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

Abstract

Background: Exposure to violence (ETV) or stress may cause asthma through unclear mechanisms. Methods: Epigenome-wide association study (EWAS) of DNA methylation in nasal epithelium and four ETV or chronic stress measures in 487 Puerto Ricans aged 9-20 years who participated in the Epigenetic Variation and Childhood Asthma in Puerto Ricans study [EVA-PR]). We assessed measures of ETV or 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: In the EWAS of stress/violence in EVA-PR, gun violence was associated with methylation of cg18961589 in LINC01164 (beta=0.03, P=1.28E-7), and maternal stress was associated with methylation of cg03402351 in SNN (beta=0.04, P=1.69E-7) and cg19064846 in PTPRN2 (beta=0.03, P=3.36E-7). In a meta-analysis of three cohorts, which included the top CpGs associated with stress/violence in EVA-PR, CpGs in STARD3NL, SLC35F4, TSR3, CDC42SE2, KLHL25, PLCB1, BUD13, OR2B3, GALR1, TMEM196, TEAD4 and ANAPC13 were associated with atopic asthma at FDR-P < 0.05. Conclusions: ETV and chronic stress may increase the risk of atopic asthma through DNA methylation in airway epithelium, though this needs confirmation in future longitudinal studies.

CNest: A Novel Copy Number Association Discovery Method Uncovers 862 New Associations from 200,629 Whole Exome Sequence Datasets in the UK Biobank

“…Unsurprisingly the strongest signal for asthma is found in the HLA with the lead signal specifically restricted to the HLA-DQA2 gene which has strong prior associations to asthma and hay fever all based on intergenic SNPs from multiple SNP based GWAS investigations (95)(96)(97)(98)(99). Some of our novel CNV associations for asthma (Supplementary Table 5) include signals in genes, TAP2 and STARD3NL, which have not been linked with asthma by previous SNP GWAS studies but have evidence of association to certain other respiratory diseases (100,101).…”

The complexity in DNA methylation analysis of allergic diseases

“…Among a high-risk group, the Puerto Rican children, exposure to gun violence was significantly associated with increased methylation of a CpG site LINC01164. Additional 12 CpG sites were associated with atopic asthma in genes STARD3NL , TSR3 , CDC42SE2 , KLHL25 , GALR1 , TMEM196 , ANAPC13 , SLC35F4 , PLCB1 , BUD13 , OR2B3 , and TEAD4 [54].…”

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

“…17 Moreover, environmental exposure can alter cellular epigenetic states. 18,19 Among these epigenetic markers, DNA methylation provides a stable marker that is suitable for investigating mechanisms for long-term regulation of gene expression upon environmental stimulation. 20 Many studies relate early life exposures to DNA methylation signatures later in life, yet these observational studies may be subject to confounding and causation remains to be verified by future studies.…”

“…Moreover, RSV has been related to a nasal airway microRNA profile which is predicted to have a downregulated NF‐kB signaling pathway 17 . Moreover, environmental exposure can alter cellular epigenetic states 18,19 . Among these epigenetic markers, DNA methylation provides a stable marker that is suitable for investigating mechanisms for long‐term regulation of gene expression upon environmental stimulation 20 .…”