Alu and LINE-1 methylation and lung function in the normative ageing study

Objectives: To investigate the association between methylation of transposable elements Alu and long-interspersed nuclear elements (LINE-1) and lung function. Design: Cohort study. Setting: Outpatient Veterans Administration facilities in greater Boston, Massachusetts, USA. Participants: Individuals from the Veterans Administration Normative Aging Study, a longitudinal study of aging in men, evaluated between 1999 and 2007. The majority (97%) were white. Primary and secondary outcome measures: Primary predictor was methylation, assessed using PCR-pyrosequencing after bisulphite treatment. Primary outcome was lung function as assessed by spirometry, performed according to American Thoracic Society/European Respiratory Society guidelines at the same visit as the blood draws. Results: In multivariable models adjusted for age, height, body mass index (BMI), pack-years of smoking, current smoking and race, Alu hypomethylation was associated with lower forced expiratory volume in 1 s (FEV1) (β=28 ml per 1% change in Alu methylation, p=0.017) and showed a trend towards association with a lower forced vital capacity (FVC) (β=27 ml, p=0.06) and lower FEV1/FVC (β=0.3%, p=0.058). In multivariable models adjusted for age, height, BMI, pack-years of smoking, current smoking, per cent lymphocytes, race and baseline lung function, LINE-1 hypomethylation was associated with more rapid decline of FEV1 (β=6.9 ml/year per 1% change in LINE-1 methylation, p=0.005) and of FVC (β=9.6 ml/year, p=0.002). Conclusions: In multiple regression analysis, Alu hypomethylation was associated with lower lung function, and LINE-1 hypomethylation was associated with more rapid lung function decline in a cohort of older and primarily white men from North America. Future studies should aim to replicate these findings and determine if Alu or LINE-1 hypomethylation may be due to specific and modifiable environmental exposures

Indoor bacterial microbiota and development of asthma by 10.5 years of age

Background: Early-life indoor bacterial exposure is associated with the risk of asthma, but the roles of specific bacterial genera are poorly understood. Objective: We sought to determine whether individual bacterial genera in indoor microbiota predict the development of asthma. Methods: Dust samples from living rooms were collected at 2 months of age. The dust microbiota was characterized by using Illumina MiSeq sequencing amplicons of the bacterial 16S ribosomal RNA gene. Children (n = 373) were followed up for ever asthma until the age of 10.5 years. Results: Richness was inversely associated with asthma after adjustments (P = .03). The phylogenetic microbiota composition in asthmatics patients' homes was characteristically different from that in nonasthmatic subjects' homes (P = .02, weighted UniFrac, adjusted association, permutational multivariate analysis of variance, PERMANOVA-S). The first 2 axis scores of principal coordinate analysis of the weighted UniFrac distance matrix were inversely associated with asthma. Of 658 genera detected in the dust samples, the relative abundances of 41 genera correlated (r > vertical bar 0.4 vertical bar) with one of these axes. Lactococcus genus was a risk factor for asthma (adjusted odds ratio, 1.36 [95% CI, 1.13-1.63] per interquartile range change). The abundance of 12 bacterial genera (mostly from the Actinomycetales order) was associated with lower asthma risk (P <.10), although not independently of each other. The sum relative abundance of these 12 intercorrelated genera was significantly protective and explained the majority of the association of richness with less asthma. Conclusion: Our data confirm that phylogenetic differences in the microbiota of infants' homes are associated with subsequent asthma risk and suggest that communities of selected bacteria are more strongly linked to asthma protection than individual bacterial taxa or mere richness.Peer reviewe

Effects of endotoxin exposure on childhood asthma risk are modified by a genetic polymorphism in ACAA1

<p>Abstract</p> <p>Background</p> <p>Polymorphisms in the endotoxin-mediated TLR4 pathway genes have been associated with asthma and atopy. We aimed to examine how genetic polymorphisms in innate immunity pathways interact with endotoxin to influence asthma risk in children.</p> <p>Methods</p> <p>In a previous analysis of 372 children from the Boston Home Allergens and the Connecticut Childhood Asthma studies, 7 SNPs in 6 genes (CARD15, TGFB1, LY96, ACAA1, DEFB1 and IFNG) involved in innate immune pathways were associated with asthma, and 5 SNPs in 3 genes (CD80, STAT4, IRAK2) were associated with eczema. We tested these SNPs for interaction with early life endotoxin exposure (n = 291), in models for asthma and eczema by age 6.</p> <p>Results</p> <p>We found a significant interaction between endotoxin and a SNP (rs156265) in ACAA1 (p = 0.0013 for interaction). Increased endotoxin exposure (by quartile) showed protective effects for asthma in individuals with at least one copy of the minor allele (OR = 0.39 per quartile increase in endotoxin, 95% CI 0.15 to 1.01). Endotoxin exposure did not reduce the risk of asthma in children homozygous for the major allele.</p> <p>Conclusion</p> <p>Our findings suggest that protective effects of endotoxin exposure on asthma may vary depending upon the presence or absence of a polymorphism in ACAA1.</p

Association of the infant gut microbiome with early childhood neurodevelopmental outcomes: An ancillary study to the VDAART randomized clinical trial

Importance: In animal models, the early life gut microbiome influences later neurodevelopment. Corresponding data in human populations are lacking. Objective: To study associations between the gut microbiome in infants and development at preschool age measured by the Ages and Stages Questionnaire, third edition (ASQ-3). Design, Setting, and Participants: This ancillary cohort study of the Vitamin D Antenatal Asthma Reduction Trial (VDAART) used data from 715 participants who had development assessed at 3 years of age by the ASQ-3, which included scores in 5 domains (gross motor skills, fine motor skills, problem solving, communication, and personal and social skills). A total of 309 stool samples were collected from infants aged 3 to 6 months for microbiome analysis using 16S rRNA gene sequencing. Exposures: Infant gut microbiome. Main Outcomes and Measures: Continuous ASQ-3 scores and typical vs potential delay in the 5 developmental domains. Factor scores for bacterial coabundance groups were used as predictors in regression models of continuous ASQ-3 scores. Logistic regression was used to examine bacterial coabundance scores and odds of scoring below the threshold for typical development. Multivariate analysis examined the abundance of individual taxa and ASQ-3 scores. Results: The 309 participants (170 [55.0%] male) with ASQ-3 scores and stool samples were ethnically diverse (136 [44.0%] black, 41 [13.3%] Hispanic, 86 [27.8%] white, and 46 [14.9%] other race/ethnicity); the mean (SD) age at ASQ-3 assessment was 3.0 (0.07) years. Coabundance scores dominated by Clostridiales (Lachnospiraceae genera and other, unclassified Clostridiales taxa) were associated with poorer ASQ-3 communication (β, -1.12; 95% CI, -2.23 to -0.01; P = .05) and personal and social (β, -1.44; 95% CI, -2.47 to -0.40; P = .01) scores and with increased odds of potential delay for communication (odds ratio [OR], 1.69; 95% CI, 1.06 to 2.68) and personal and social skills (OR, 1.96; 95% CI, 1.22 to 3.15) per unit increase in coabundance score. The Bacteroides-dominated coabundance grouping was associated with poorer fine motor scores (β, -2.42; 95% CI, -4.29 to -0.55; P = .01) and with increased odds of potential delay for fine motor skills (OR, 1.52; 95% CI, 1.07 to 2.16) per unit increase in coabundance score. Multivariate analysis detected similar family-level and order-level associations. Conclusions and Relevance: These findings suggest an association between infant gut microbiome composition and communication, personal and social, and fine motor skills at age 3 years. The majority of associations were driven by taxa within the order Clostridiales

Expression of SMARCD1 interacts with age in association with asthma control on inhaled corticosteroid therapy.

BackgroundGlobal gene expression levels are known to be highly dependent upon gross demographic features including age, yet identification of age-related genomic indicators has yet to be comprehensively undertaken in a disease and treatment-specific context.MethodsWe used gene expression data from CD4+ lymphocytes in the Asthma BioRepository for Integrative Genomic Exploration (Asthma BRIDGE), an open-access collection of subjects participating in genetic studies of asthma with available gene expression data. Replication population participants were Puerto Rico islanders recruited as part of the ongoing Genes environments &amp; Admixture in Latino Americans (GALA II), who provided nasal brushings for transcript sequencing. The main outcome measure was chronic asthma control as derived by questionnaires. Genomic associations were performed using regression of chronic asthma control score on gene expression with age in years as a covariate, including a multiplicative interaction term for gene expression times age.ResultsThe SMARCD1 gene (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1) interacted with age to influence chronic asthma control on inhaled corticosteroids, with a doubling of expression leading to an increase of 1.3 units of chronic asthma control per year (95% CI [0.86, 1.74], p = 6 × 10- 9), suggesting worsening asthma control with increasing age. This result replicated in GALA II (p = 3.8 × 10- 8). Cellular assays confirmed the role of SMARCD1 in glucocorticoid response in airway epithelial cells.ConclusionFocusing on age-dependent factors may help identify novel indicators of asthma medication response. Age appears to modulate the effect of SMARCD1 on asthma control with inhaled corticosteroids

Multi-omic association study identifies DNA methylation-mediated genotype and smoking exposure effects on lung function in children living in urban settings

Impaired lung function in early life is associated with the subsequent development of chronic respiratory disease. Most genetic associations with lung function have been identified in adults of European descent and therefore may not represent those most relevant to pediatric populations and populations of different ancestries. In this study, we performed genome-wide association analyses of lung function in a multiethnic cohort of children (n = 1,035) living in low-income urban neighborhoods. We identified one novel locus at the TDRD9 gene in chromosome 14q32.33 associated with percent predicted forced expiratory volume in one second (FEV1) (p = 2.4x10-9; βz = -0.31, 95% CI = -0.41- -0.21). Mendelian randomization and mediation analyses revealed that this genetic effect on FEV1 was partially mediated by DNA methylation levels at this locus in airway epithelial cells, which were also associated with environmental tobacco smoke exposure (p = 0.015). Promoter-enhancer interactions in airway epithelial cells revealed chromatin interaction loops between FEV1-associated variants in TDRD9 and the promoter region of the PPP1R13B gene, a stimulator of p53-mediated apoptosis. Expression of PPP1R13B in airway epithelial cells was significantly associated the FEV1 risk alleles (p = 1.3x10-5; β = 0.12, 95% CI = 0.06–0.17). These combined results highlight a potential novel mechanism for reduced lung function in urban youth resulting from both genetics and smoking exposure

Residential PM2.5 exposure and the nasal methylome in children

Rationale: PM2.5-induced adverse effects on respiratory health may be driven by epigenetic modifications in airway cells. The potential impact of exposure duration on epigenetic alterations in the airways is not yet known. Objectives: We aimed to study associations of fine particulate matter PM2.5 exposure with DNA methylation in nasal cells. Methods: We conducted nasal epigenome-wide association analyses within 503 children from Project Viva (mean age 12.9 y), and examined various exposure durations (1-day, 1-week, 1-month, 3-months and 1-year) prior to nasal sampling. We used residential addresses to estimate average daily PM2.5 at 1 km resolution. We collected nasal swabs from the anterior nares and measured DNA methylation (DNAm) using the Illumina Methylation EPIC BeadChip. We tested 719,075 high quality autosomal CpGs using CpG-by-CpG and regional DNAm analyses controlling for multiple comparisons, and adjusted for maternal education, household smokers, child sex, race/ethnicity, BMI z-score, age, season at sample collection and cell-type heterogeneity. We further corrected for bias and genomic inflation. We tested for replication in a cohort from the Netherlands (PIAMA). Results: In adjusted analyses, we found 362 CpGs associated with 1-year PM2.5 (FDR < 0.05), 20 CpGs passing Bonferroni correction (P < 7.0 x 10(-8)) and 10 Differentially Methylated Regions (DMRs). In 445 PIAMA participants (mean age 16.3 years) 11 of 203 available CpGs replicated at P < 0.05. We observed differential DNAm at/ near genes implicated in cell cycle, immune and inflammatory responses. There were no CpGs or regions associated with PM2.5 levels at 1-day, 1-week, or 1-month prior to sample collection, although 2 CpGs were associated with past 3-month PM2.5. Conclusion: We observed wide-spread DNAm variability associated with average past year PM2.5 exposure but we did not detect associations with shorter-term exposure. Our results suggest that nasal DNAm marks reflect chronic air pollution exposure

The metabolomics of asthma control: a promising link between genetics and disease

Short-acting β agonists (e.g., albuterol) are the most commonly used medications for asthma, a disease that affects over 300 million people in the world. Metabolomic profiling of asthmatics taking β agonists presents a new and promising resource for identifying the molecular determinants of asthma control. The objective is to identify novel genetic and biochemical predictors of asthma control using an integrative “omics” approach. We generated lipidomic data by liquid chromatography tandem mass spectrometry (LC-MS), ­ using plasma samples from 20 individuals with asthma. The outcome of interest was a binary indicator of asthma control defined by the use of albuterol inhalers in the preceding week. We integrated metabolomic data with genome-wide genotype, gene expression, and methylation data of this cohort to identify genomic and molecular indicators of asthma control. A Conditional Gaussian Bayesian Network (CGBN) was generated using the strongest predictors from each of these analyses. Integrative and metabolic pathway over-representation analyses (ORA) identified enrichment of known biological pathways within the strongest molecular determinants. Of the 64 metabolites measured, 32 had known identities. The CGBN model based on four SNPs (rs9522789, rs7147228, rs2701423, rs759582) and two metabolites—monoHETE_0863 and sphingosine-1-phosphate (S1P) could predict asthma control with an AUC of 95%. Integrative ORA identified 17 significantly enriched pathways related to cellular immune response, interferon signaling, and cytokine-related signaling, for which arachidonic acid, PGE2 and S1P, in addition to six genes (CHN1, PRKCE, GNA12, OASL, OAS1, and IFIT3) appeared to drive the pathway results. Of these predictors, S1P, GNA12, and PRKCE were enriched in the results from integrative and metabolic ORAs. Through an integrative analysis of metabolomic, genomic, and methylation data from a small cohort of asthmatics, we implicate altered metabolic pathways, related to sphingolipid metabolism, in asthma control. These results provide insight into the pathophysiology of asthma control

Metabolic trajectories across early adolescence: differences by sex, weight, pubertal status and race/ethnicity

Background: Biomarkers of cardiovascular and metabolic risk track from adolescence into adulthood, therefore characterising the direction and magnitude of these changes is an important first step to identifying health trajectories that presage future disease risk. Aim: To characterise changes in metabolic biomarkers across early adolescence in a multi-ethnic cohort. Subjects and methods: Among 891 participants in Project Viva we estimated changes in insulin resistance (HOMA-IR), adipokines, lipids, and SBP between ages 6–10 years and 11–16 years. Next, we used multivariable linear regression to examine associations of sex, baseline overweight/obesity, baseline pubertal status and race/ethnicity with change in the biomarkers during follow-up. Results: Boys exhibited a larger decrement in adiponectin (−0.66 [95% CI = −1.14, −0.18)] ng/mL) and a greater increase in SBP (3.20 [2.10, 4.30] mmHg) than girls. Overweight/obese participants experienced larger increases in HOMA-IR, leptin, and triglycerides; and a steeper decrement in HDL. Pubertal youth showed larger decrements in total and LDL cholesterol than their pre-pubertal counterparts. In comparison to White participants, Black youth experienced a larger magnitude of increase in HOMA-IR, and Hispanic youth exhibited larger decrements in adiponectin and HDL. Conclusions: Change in metabolic biomarkers across early adolescence differed by sex, weight status, pubertal status and race/ethnicity. Some of the metabolic changes may reflect normal physiological changes of puberty, while others may presage future disease risk. Future studies are warranted to link metabolic changes during adolescence to long-term health