Epigenome-wide association study on asthma and chronic obstructive pulmonary disease overlap reveals aberrant DNA methylations related to clinical phenotypes

Chen, Yung‐Che; Tsai, Ying‐Huang; Wang, Chin‐Chou; Liu, Shih-Feng; Chen, Ting-Wen; Fang, Wen‐Feng; Lee, Chiu-Ping; Hsu, Po‐Yuan; Chao, Tung‐Ying; Wu, Cheng-Jang; Wei, Yufeng; Chang, Hsien‐Kun; Tsen, Chia-Cheng; Chang, Yu-Ping

doi:10.1038/s41598-021-83185-1

Cited by 22 publications

(10 citation statements)

References 58 publications

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“…The PTPs remove phosphate groups from tyrosine residues, thereby influencing signal transduction and cellular processes such as cell metabolism, motility and survival. Chen et al ( 24 ) studied epigenome-wide associations between smoke/allergen exposure and the development of asthma and chronic obstructive pulmonary disease, and found that hypomethylated PTPRN2 was associated with rapid lung function.…”

Section: Discussionmentioning

confidence: 99%

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Genome-wide association study identifies WWC2 as a possible locus associated with persistent pulmonary hypertension of the newborn in the Thai population

Nakwan¹,

Kunhapan²,

Chaiyasung³

et al. 2023

Transl Pediatr

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Background There is known to be significant genetic involvement in persistent pulmonary hypertension of the newborn (PPHN), but to date there is not a clear understanding of this situation, and clarifying that involvement would be of considerable assistance in devising effective treatments for the disease. This case-control study was undertaken to search for genetic variants associated with PPHN in the Thai population using a genome-wide association study (GWAS). Methods A 659,184 single nucleotide polymorphisms from 387 participants (54 PPHN cases and 333 healthy participants) were genotyped across the human genome using an Illumina Asian Screening Array-24 v1.0 BeadChip Array. After quality control, we obtained 443,063 autosomal SNPs for the GWAS analysis. The FaST-LMM and R packages were used for all statistical analyses. Results For the case-control analysis, the genomic inflation factor (λ) was 1.016, rs149768622 T>C in the first intron of WWC2 gene showed the strongest association with a P value of 3.76E-08 and odds ratio (OR) of 13.24 (95% CI: 3.91–44.78). The variants at the LOC102723906 / LOC105377599 , CADM4 , GPM6A , CIT , RIMBP2 , LOC105374510 , LOC105375193 , PTPRN2 , CDK14 , and LCORL loci showed suggestive evidence of associations with PPHN (P<1E-05). Conclusions This GWAS found that rs149768622 T>C in the WWC2 gene was possibly associated with PPHN. However, replication and functional studies are needed to validate this association and further explore the role(s) of the WWC2 gene in PPHN.

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Section: Discussionmentioning

confidence: 99%

“…Length of hospital stay (days)22(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34) In-hospital mortality2 (3.7) Data are presented as mean ± standard deviation, median (interquartile range), or n (%). PPHN, persistent pulmonary hypertension of the newborn.…”

mentioning

confidence: 99%

Genome-wide association study identifies WWC2 as a possible locus associated with persistent pulmonary hypertension of the newborn in the Thai population

Nakwan¹,

Kunhapan²,

Chaiyasung³

et al. 2023

Transl Pediatr

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“… 52 However, upregulation in EMT-associated proteins could potentially signify a transition of the airway smooth muscle cells into a more contractile phenotype and further support a shift toward airway remodeling. Similarly, increases in pathways involved in myogenesis, 53 cholesterol homeostasis, 54 and STAT5 signaling 55 can also be indicative of a shift toward the asthma phenotype, as all three pathways have been shown to play a role in allergic asthma inflammation and smooth muscle cell contractility. Given the link between many of the highlighted pathways with asthma and the changes in the contractile phenotype of the microtissues, we believe our system provides an important high-throughput avenue for investigation of therapeutics for the repair and reversal of airway smooth muscle hypercontractility and remodeling.…”

Section: Discussionmentioning

confidence: 99%

A high-throughput 3D cantilever array to model airway smooth muscle hypercontractility in asthma

et al. 2023

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Asthma is often characterized by tissue-level mechanical phenotypes that include remodeling of the airway and an increase in airway tightening, driven by the underlying smooth muscle. Existing therapies only provide symptom relief and do not improve the baseline narrowing of the airway or halt progression of the disease. To investigate such targeted therapeutics, there is a need for models that can recapitulate the 3D environment present in this tissue, provide phenotypic readouts of contractility, and be easily integrated into existing assay plate designs and laboratory automation used in drug discovery campaigns. To address this, we have developed DEFLCT, a high-throughput plate insert that can be paired with standard labware to easily generate high quantities of microscale tissues in vitro for screening applications. Using this platform, we exposed primary human airway smooth muscle cell-derived microtissues to a panel of six inflammatory cytokines present in the asthmatic niche, identifying TGF-β1 and IL-13 as inducers of a hypercontractile phenotype. RNAseq analysis further demonstrated enrichment of contractile and remodeling-relevant pathways in TGF-β1 and IL-13 treated tissues as well as pathways generally associated with asthma. Screening of 78 kinase inhibitors on TGF-β1 treated tissues suggests that inhibition of protein kinase C and mTOR/Akt signaling can prevent this hypercontractile phenotype from emerging, while direct inhibition of myosin light chain kinase does not. Taken together, these data establish a disease-relevant 3D tissue model for the asthmatic airway, which combines niche specific inflammatory cues and complex mechanical readouts that can be utilized in drug discovery efforts.

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“…4 ). For the majority of genes such as Elac2 , Csnk1a1 , Eif3a , Eif4g2 , Tmed2 and Mpv17l, a role in the pathogenesis of lung diseases was indicated by previous studies 22 – 27 , although their functions in the neonatal lung remain unexplored. The data resource provided by the study not only gives insight into an unexplored field of significant relevance for studies in lung development but could serve as a guide for reference gene selection, specifically considering commonly relevant biological, technical and experimental conditions.…”

Section: Discussionmentioning

confidence: 99%

Reference genes for the developing mouse lung under consideration of biological, technical and experimental confounders

Morty

Sucre

Negretti

et al. 2022

Sci Rep

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For gene expression analysis, the raw data obtained from RT-qPCR are preferably normalized to reference genes, which should be constantly expressed regardless of experimental conditions. Selection of reference genes is particularly challenging for the developing lung because of the complex transcriptional and epigenetic regulation of genes during organ maturation and injury repair. To date, there are only limited experimental data addressing reliable reference genes for this biological circumstance. In this study, we evaluated reference genes for the lung in neonatal C57BL/6 mice under consideration of biological, technical and experimental conditions. For that, we thoroughly selected candidates from commonly used reference genes side-by-side with novel ones by analyzing publicly available microarray datasets. We performed RT-qPCR of the selected candidate genes and analyzed their expression variability using GeNorm and Normfinder. Cell-specific expression of the candidate genes was analyzed using our own single-cell RNA-sequencing data from the developing mouse lung. Depending on the investigated conditions, i.e., developmental stages, sex, RNA quality, experimental condition (hyperoxia) and cell types, distinct candidate genes demonstrated stable expression confirming their eligibility as reliable reference genes. Our results provide valuable information for the selection of proper reference genes in studies investigating the neonatal mouse lung.

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Epigenome-wide association study on asthma and chronic obstructive pulmonary disease overlap reveals aberrant DNA methylations related to clinical phenotypes

Cited by 22 publications

References 58 publications

Genome-wide association study identifies WWC2 as a possible locus associated with persistent pulmonary hypertension of the newborn in the Thai population

Genome-wide association study identifies WWC2 as a possible locus associated with persistent pulmonary hypertension of the newborn in the Thai population

A high-throughput 3D cantilever array to model airway smooth muscle hypercontractility in asthma

Reference genes for the developing mouse lung under consideration of biological, technical and experimental confounders

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