Abstract 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. Methods: In this study we analyzed DNA methylation (DNAm) in saliva at two time points across the pubertal transition within the same individuals. We targeted 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.
Abstract 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.
Background: The COVID-19 pandemic changed the landscape of hepatitis C virus (HCV) treatment in Canada. In this study, we sought to describe the characteristics, management, and outcomes of patients treated during the pandemic. Methods: Retrospective analysis of the British Columbia HCV Network included HCV patients treated from March 17, 2018 to February 22, 2022. Patients who started treatment before and after March 17, 2020 were designated pre-pandemic and pandemic groups, respectively. Patients were followed until sustained virologic response 12 weeks post-treatment (SVR12). Results: A total of 851 patients underwent 854 treatments, with 481 (56%) pre-pandemic and 373 (44%) pandemic. Pandemic patients were younger (median age 57 versus 61 pre-pandemic; p <0.01) and 23% were on opioid agonist therapy (versus 11% pre-pandemic; p = 0.01). Fewer pandemic patients completed transient elastography (36% versus 56% pre-pandemic; p < 0.01). Pandemic patients utilized fewer in-person appointments and more telehealth appointments ( p < 0.01). Fewer pandemic patients completed treatment (85% versus 91% pre-pandemic; p = 0.23); the SVR12 rate was 97.8% in those completing treatment and lab work (versus 99.5% pre-pandemic; p < 0.01). Younger age, substance use, and opioid agonist therapy were associated with loss to follow-up during the pandemic. Conclusions: Patients treated for HCV in British Columbia during the pandemic utilized fewer resources and had more loss to follow-up but maintained high SVR12 rates. Transitioning from in-person to telehealth appointments proved effective in a real-world setting. Individualized strategies are required for special populations prone to loss to follow-up.
DNA methylation is influenced by both environmental and genetic factors and is increasingly thought to affect variation in complex traits and diseases. Yet, the extent of ancestry-related differences in DNA methylation, their genetic determinants, and their respective causal impact on immune gene regulation remain elusive. We report extensive population differences in DNA methylation between 156 individuals of African and European descent, detected in primary monocytes that are used as a model of a major innate immunity cell type. Most of these differences (~ 70%) are driven by DNA sequence variants nearby CpG sites, which account for ~ 60% of the variance in DNA methylation. We also identify several master regulators of DNA methylation variation in trans, including a regulatory hub nearby the transcription factor-encoding CTCF gene, which contributes markedly to ancestry-related differences in DNA methylation. Furthermore, we establish that variation in DNA methylation is associated with varying gene expression levels following mostly, but not exclusively, a canonical model of negative associations, particularly in enhancer regions. Specifically, we find that DNA methylation highly correlates with transcriptional activity of 811 and 230 genes, at the basal state and upon immune stimulation, respectively. Finally, using a Bayesian approach, we estimate causal mediation effects of DNA methylation on gene expression in ~ 20% of the studied cases, indicating that DNA methylation can play an active role in immune gene regulation. Using a system-level approach, our study reveals substantial ancestry-related differences in DNA methylation and provides evidence for their causal impact on immune gene regulation.
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease of the lungs that is currently the fourth leading cause of death worldwide. Genetic factors account for only a small amount of COPD risk, but epigenetic mechanisms, including DNA methylation, have the potential to mediate the interactions between an individual's genetics and environmental exposure. DNA methylation is highly cell type-specific, and individual cell type studies of DNA methylation in COPD are sparse. Fibroblasts are present within the airway and parenchyma of the lung and contribute to the aberrant deposition of extracellular matrix in COPD. No assessment or comparison of genome-wide DNA methylation profiles in the airway and parenchymal fibroblasts from individuals with and without COPD has been undertaken. These data provide valuable insight into the molecular mechanisms contributing to COPD and the differing pathologies of small airways disease and emphysema in COPD.Genome-wide DNA methylation was evaluated at over 485,000 CpG sites using the Illumina Infinium HumanMethylation450 BeadChip array in the airway (non-COPD n = 8, COPD n = 7) and parenchymal fibroblasts (non-COPD n = 17, COPD n = 29) isolated from individuals with and without COPD. Targeted gene expression was assessed by qPCR in matched RNA samples.Differentially methylated DNA regions were identified between cells isolated from individuals with and without COPD in both airway and parenchymal fibroblasts. Only in parenchymal fibroblasts was differential DNA methylation associated with differential gene expression. A second analysis of differential DNA methylation variability identified 359 individual differentially variable CpG sites in parenchymal fibroblasts. No differentially variable CpG sites were identified in the airway fibroblasts. Five differentially variable-methylated CpG sites, associated with three genes, were subsequently assessed for gene expression differences. Two genes (OAT and GRIK2) displayed significantly increased gene expression in cells isolated from individuals with COPD.Differential and variable DNA methylation was associated with COPD status in the parenchymal fibroblasts but not airway fibroblasts. Aberrant DNA methylation was associated with altered gene expression imparting biological function to DNA methylation changes. Changes in DNA methylation are therefore implicated in the molecular mechanisms underlying COPD pathogenesis and may represent novel therapeutic targets.
Abstract Prenatal adversity shapes child neurodevelopment and risk for later mental health problems. The quality of the early care environment can buffer some of the negative effects of prenatal adversity on child development. Retrospective studies, in adult samples, highlight epigenetic modifications as sentinel markers of the quality of the early care environment; however, comparable data from pediatric cohorts are lacking. Participants were drawn from the Maternal Adversity Vulnerability and Neurodevelopment (MAVAN) study, a longitudinal cohort with measures of infant attachment, infant development, and child mental health. Children provided buccal epithelial samples (mean age = 6.99, SD = 1.33 years, n = 226), which were used for analyses of genome-wide DNA methylation and genetic variation. We used a series of linear models to describe the association between infant attachment and (a) measures of child outcome and (b) DNA methylation across the genome. Paired genetic data was used to determine the genetic contribution to DNA methylation at attachment-associated sites. Infant attachment style was associated with infant cognitive development (Mental Development Index) and behavior (Behavior Rating Scale) assessed with the Bayley Scales of Infant Development at 36 months. Infant attachment style moderated the effects of prenatal adversity on Behavior Rating Scale scores at 36 months. Infant attachment was also significantly associated with a principal component that accounted for 11.9% of the variation in genome-wide DNA methylation. These effects were most apparent when comparing children with a secure versus a disorganized attachment style and most pronounced in females. The availability of paired genetic data revealed that DNA methylation at approximately half of all infant attachment-associated sites was best explained by considering both infant attachment and child genetic variation. This study provides further evidence that infant attachment can buffer some of the negative effects of early adversity on measures of infant behavior. We also highlight the interplay between infant attachment and child genotype in shaping variation in DNA methylation. Such findings provide preliminary evidence for a molecular signature of infant attachment and may help inform attachment-focused early intervention programs.
This study reveals the influence of child maltreatment on DNA methylation across the genome and provides the first evidence that a psychosocial intervention program, the Nurse Family Partnership (NFP), which targets mothers at risk for abusive parenting, associates with variation in the DNA methylome in adult offspring. The 188 participants were born to women randomly assigned to control (n = 99) or nurse-visited intervention groups (n = 89) and provided blood samples and a diagnostic interview at age 27 years. Interindividual variation in the blood DNA methylome was described using principal components (PC) scores derived from principal component analysis and showed that the NFP program (PC10: p = 0.029) and a history of abuse/neglect (PC1: p = 0.029, PC2: p = 0.009) significantly associated with DNA methylome variation at 27 years of age independent of gender, ancestry, cellular heterogeneity, and a polygenic risk index for major psychiatric disorders. The magnitude of the association between child maltreatment and DNA methylation was reduced when accounting for lifestyle factors, including smoking. These findings reflect the sustained impact of both childhood adversity as well as intervention programs that target such adversity on the epigenome but highlight the need for prospective longitudinal studies of DNA methylome variation in the context of early intervention programs.
Abstract Background The COVID-19 pandemic has impacted healthcare access, including to curative treatment for hepatitis C (HCV) infection in the form of direct-acting antivirals (DAAs). A 49% decrease in DAA dispensations in Canada during the pandemic has been reported, but little is known about these treated populations. Aims To explore the patient characteristics and treatment patterns in those who were treated for HCV during the COVID pandemic. Methods A retrospective chart review was conducted at one site of utilizing the British Columbia Hepatitis C Network. Only patients included into the database were analyzed. Patients started on treatment between 03/17/2020-03/16/2021 were included as the “pandemic group” and patients from the 03/17/2019-03/16/2020 were included as a comparison “pre-pandemic group”. Data were extracted for clinicodemographic variables, laboratory investigations, treatment start date, regimen, and sustained virologic response at 12 weeks (SVR12). Results 97 patients were treated during the pandemic compared to 143 patients the year prior, representing a 32% decline. Patients treated during the pandemic were predominantly new referrals (n=70, 72% vs n=64, 45% pre-pandemic, p<0.01) and had fewer total appointments (median 2 per patient vs 4 per patient pre-pandemic, p<0.01). There was a median of 1 in-person visit and 1 telehealth appointment per patient during the pandemic (vs median 2 per patient of each type pre-pandemic). Pandemic patients were younger (mean age 56.0 years vs 59.6 pre-pandemic, p=0.04), and a greater proportion were on opioid agonist therapy (28% vs 13% pre-pandemic, p<0.01). Less transient elastography (TE) was performed during the pandemic (69% vs 89% pre-pandemic). Amongst those with TE scores, a lower proportion of those treated during the pandemic were cirrhotic (13% vs 21% pre-pandemic). During the pandemic, treatment patterns shifted towards more prescriptions for glecaprevir/pibrentasvir (56% of all prescriptions vs 44% pre-pandemic) and sofosbuvir/velpatasvir (37% vs 29% pre-pandemic). There was slightly less use of sofosbuvir/velpatasvir/voxilaprevir at (2% vs 4% pre-pandemic). The proportion of patients who completed lab work for SVR was similar during the pandemic (n=83/97, 85.6%) compared to pre-pandemic (n=120/143, 83.9%). Similarly, SVR12 remained high during the pandemic at 98.7% (vs 99.3% pre-pandemic). Of all 97 patients prescribed DAAs during the pandemic, 92 (94.8%) completed treatment. Conclusions Less persons were treated during the COVID pandemic, which may deter progress towards HCV elimination targets. Very high SVR12 and treatment completion rates during the pandemic suggest that patients can be effectively treated with less pre-treatment investigations and fewer appointments. Funding Agencies None
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