Multi-omics approaches to understand respiratory disease

The main scope of this thesis is to improve our understanding of the biological mechanisms of allergic disease, in particular asthma and rhinitis, by applying multi-omics approaches. We collected multi-omics data from the genome, epigenome, bulk and single-cell transcriptome, and the exposome. By applying association and machine learning approaches, we investigated epigenetic mechanisms of the development of allergic disease, revealed cell-type specific molecular regulation of asthma risk variants, identified biomarkers of allergy, and provided a prediction tool for allergic disease

Association of baseline and dynamic arterial stiffness status with dyslipidemia: a cohort study

Background and aimsDyslipidemia is known to contribute to arterial stiffness, while the inverse association remains unknown. This study aimed to explore the association of baseline arterial stiffness and its changes, as determined by brachial-ankle pulse wave velocity (baPWV), with dyslipidemia onset in the general population.MethodsThis study enrolled participants from Beijing Health Management Cohort using measurements of the first visit from 2012 to 2013 as baseline, and followed until the dyslipidemia onset or the end of 2019. Unadjusted and adjusted Cox proportional regression models were used to evaluate the associations of baseline baPWV and baPWV transition (persistent low, onset, remitted and persistent high) with incident dyslipidemia.ResultsOf 4362 individuals (mean age: 55.5 years), 1490 (34.2%) developed dyslipidemia during a median follow-up of 5.9 years. After adjusting for potential confounders, participants with elevated arterial stiffness at baseline had an increased risk of dyslipidemia (HR, 1.194; 95% CI, 1.050-1.358). Compared with persistent low baPWV, new-onset and persistent high baPWV were associated with a 51.2% and 37.1% excess risk of dyslipidemia.ConclusionThe findings indicated that arterial stiffness is an early risk factor of dyslipidemia, suggesting a bidirectional association between arterial stiffness and lipid metabolism

Determinants of expression of SARS-CoV-2 entry-related genes in upper and lower airways

Peer reviewe

Infant RSV immunoprophylaxis changes nasal epithelial DNA methylation at 6 years of age

BackgroundRespiratory syncytial virus (RSV) infection has been associated with childhood wheeze and asthma, and potential mechanisms include persistent epigenetic effects.MethodsIn the randomized, placebo-controlled MAKI trial, 429 preterm infants randomly received RSV immunoprophylaxis with palivizumab or placebo during their first RSV season. Children were followed until age 6 for asthma evaluation. DNA methylation in cells obtained by nasal brushes at age 6 was measured by Illumina MethylationEPIC array.ResultsRSV immunoprophylaxis in infancy had a significant impact on global methylation patterns in nasal cells at age 6. The first principal component (PC) related to the immunoprophylaxis intervention was enriched for the pathway "detection of chemical stimulus involved in sensory perception of smell" and "T cell differentiation." Subsequent analysis of these PCs indicated an effect of RSV immunoprophylaxis on cell type composition of nasal brushed cells. Three CpG sites, cg18040241, cg08243963, and cg19555973 which are annotated to genes GLB1L2, SC5D, and BPIFB1, were differentially methylated at genome-wide significance, but were not associated with asthma. ConclusionThe study provides the first proof of concept that RSV immunoprophylaxis during infancy has long-term effects on nasal epigenetic signatures at age 6, relating to host sensory perception, epidermal growth factor receptor signaling, and adaptive immune responses.</p

Exposure to violence, chronic stress, nasal DNA methylation, and atopic asthma in children

BACKGROUND: Exposure to violence (ETV) or chronic stress may influence asthma through unclear mechanisms. METHODS: Epigenome-wide association study (EWAS) of ETV or chronic stress measures and DNA methylation in nasal epithelium from 487 Puerto Ricans aged 9-20 years who participated in the Epigenetic Variation and Childhood Asthma in Puerto Ricans study [EVA-PR]). We assessed four measures of ETV and chronic stress in children (ETV scale, gun violence, and perceived stress) and their mothers (perceived stress). Each EWAS was conducted using linear regression, with CpGs as dependent variables and the stress/violence measure as a predictor, adjusting for age, sex, the top five principal components, and SVA latent factors. We then selected the top 100 CpGs (by p value) associated with each stress/violence measure in EVA-PR and conducted a meta-analysis of the selected CpGs and atopic asthma using data from EVA-PR and two additional cohorts (Project Viva and PIAMA). RESULTS: Three CpGs (in SNN, PTPRN2, and LINC01164) were associated with maternal perceived stress or gun violence (p = 1.28-3.36 × 10-7 ), but not with atopic asthma, in EVA-PR. In a meta-analysis of three cohorts, which included the top CpGs associated with stress/violence measures in EVA-PR, 12 CpGs (in STARD3NL, SLC35F4, TSR3, CDC42SE2, KLHL25, PLCB1, BUD13, OR2B3, GALR1, TMEM196, TEAD4, and ANAPC13) were associated with atopic asthma at FDR-p < .05. CONCLUSIONS: Pending confirmation in longitudinal studies, our findings suggest that nasal epithelial methylation markers associated with measures of ETV and chronic stress may be linked to atopic asthma in children and adolescents

Effect of Emodin on Preventing Postoperative Intra-Abdominal Adhesion Formation

Background. Postoperative intra-abdominal adhesions are a major complication after abdominal surgery. Although various methods have been used to prevent and treat adhesions, the effects have not been satisfactory. Emodin, a naturally occurring anthraquinone derivative and an active ingredient in traditional Chinese herbs, exhibits a variety of pharmacological effects. In our study, we demonstrated the effect of emodin treatment on preventing postoperative adhesion formation. Materials and Methods. A total of 48 rats were divided into six groups. Abdominal adhesions were created by abrasion of the cecum and its opposite abdominal wall. In the experimental groups, the rats were administered daily oral doses of emodin. On the seventh day after operation, the rats were euthanized, and blood and pathological specimens were collected. Abdominal adhesion formation was evaluated by necropsy, pathology, immunohistochemistry, Western blot, and enzyme-linked immunosorbent assay analyses. Results. Abdominal adhesions were markedly reduced by emodin treatment. Compared with the control group, collagen deposition was reduced and the peritoneal mesothelial completeness rate was higher in the emodin-treated groups. Emodin had anti-inflammatory effects, reduced oxidative stress, and promoted the movement of the intestinal tract (P<0.05). Conclusion. Emodin significantly reduced intra-abdominal adhesion formation in a rat model

Epigenome-Wide DNA Methylation and Pesticide Use in the Agricultural Lung Health Study

Using family-wise error rate (p<9×10-8) or false-discovery rate (FDR<0.05), we identified 162 differentially methylated CpGs across 8 of 9 currently marketed active ingredients (acetochlor, atrazine, dicamba, glyphosate, malathion, metolachlor, mesotrione, and picloram) and one banned organochlorine (heptachlor). Differentially methylated CpGs were unique to each active ingredient, and a dose-response relationship with lifetime days of use was observed for most. Significant CpGs were enriched for transcription motifs and 28% of CpGs were associated with whole blood cis-gene expression, supporting functional effects of findings. We corroborated a previously reported association between dichlorodiphenyltrichloroethane (banned in the United States in 1972) and epigenetic age acceleration

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