | MEDLINE | ID: mdl-35567546

RESUMEN

Parkinson's disease (PD) is a neurological disorder with complex interindividual etiology that is becoming increasingly prevalent worldwide. Elevated alpha-synuclein levels can increase risk of PD and may influence epigenetic regulation of PD pathways. Here, we report genome-wide DNA methylation and hydroxymethylation alterations associated with overexpression of two PD-linked alpha-synuclein variants (wild-type and A30P) in LUHMES cells differentiated to dopaminergic neurons. Alpha-synuclein altered DNA methylation at thousands of CpGs and DNA hydroxymethylation at hundreds of CpGs in both genotypes, primarily in locomotor behavior and glutamate signaling pathway genes. In some cases, epigenetic changes were associated with transcription. SMITE network analysis incorporating H3K4me1 ChIP-seq to score DNA methylation and hydroxymethylation changes across promoters, enhancers, and gene bodies confirmed epigenetic and transcriptional deregulation of glutamate signaling modules in both genotypes. Our results identify distinct and shared impacts of alpha-synuclein variants on the epigenome, and associate alpha-synuclein with the epigenetic etiology of PD.


Asunto(s)
Enfermedad de Parkinson , alfa-Sinucleína , Humanos , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Epigénesis Genética , Epigenómica , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Transducción de Señal/genética , Glutamatos/genética , Glutamatos/metabolismo
2.
Allergy ; 79(7): 1831-1843, 2024 07.
Artículo en Inglés | MEDLINE | ID: mdl-38686450

RESUMEN

BACKGROUND: The effects of inhaled corticosteroids (ICS) on healthy airways are poorly defined. OBJECTIVES: To delineate the effects of ICS on gene expression in healthy airways, without confounding caused by changes in disease-related genes and disease-related alterations in ICS responsiveness. METHODS: Randomized open-label bronchoscopy study of high-dose ICS therapy in 30 healthy adult volunteers randomized 2:1 to (i) fluticasone propionate 500 mcg bd daily or (ii) no treatment, for 4 weeks. Laboratory staff were blinded to allocation. Biopsies and brushings were analysed by immunohistochemistry, bulk RNA sequencing, DNA methylation array and metagenomics. RESULTS: ICS induced small between-group differences in blood and lamina propria eosinophil numbers, but not in other immunopathological features, blood neutrophils, FeNO, FEV1, microbiome or DNA methylation. ICS treatment upregulated 72 genes in brushings and 53 genes in biopsies, and downregulated 82 genes in brushings and 416 genes in biopsies. The most downregulated genes in both tissues were canonical markers of type-2 inflammation (FCER1A, CPA3, IL33, CLEC10A, SERPINB10 and CCR5), T cell-mediated adaptive immunity (TARP, TRBC1, TRBC2, PTPN22, TRAC, CD2, CD8A, HLA-DQB2, CD96, PTPN7), B-cell immunity (CD20, immunoglobulin heavy and light chains) and innate immunity, including CD48, Hobit, RANTES, Langerin and GFI1. An IL-17-dependent gene signature was not upregulated by ICS. CONCLUSIONS: In healthy airways, 4-week ICS exposure reduces gene expression related to both innate and adaptive immunity, and reduces markers of type-2 inflammation. This implies that homeostasis in health involves tonic type-2 signalling in the airway mucosa, which is exquisitely sensitive to ICS.


Asunto(s)
Corticoesteroides , Voluntarios Sanos , Humanos , Adulto , Masculino , Administración por Inhalación , Femenino , Corticoesteroides/administración & dosificación , Adulto Joven , Persona de Mediana Edad , Metilación de ADN/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/efectos de los fármacos , Fluticasona/administración & dosificación , Fluticasona/farmacología
3.
Psychol Sci ; : 9567976241260247, 2024 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-39141017

RESUMEN

Early-life adversity increases the risk of health problems. Interventions supporting protective and responsive caregiving offer a promising approach to attenuating adversity-induced changes in stress-sensitive biomarkers. This study tested whether participation in an evidence-based dyadic psychosocial intervention, child-parent psychotherapy (CPP), was related to lower epigenetic age acceleration, a trauma-sensitive biomarker of accelerated biological aging that is associated with later health impairment, in a sample of children with trauma histories. Within this quasi-experimental, repeated-measures study, we examined epigenetic age acceleration at baseline and postintervention in a low-income sample of children receiving CPP treatment (n = 45; age range = 2-6 years; 76% Latino) compared with a weighted, propensity-matched community-comparison sample (n = 110; age range = 3-6 years; 40% Latino). Baseline epigenetic age acceleration was equivalent across groups. However, posttreatment, epigenetic age acceleration in the treatment group was lower than in the matched community sample. Findings highlight the potential for a dyadic psychosocial intervention to ameliorate accelerated biological aging in trauma-exposed children.

4.
Brain Behav Immun ; 115: 101-108, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37820972

RESUMEN

BACKGROUND: Socioeconomic status (SES) gradients in health are well-documented, and while biological pathways are incompletely understood, chronic inflammation and accelerated immune aging (immunosenescence) among lower SES individuals have been implicated. However, previous findings have come from samples in higher income countries, and it is unclear how generalizable they are to lower- and middle-income countries (LMIC) with different infectious exposures and where adiposity-an important contributor to chronic inflammation-might show different SES patterning. To address this gap, we explored associations between SES and inflammation and immunosenescence in a sample of women in Cebu, Philippines. METHODS: Data came from the mothers of the Cebu Longitudinal Health and Nutrition Survey birth cohort (mean age: 47.7, range: 35-69 years). SES was measured as a combination of annual household income, education level, and assets. Chronic inflammation was measured using C-reactive protein (CRP) in plasma samples from 1,834 women. Immunosenescence was measured by the abundance of exhausted CD8T (CD8 + CD28-CD45RA-) and naïve CD8T and CD4T cells, estimated from DNA methylation in whole blood in a random subsample of 1,028. Possible mediators included waist circumference and a collection of proxy measures of pathogen exposure. RESULTS: SES was negatively associated with the measures of immunosenescence, with slight evidence for mediation by a proxy measure for pathogen exposure from the household's drinking water source. In contrast, SES was positively associated with CRP, which was explained by the positive association with waist circumference. CONCLUSIONS: Similar to higher income populations, in Cebu there is an SES-gradient in pathogen exposures and immunosenescence. However, lifestyle changes occurring more rapidly among higher SES individuals is contributing to a positive association between SES and adiposity and inflammation. Our results suggest more studies are needed to clarify the relationship between SES and inflammation and immunosenescence across LMIC.


Asunto(s)
Inmunosenescencia , Clase Social , Persona de Mediana Edad , Humanos , Femenino , Filipinas/epidemiología , Inflamación , Factores Socioeconómicos , Proteína C-Reactiva/análisis , Obesidad
5.
Am J Hum Biol ; 35(11): e23948, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37338007

RESUMEN

OBJECTIVES: The drivers of human life expectancy gains over the past 200 years are not well-established, with a potential role for historical reductions in infectious disease. We investigate whether infectious exposures in infancy predict biological aging using DNA methylation-based markers that forecast patterns of morbidity and mortality later in life. METHODS: N = 1450 participants from the Cebu Longitudinal Health and Nutrition Survey-a prospective birth cohort initiated in 1983-provided complete data for the analyses. Mean chronological age was 20.9 years when venous whole blood samples were drawn for DNA extraction and methylation analysis, with subsequent calculation of three epigenetic age markers: Horvath, GrimAge, and DunedinPACE. Unadjusted and adjusted least squares regression models were evaluated to test the hypothesis that infectious exposures in infancy are associated with epigenetic age. RESULTS: Birth in the dry season, a proxy measure for increased infectious exposure in the first year of life, as well as the number of symptomatic infections in the first year of infancy, predicted lower epigenetic age. Infectious exposures were associated with the distribution of white blood cells in adulthood, which were also associated with measures of epigenetic age. CONCLUSIONS: We document negative associations between measures of infectious exposure in infancy and DNA methylation-based measures of aging. Additional research, across a wider range of epidemiological settings, is needed to clarify the role of infectious disease in shaping immunophenotypes and trajectories of biological aging and human life expectancy.


Asunto(s)
Envejecimiento , Enfermedades Transmisibles , Humanos , Lactante , Adulto Joven , Adulto , Estudios Prospectivos , Filipinas/epidemiología , Envejecimiento/genética , Metilación de ADN , Marcadores Genéticos , Epigénesis Genética
6.
Am J Respir Crit Care Med ; 206(2): 150-160, 2022 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-35426765

RESUMEN

Rationale: Age-related diseases like chronic obstructive pulmonary disease (COPD) occur at higher rates in people living with human immunodeficiency virus (PLWH) than in uninfected populations. Objectives: To identify whether accelerated aging can be observed in the airways of PLWH with COPD, manifest by a unique DNA methylation signature. Methods: Bronchial epithelial brushings from PLWH with and without COPD and HIV-uninfected adults with and without COPD (N = 76) were profiled for DNA methylation and gene expression. We evaluated global Alu and LINE-1 methylation and calculated the epigenetic age using the Horvath clock and the methylation telomere length estimator. To identify genome-wide differential DNA methylation and gene expression associated with HIV and COPD, robust linear models were used followed by an expression quantitative trait methylation (eQTM) analysis. Measurements and Main Results: Epigenetic age acceleration and shorter methylation estimates of telomere length were found in PLWH with COPD compared with PLWH without COPD and uninfected patients with and without COPD. Global hypomethylation was identified in PLWH. We identified 7,970 cytosine bases located next to a guanine base (CpG sites), 293 genes, and 9 expression quantitative trait methylation-gene pairs associated with the interaction between HIV and COPD. Actin binding LIM protein family member 3 (ABLIM3) was one of the novel candidate genes for HIV-associated COPD highlighted by our analysis. Conclusions: Methylation age acceleration is observed in the airway epithelium of PLWH with COPD, a process that may be responsible for the heightened risk of COPD in this population. Their distinct methylation profile, differing from that observed in patients with COPD alone, suggests a unique pathogenesis to HIV-associated COPD. The associations warrant further investigation to establish causality.


Asunto(s)
Infecciones por VIH , Enfermedad Pulmonar Obstructiva Crónica , Adulto , Envejecimiento/genética , Metilación de ADN/genética , Epigenómica , Infecciones por VIH/complicaciones , Infecciones por VIH/genética , Humanos , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/genética
7.
Proc Natl Acad Sci U S A ; 117(38): 23329-23335, 2020 09 22.
Artículo en Inglés | MEDLINE | ID: mdl-31611402

RESUMEN

The development of biological markers of aging has primarily focused on adult samples. Epigenetic clocks are a promising tool for measuring biological age that show impressive accuracy across most tissues and age ranges. In adults, deviations from the DNA methylation (DNAm) age prediction are correlated with several age-related phenotypes, such as mortality and frailty. In children, however, fewer such associations have been made, possibly because DNAm changes are more dynamic in pediatric populations as compared to adults. To address this gap, we aimed to develop a highly accurate, noninvasive, biological measure of age specific to pediatric samples using buccal epithelial cell DNAm. We gathered 1,721 genome-wide DNAm profiles from 11 different cohorts of typically developing individuals aged 0 to 20 y old. Elastic net penalized regression was used to select 94 CpG sites from a training dataset (n = 1,032), with performance assessed in a separate test dataset (n = 689). DNAm at these 94 CpG sites was highly predictive of age in the test cohort (median absolute error = 0.35 y). The Pediatric-Buccal-Epigenetic (PedBE) clock was characterized in additional cohorts, showcasing the accuracy in longitudinal data, the performance in nonbuccal tissues and adult age ranges, and the association with obstetric outcomes. The PedBE tool for measuring biological age in children might help in understanding the environmental and contextual factors that shape the DNA methylome during child development, and how it, in turn, might relate to child health and disease.


Asunto(s)
Epigenómica/métodos , Células Epiteliales/metabolismo , Mucosa Bucal/citología , Adolescente , Adulto , Niño , Preescolar , Estudios de Cohortes , Islas de CpG , Epigénesis Genética , Femenino , Humanos , Lactante , Estudios Longitudinales , Masculino , Mucosa Bucal/metabolismo , Adulto Joven
8.
Clin Infect Dis ; 74(4): 575-583, 2022 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-34125883

RESUMEN

BACKGROUND: Evidence that opioid agonist therapy (OAT) is associated with increased odds of hepatitis C virus (HCV) treatment initiation among people who use drugs (PWUD) is emerging. The objective of this study was to determine the association between current OAT and HCV treatment initiation among PWUD in a population-level linked administrative dataset. METHODS: The British Columbia Hepatitis Testers Cohort was used for this study, which includes all people tested for or diagnosed with HCV in British Columbia, linked to medical visits, hospitalizations, laboratory, prescription drug, and mortality data from 1992 until 2019. PWUD with injecting drug use or opioid use disorder and chronic HCV infection were identified for inclusion in this study. HCV treatment initiation was the main outcome, and subdistribution proportional hazards modeling was used to assess the relationship with current OAT. RESULTS: In total, 13 803 PWUD with chronic HCV were included in this study. Among those currently on OAT at the end of the study period, 47% (2704/5770) had started HCV treatment, whereas 22% (1778/8033) of those not currently on OAT had started HCV treatment. Among PWUD with chronic HCV infection, current OAT was associated with higher likelihood of HCV treatment initiation in time to event analysis (adjusted hazard ratio 1.84 [95% confidence interval {CI}, 1.50, 2.26]). CONCLUSIONS: Current OAT was associated with a higher likelihood of HCV treatment initiation. However, many PWUD with HCV currently receiving OAT have yet to receive HCV treatment. Enhanced integration between substance use care and HCV treatment is needed to improve the overall health of PWUD.


Asunto(s)
Hepatitis C Crónica , Hepatitis C , Abuso de Sustancias por Vía Intravenosa , Analgésicos Opioides/uso terapéutico , Antivirales/uso terapéutico , Hepacivirus , Hepatitis C/complicaciones , Hepatitis C/tratamiento farmacológico , Hepatitis C/epidemiología , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/epidemiología , Humanos , Abuso de Sustancias por Vía Intravenosa/complicaciones
9.
N Engl J Med ; 380(15): 1433-1441, 2019 04 11.
Artículo en Inglés | MEDLINE | ID: mdl-30970188

RESUMEN

We report an inborn error of metabolism caused by an expansion of a GCA-repeat tract in the 5' untranslated region of the gene encoding glutaminase (GLS) that was identified through detailed clinical and biochemical phenotyping, combined with whole-genome sequencing. The expansion was observed in three unrelated patients who presented with an early-onset delay in overall development, progressive ataxia, and elevated levels of glutamine. In addition to ataxia, one patient also showed cerebellar atrophy. The expansion was associated with a relative deficiency of GLS messenger RNA transcribed from the expanded allele, which probably resulted from repeat-mediated chromatin changes upstream of the GLS repeat. Our discovery underscores the importance of careful examination of regions of the genome that are typically excluded from or poorly captured by exome sequencing.


Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/genética , Ataxia/genética , Discapacidades del Desarrollo/genética , Glutaminasa/deficiencia , Glutaminasa/genética , Glutamina/metabolismo , Repeticiones de Microsatélite , Mutación , Atrofia/genética , Cerebelo/patología , Preescolar , Femenino , Genotipo , Glutamina/análisis , Humanos , Masculino , Fenotipo , Reacción en Cadena de la Polimerasa , Secuenciación Completa del Genoma
10.
Proc Natl Acad Sci U S A ; 116(38): 19098-19108, 2019 09 17.
Artículo en Inglés | MEDLINE | ID: mdl-31471491

RESUMEN

Glioblastoma multiforme (GBM) is the most deadly brain tumor, and currently lacks effective treatment options. Brain tumor-initiating cells (BTICs) and orthotopic xenografts are widely used in investigating GBM biology and new therapies for this aggressive disease. However, the genomic characteristics and molecular resemblance of these models to GBM tumors remain undetermined. We used massively parallel sequencing technology to decode the genomes and transcriptomes of BTICs and xenografts and their matched tumors in order to delineate the potential impacts of the distinct growth environments. Using data generated from whole-genome sequencing of 201 samples and RNA sequencing of 118 samples, we show that BTICs and xenografts resemble their parental tumor at the genomic level but differ at the mRNA expression and epigenomic levels, likely due to the different growth environment for each sample type. These findings suggest that a comprehensive genomic understanding of in vitro and in vivo GBM model systems is crucial for interpreting data from drug screens, and can help control for biases introduced by cell-culture conditions and the microenvironment in mouse models. We also found that lack of MGMT expression in pretreated GBM is linked to hypermutation, which in turn contributes to increased genomic heterogeneity and requires new strategies for GBM treatment.


Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Encefálicas/patología , Regulación Neoplásica de la Expresión Génica , Genómica/métodos , Glioblastoma/patología , Células Madre Neoplásicas/patología , Microambiente Tumoral/genética , Adulto , Anciano , Anciano de 80 o más Años , Animales , Apoptosis , Neoplasias Encefálicas/genética , Estudios de Casos y Controles , Proliferación Celular , Metilación de ADN , Resistencia a Antineoplásicos , Femenino , Perfilación de la Expresión Génica , Glioblastoma/genética , Humanos , Masculino , Ratones , Ratones SCID , Persona de Mediana Edad , Células Madre Neoplásicas/metabolismo , Transcriptoma , Células Tumorales Cultivadas , Secuenciación Completa del Genoma , Ensayos Antitumor por Modelo de Xenoinjerto
11.
J Psychiatry Neurosci ; 46(6): E663-E674, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34916236

RESUMEN

BACKGROUND: Social anxiety disorder is characterized by intense fear and avoidance of social interactions and scrutiny by others. Although alterations in attentional control seem to play a central role in the psychopathology of social anxiety disorder, the neural underpinnings in prefrontal brain regions have not yet been fully clarified. METHODS: The present study used functional MRI in participants (age 18-50 yr) with social anxiety disorder (n = 42, 31 female) and without (n = 58, 33 female). It investigated the interrelation of the effects of social anxiety disorder and early-life adversity (a main environmental risk factor of social anxiety disorder) on brain activity during an attentional control task. We applied DNA methylation analysis to determine whether epigenetic modulation in the gene encoding the glucocorticoid receptor, NR3C1, might play a mediating role in this process. RESULTS: We identified 2 brain regions in the left and medial prefrontal cortex that exhibited an interaction effect of social anxiety disorder and early-life adversity. In participants with low levels of early-life adversity, neural activity in response to disorder-related stimuli was increased in association with social anxiety disorder. In participants with high levels of early-life adversity, neural activity was increased only in participants without social anxiety disorder. NR3C1 DNA methylation partly mediated the effect of social anxiety disorder on brain activity as a function of early-life adversity. LIMITATIONS: The absence of behavioural correlates associated with social anxiety disorder limited functional interpretation of the results. CONCLUSION: These findings demonstrate that the neurobiological processes that underlie social anxiety disorder might be fundamentally different depending on experiences of early-life adversity. Long-lasting effects of early-life adversity might be encoded in NR3C1 DNA methylation and entail alterations in social anxiety disorder-related activity patterns in the neural network of attentional control.


Asunto(s)
Experiencias Adversas de la Infancia , Fobia Social , Adolescente , Adulto , Ansiedad , Encéfalo/diagnóstico por imagen , Metilación de ADN , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fobia Social/diagnóstico por imagen , Adulto Joven
12.
BMC Genomics ; 21(1): 389, 2020 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-32493224

RESUMEN

BACKGROUND: There are significant sex differences in human physiology and disease; the genomic sources of these differences, however, are not well understood. During puberty, a drastic neuroendocrine shift signals physical changes resulting in robust sex differences in human physiology. Here, we explore how shifting patterns of DNA methylation may inform these pathways of biological plasticity during the pubertal transition. In this study we analyzed DNA methylation (DNAm) in saliva at two time points across the pubertal transition within the same individuals. Our purpose was to compare two domains of DNAm patterns that may inform processes of sexual differentiation 1) sex related sites, which demonstrated differences between males from females and 2) time related sites in which DNAm shifted significantly between timepoints. We further explored the correlated network structure sex and time related DNAm networks and linked these patterns to pubertal stage, assays of salivary testosterone, a reliable diagnostic of free, unbound hormone that is available to act on target tissues, and overlap with androgen response elements. RESULTS: Sites that differed by biological sex were largely independent of sites that underwent change across puberty. Time-related DNAm sites, but not sex-related sites, formed correlated networks that were associated with pubertal stage. Both time and sex DNAm networks reflected salivary testosterone levels that were enriched for androgen response elements, with sex-related DNAm networks being informative of testosterone levels above and beyond biological sex later in the pubertal transition. CONCLUSIONS: These results inform our understanding of the distinction between sex- and time-related differences in DNAm during the critical period of puberty and highlight a novel linkage between correlated patterns of sex-related DNAm and levels of salivary testosterone.


Asunto(s)
Metilación de ADN , Redes Reguladoras de Genes , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Pubertad/genética , Adolescente , Niño , Epigénesis Genética , Femenino , Ontología de Genes , Humanos , Masculino , Pubertad/metabolismo , Saliva/química , Caracteres Sexuales , Testosterona/análisis , Factores de Tiempo
13.
PLoS Med ; 17(11): e1003229, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-33151971

RESUMEN

BACKGROUND: Higher maternal plasma glucose (PG) concentrations, even below gestational diabetes mellitus (GDM) thresholds, are associated with adverse offspring outcomes, with DNA methylation proposed as a mediating mechanism. Here, we examined the relationships between maternal dysglycaemia at 24 to 28 weeks' gestation and DNA methylation in neonates and whether a dietary and physical activity intervention in pregnant women with obesity modified the methylation signatures associated with maternal dysglycaemia. METHODS AND FINDINGS: We investigated 557 women, recruited between 2009 and 2014 from the UK Pregnancies Better Eating and Activity Trial (UPBEAT), a randomised controlled trial (RCT), of a lifestyle intervention (low glycaemic index (GI) diet plus physical activity) in pregnant women with obesity (294 contol, 263 intervention). Between 27 and 28 weeks of pregnancy, participants had an oral glucose (75 g) tolerance test (OGTT), and GDM diagnosis was based on diagnostic criteria recommended by the International Association of Diabetes and Pregnancy Study Groups (IADPSG), with 159 women having a diagnosis of GDM. Cord blood DNA samples from the infants were interrogated for genome-wide DNA methylation levels using the Infinium Human MethylationEPIC BeadChip array. Robust regression was carried out, adjusting for maternal age, smoking, parity, ethnicity, neonate sex, and predicted cell-type composition. Maternal GDM, fasting glucose, 1-h, and 2-h glucose concentrations following an OGTT were associated with 242, 1, 592, and 17 differentially methylated cytosine-phosphate-guanine (dmCpG) sites (false discovery rate (FDR) ≤ 0.05), respectively, in the infant's cord blood DNA. The most significantly GDM-associated CpG was cg03566881 located within the leucine-rich repeat-containing G-protein coupled receptor 6 (LGR6) (FDR = 0.0002). Moreover, we show that the GDM and 1-h glucose-associated methylation signatures in the cord blood of the infant appeared to be attenuated by the dietary and physical activity intervention during pregnancy; in the intervention arm, there were no GDM and two 1-h glucose-associated dmCpGs, whereas in the standard care arm, there were 41 GDM and 160 1-h glucose-associated dmCpGs. A total of 87% of the GDM and 77% of the 1-h glucose-associated dmCpGs had smaller effect sizes in the intervention compared to the standard care arm; the adjusted r2 for the association of LGR6 cg03566881 with GDM was 0.317 (95% confidence interval (CI) 0.012, 0.022) in the standard care and 0.240 (95% CI 0.001, 0.015) in the intervention arm. Limitations included measurement of DNA methylation in cord blood, where the functional significance of such changes are unclear, and because of the strong collinearity between treatment modality and severity of hyperglycaemia, we cannot exclude that treatment-related differences are potential confounders. CONCLUSIONS: Maternal dysglycaemia was associated with significant changes in the epigenome of the infants. Moreover, we found that the epigenetic impact of a dysglycaemic prenatal maternal environment appeared to be modified by a lifestyle intervention in pregnancy. Further research will be needed to investigate possible medical implications of the findings. TRIAL REGISTRATION: ISRCTN89971375.


Asunto(s)
Diabetes Gestacional/epidemiología , Dieta , Epigenoma , Estilo de Vida , Adulto , Dieta/efectos adversos , Epigenoma/efectos de los fármacos , Epigenoma/fisiología , Ejercicio Físico/fisiología , Femenino , Edad Gestacional , Humanos , Lactante , Recién Nacido , Obesidad/epidemiología , Obesidad/terapia , Embarazo
14.
Eur Respir J ; 55(3)2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31949118

RESUMEN

INTRODUCTION: Indoor air pollution and maternal smoking during pregnancy are associated with respiratory symptoms in infants, but little is known about the direct association with lung function or interactions with genetic risk factors. We examined associations of exposure to indoor particulate matter with a 50% cut-off aerodynamic diameter of 10 µm (PM10) and maternal smoking with infant lung function and the role of gene-environment interactions. METHODS: Data from the Drakenstein Child Health Study, a South African birth cohort, were analysed (n=270). Lung function was measured at 6 weeks and 1 year of age, and lower respiratory tract infection episodes were documented. We measured pre- and postnatal PM10 exposures using devices placed in homes, and prenatal tobacco smoke exposure using maternal urine cotinine levels. Genetic risk scores determined from associations with childhood-onset asthma in the UK Biobank were used to investigate effect modifications. RESULTS: Pre- and postnatal exposure to PM10 as well as maternal smoking during pregnancy were associated with reduced lung function at 6 weeks and 1 year as well as with lower respiratory tract infection in the first year. Due to a significant interaction between the genetic risk score and prenatal exposure to PM10, infants carrying more asthma-related risk alleles were more susceptible to PM10-associated reduced lung function (pinteraction=0.007). This interaction was stronger in infants with Black African ancestry (pinteraction=0.001) and nonexistent in children with mixed ancestry (pinteraction=0.876). CONCLUSIONS: PM10 and maternal smoking exposures were associated with reduced lung function, with a higher susceptibility for infants with an adverse genetic predisposition for asthma that also depended on the infant's ancestry.


Asunto(s)
Contaminantes Atmosféricos , Contaminación del Aire Interior , Contaminación del Aire , Asma , Contaminantes Atmosféricos/análisis , Contaminación del Aire/análisis , Contaminación del Aire Interior/efectos adversos , Contaminación del Aire Interior/análisis , Asma/etiología , Asma/genética , Niño , Femenino , Predisposición Genética a la Enfermedad , Humanos , Lactante , Material Particulado/efectos adversos , Material Particulado/análisis , Embarazo
15.
Dev Psychopathol ; 32(5): 1810-1821, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33427178

RESUMEN

Maternal antenatal depression strongly influences child mental health but with considerable inter-individual variation that is, in part, linked to genotype. The challenge is to effectively capture the genotypic influence. We outline a novel approach to describe genomic susceptibility to maternal antenatal depression focusing on child emotional/behavioral difficulties. Two cohorts provided measures of maternal depression, child genetic variation, and child mental health symptoms. We constructed a conventional polygenic risk score (PRS) for attention-deficit/hyperactivity disorder (ADHD) (PRSADHD) that significantly moderated the association between maternal antenatal depression and internalizing problems at 60 months (p = 2.94 × 10-4, R2 = .18). We then constructed an interaction PRS (xPRS) based on a subset of those single nucleotide polymorphisms from the PRSADHD that most accounted for the moderation of the association between maternal antenatal depression and child outcome. The interaction between maternal antenatal depression and this xPRS accounted for a larger proportion of the variance in child emotional/behavioral problems than models based on any PRSADHD (p = 5.50 × 10-9, R2 = .27), with similar findings in the replication cohort. The xPRS was significantly enriched for genes involved in neuronal development and synaptic function. Our study illustrates a novel approach to the study of genotypic moderation on the impact of maternal antenatal depression on child mental health and highlights the utility of the xPRS approach. These findings advance our understanding of individual differences in the developmental origins of mental health.


Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad , Trastorno por Déficit de Atención con Hiperactividad/genética , Niño , Depresión/genética , Femenino , Genómica , Humanos , Salud Mental , Madres , Embarazo
16.
Proc Natl Acad Sci U S A ; 114(29): 7611-7616, 2017 07 18.
Artículo en Inglés | MEDLINE | ID: mdl-28673994

RESUMEN

Chronic inflammation contributes to a wide range of human diseases, and environments in infancy and childhood are important determinants of inflammatory phenotypes. The underlying biological mechanisms connecting early environments with the regulation of inflammation in adulthood are not known, but epigenetic processes are plausible candidates. We tested the hypothesis that patterns of DNA methylation (DNAm) in inflammatory genes in young adulthood would be predicted by early life nutritional, microbial, and psychosocial exposures previously associated with levels of inflammation. Data come from a population-based longitudinal birth cohort study in metropolitan Cebu, the Philippines, and DNAm was characterized in whole blood samples from 494 participants (age 20-22 y). Analyses focused on probes in 114 target genes involved in the regulation of inflammation, and we identified 10 sites across nine genes where the level of DNAm was significantly predicted by the following variables: household socioeconomic status in childhood, extended absence of a parent in childhood, exposure to animal feces in infancy, birth in the dry season, or duration of exclusive breastfeeding. To evaluate the biological significance of these sites, we tested for associations with a panel of inflammatory biomarkers measured in plasma obtained at the same age as DNAm assessment. Three sites predicted elevated inflammation, and one site predicted lower inflammation, consistent with the interpretation that levels of DNAm at these sites are functionally relevant. This pattern of results points toward DNAm as a potentially important biological mechanism through which developmental environments shape inflammatory phenotypes across the life course.


Asunto(s)
Metilación de ADN , Ambiente , Inflamación/genética , Medio Social , Biomarcadores , Lactancia Materna , Proteína C-Reactiva/metabolismo , Enfermedades Cardiovasculares/genética , Preescolar , Estudios de Cohortes , Epigénesis Genética , Femenino , Perfilación de la Expresión Génica , Genoma , Encuestas Epidemiológicas , Humanos , Sistema Inmunológico , Lactante , Recién Nacido , Estudios Longitudinales , Masculino , Filipinas , Factores de Riesgo , Clase Social , Adulto Joven
17.
Dev Psychobiol ; 62(2): 138-153, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31724171

RESUMEN

Developmental environments influence individuals' long-term health trajectories, and there is increasing emphasis on understanding the biological pathways through which this occurs. Epigenetic aging evaluates DNA methylation at a suite of distinct CpG sites in the genome, and epigenetic age acceleration (EAA) is linked to heightened chronic morbidity and mortality risks in adults. Consequently, EAA provides insights on trajectories of biological aging, which early life experiences may help shape. However, few studies have measured correlates of children's epigenetic aging, especially outside of the U.S. and Europe. In particular, little is known about how children's growth and development relate to EAA in ecologies in which energetic and pathogenic stressors are commonplace. We studied EAA from dried blood spots among Bondongo children (n = 54) residing in a small-scale, fisher-farmer society in a remote region of the Republic of the Congo. Here, infectious disease burdens and their resultant energy demands are high. Children who were heavier for height or taller for age, respectively, exhibited greater EAA, including intrinsic EAA, which is considered to measure EAA internal to cells. Furthermore, we found that children in families with more conflict between parents had greater intrinsic EAA. These results suggest that in contexts in which limited energy must be allocated to competing demands, more investment in growth may coincide with greater EAA, which parallels findings in European children who do not face similar energetic constraints. Our findings also indicate that associations between adverse family environments and greater intrinsic EAA were nonetheless observable but only after adjustment for covariates relevant to the energetically and immunologically demanding nature of the local ecology.


Asunto(s)
Desarrollo del Adolescente/fisiología , Experiencias Adversas de la Infancia , Envejecimiento/fisiología , Desarrollo Infantil/fisiología , Metilación de ADN/fisiología , Epigénesis Genética/fisiología , Conflicto Familiar , Estrés Psicológico/fisiopatología , Adolescente , Envejecimiento/genética , Población Negra/etnología , Población Negra/genética , Niño , Preescolar , Congo/etnología , Metilación de ADN/genética , Epigénesis Genética/genética , Conflicto Familiar/etnología , Femenino , Humanos , Masculino , Estrés Psicológico/etnología , Estrés Psicológico/genética
18.
Mutagenesis ; 34(4): 315-322, 2019 12 19.
Artículo en Inglés | MEDLINE | ID: mdl-31587037

RESUMEN

DNA methylation has been widely studied for associations with exposures and health outcomes. Both 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are epigenetic marks that may function differently to impact gene expression; however, the most commonly used technology to assess methylation for population studies in blood use are the Illumina 450K and EPIC BeadChips, for which the traditional bisulfite conversion does not differentiate 5mC and 5hmC marks. We used a modified protocol originally developed by Stewart et al. to analyse oxidative bisulfite-converted and conventional bisulfite-converted DNA for the same subject in parallel by the EPIC chip, allowing us to isolate the two measures. We measured 5mC and 5hmC in cord blood of 41 newborn participants of the Center for Health Assessment of Mothers and Children of Salinas (CHAMACOS) birth cohort and investigated differential methylation of 5mC + 5hmC, isolated 5mC and isolated 5hmC with sex at birth as an example of a biological variable previously associated with DNA methylation. Results showed low levels of 5hmC throughout the epigenome in the cord blood samples in comparison to 5mC. The concordance of autosomal hits between 5mC + 5hmC and exclusive 5mC analyses were low (25%); however, overlap was larger with increased effect size difference. There were 43 autosomal cytosine nucleotide followed by a guanine nucleotide (CpG) sites where 5hmC was associated with sex, 21 of which were unique to 5hmC after adjustment for cell composition. 5hmC only accounts for a small portion of overall methylation in cord blood; however, it has the potential to impact interpretation of combined 5hmC + 5mC studies in cord blood, especially given that effect sizes of differential methylation analyses are often small. Several significant CpG sites were unique to 5hmC, suggesting some functions distinct from 5mC. More studies of genome-wide 5hmC in children are warranted.


Asunto(s)
5-Metilcitosina/análogos & derivados , Biomarcadores , Metilación de ADN , Sangre Fetal , 5-Metilcitosina/sangre , Epigénesis Genética , Epigenómica/métodos , Femenino , Humanos , Recién Nacido , Masculino , Factores Sexuales
19.
BMC Bioinformatics ; 19(1): 295, 2018 08 08.
Artículo en Inglés | MEDLINE | ID: mdl-30089455

RESUMEN

BACKGROUND: Polygenic risk scores (PRS) describe the genomic contribution to complex phenotypes and consistently account for a larger proportion of variance in outcome than single nucleotide polymorphisms (SNPs) alone. However, there is little consensus on the optimal data input for generating PRS, and existing approaches largely preclude the use of imputed posterior probabilities and strand-ambiguous SNPs i.e., A/T or C/G polymorphisms. Our ability to predict complex traits that arise from the additive effects of a large number of SNPs would likely benefit from a more inclusive approach. RESULTS: We developed PRS-on-Spark (PRSoS), a software implemented in Apache Spark and Python that accommodates different data inputs and strand-ambiguous SNPs to calculate PRS. We compared performance between PRSoS and an existing software (PRSice v1.25) for generating PRS for major depressive disorder using a community cohort (N = 264). We found PRSoS to perform faster than PRSice v1.25 when PRS were generated for a large number of SNPs (~ 17 million SNPs; t = 42.865, p = 5.43E-04). We also show that the use of imputed posterior probabilities and the inclusion of strand-ambiguous SNPs increase the proportion of variance explained by a PRS for major depressive disorder (from 4.3% to 4.8%). CONCLUSIONS: PRSoS provides the user with the ability to generate PRS using an inclusive and efficient approach that considers a larger number of SNPs than conventional approaches. We show that a PRS for major depressive disorder that includes strand-ambiguous SNPs, calculated using PRSoS, accounts for the largest proportion of variance in symptoms of depression in a community cohort, demonstrating the utility of this approach. The availability of this software will help users develop more informative PRS for a variety of complex phenotypes.


Asunto(s)
Genómica/métodos , Herencia Multifactorial/genética , Programas Informáticos , Adulto , Alelos , Estudios de Cohortes , Trastorno Depresivo Mayor/epidemiología , Trastorno Depresivo Mayor/genética , Genotipo , Humanos , Modelos Genéticos , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo
20.
Genome Res ; 25(6): 907-17, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25910490

RESUMEN

DNA methylation is an epigenetic modification that plays a key role in gene regulation. Previous studies have investigated its genetic basis by mapping genetic variants that are associated with DNA methylation at specific sites, but these have been limited to microarrays that cover <2% of the genome and cannot account for allele-specific methylation (ASM). Other studies have performed whole-genome bisulfite sequencing on a few individuals, but these lack statistical power to identify variants associated with DNA methylation. We present a novel approach in which bisulfite-treated DNA from many individuals is sequenced together in a single pool, resulting in a truly genome-wide map of DNA methylation. Compared to methods that do not account for ASM, our approach increases statistical power to detect associations while sharply reducing cost, effort, and experimental variability. As a proof of concept, we generated deep sequencing data from a pool of 60 human cell lines; we evaluated almost twice as many CpGs as the largest microarray studies and identified more than 2000 genetic variants associated with DNA methylation. We found that these variants are highly enriched for associations with chromatin accessibility and CTCF binding but are less likely to be associated with traits indirectly linked to DNA, such as gene expression and disease phenotypes. In summary, our approach allows genome-wide mapping of genetic variants associated with DNA methylation in any tissue of any species, without the need for individual-level genotype or methylation data.


Asunto(s)
Mapeo Cromosómico , Metilación de ADN , Polimorfismo de Nucleótido Simple , Alelos , Línea Celular , Biología Computacional , Simulación por Computador , Bases de Datos Genéticas , Epigénesis Genética , Regulación de la Expresión Génica , Biblioteca de Genes , Estudios de Asociación Genética , Genoma Humano , Genotipo , Humanos , Fenotipo , Sitios de Carácter Cuantitativo , Reproducibilidad de los Resultados , Análisis de Secuencia de ADN
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