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  • 1
    Online Resource
    Online Resource
    Co-methylation analysis in lung tissue identifies pathways for fetal origins of COPD
    European Respiratory Society (ERS) ; 2020
    In:  European Respiratory Journal Vol. 56, No. 4 ( 2020-10), p. 1902347-
    Details
    In: European Respiratory Journal, European Respiratory Society (ERS), Vol. 56, No. 4 ( 2020-10), p. 1902347-
    Abstract: COPD likely has developmental origins; however, the underlying molecular mechanisms are not fully identified. Investigation of lung tissue-specific epigenetic modifications such as DNA methylation using network approaches might facilitate insights linking in utero smoke (IUS) exposure and risk for COPD in adulthood. We performed genome-wide methylation profiling for adult lung DNA from 160 surgical samples and 78 fetal lung DNA samples isolated from discarded tissue at 8–18 weeks of gestation. Co-methylation networks were constructed to identify preserved modules that shared methylation patterns in fetal and adult lung tissues and associations with fetal IUS exposure, gestational age and COPD. Weighted correlation networks highlighted preserved and co-methylated modules for both fetal and adult lung data associated with fetal IUS exposure, COPD and lower adult lung function. These modules were significantly enriched for genes involved in embryonic organ development and specific inflammation-related pathways, including Hippo, phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), Wnt, mitogen-activated protein kinase and transforming growth factor-β signalling. Gestational age-associated modules were remarkably preserved for COPD and lung function, and were also annotated to genes enriched for the Wnt and PI3K/AKT pathways. Epigenetic network perturbations in fetal lung tissue exposed to IUS and of early lung development recapitulated in adult lung tissue from ex-smokers with COPD. Overlapping fetal and adult lung tissue network modules highlighted putative disease pathways supportive of exposure-related and age-associated developmental origins of COPD.
    Type of Medium: Online Resource
    ISSN: 0903-1936 , 1399-3003
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.1183/13993003.02347-2019
    DOI: 10.1183/13993003.02347-2019.Supp1
    DOI: 10.1183/13993003.02347-2019.Shareable1
    Language: English
    Publisher: European Respiratory Society (ERS)
    Publication Date: 2020
    detail.hit.zdb_id: 2834928-3
    detail.hit.zdb_id: 1499101-9
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  • 2
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    Circulating MicroRNA: Incident Asthma Prediction and Vitamin D Effect Modification
    MDPI AG ; 2021
    In:  Journal of Personalized Medicine Vol. 11, No. 4 ( 2021-04-16), p. 307-
    Details
    In: Journal of Personalized Medicine, MDPI AG, Vol. 11, No. 4 ( 2021-04-16), p. 307-
    Abstract: Of children with recurrent wheezing in early childhood, approximately half go on to develop asthma. MicroRNAs have been described as excellent non-invasive biomarkers due to their prognostic utility. We hypothesized that circulating microRNAs can predict incident asthma and that that prediction might be modified by vitamin D. We selected 75 participants with recurrent wheezing at 3 years old from the Vitamin D Antenatal Asthma Reduction Trial (VDAART). Plasma samples were collected at age 3 and sequenced for small RNA-Seq. The read counts were normalized and filtered by depth and coverage. Logistic regression was employed to associate miRNAs at age 3 with asthma status at age 5. While the overall effect of miRNA on asthma occurrence was weak, we identified 38 miRNAs with a significant interaction effect with vitamin D and 32 miRNAs with a significant main effect in the high vitamin D treatment group in VDAART. We validated the VDAART results in Project Viva for both the main effect and interaction effect. Meta-analysis was performed on both cohorts to obtain the combined effect and a logistic regression model was used to predict incident asthma at age 7 in Project Viva. Of the 23 overlapped miRNAs in the stratified and interaction analysis above, 9 miRNAs were replicated in Project Viva with strong effect size and remained in the meta-analysis of the two populations. The target genes of the 9 miRNAs were enriched for asthma-related Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways. Using logistic regression, microRNA hsa-miR-574-5p had a good prognostic ability for incident asthma prognosis with an area under the receiver operating characteristic (AUROC) of 0.83. In conclusion, miRNAs appear to be good biomarkers of incident asthma, but only when vitamin D level is considered.
    Type of Medium: Online Resource
    ISSN: 2075-4426
    URL: Article
    DOI: 10.3390/jpm11040307
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2662248-8
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  • 3
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    COPD-associated miR-145-5p is downregulated in early-decline FEV1 trajectories in childhood asthma
    Elsevier BV ; 2021
    In:  Journal of Allergy and Clinical Immunology Vol. 147, No. 6 ( 2021-06), p. 2181-2190
    Details
    In: Journal of Allergy and Clinical Immunology, Elsevier BV, Vol. 147, No. 6 ( 2021-06), p. 2181-2190
    Type of Medium: Online Resource
    ISSN: 0091-6749
    URL: Article
    DOI: 10.1016/j.jaci.2020.11.048
    RVK:
    XA 52000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 2006613-2
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  • 4
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    Circulating MicroRNAs and Treatment Response in Childhood Asthma
    American Thoracic Society ; 2020
    In:  American Journal of Respiratory and Critical Care Medicine Vol. 202, No. 1 ( 2020-07-01), p. 65-72
    Details
    In: American Journal of Respiratory and Critical Care Medicine, American Thoracic Society, Vol. 202, No. 1 ( 2020-07-01), p. 65-72
    Type of Medium: Online Resource
    ISSN: 1073-449X , 1535-4970
    URL: Article
    DOI: 10.1164/rccm.201907-1454OC
    RVK:
    XA 21200
    Language: English
    Publisher: American Thoracic Society
    Publication Date: 2020
    detail.hit.zdb_id: 1468352-0
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  • 5
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    COMPSRA: a COMprehensive Platform for Small RNA-Seq data Analysis
    Springer Science and Business Media LLC ; 2020
    In:  Scientific Reports Vol. 10, No. 1 ( 2020-03-12)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 10, No. 1 ( 2020-03-12)
    Abstract: Small RNA-Seq is a common means to interrogate the small RNA’ome or the full spectrum of small RNAs ( 〈 200 nucleotide length) of a biological system. A pivotal problem in NGS based small RNA analysis is identifying and quantifying the small RNA’ome constituent components. For example, small RNAs in the circulatory system (circulating RNAs) are potential disease biomarkers and their function is being actively investigated. Most existing NGS data analysis tools focus on the microRNA component and a few other small RNA types like piRNA, snRNA and snoRNA. A comprehensive platform is needed to interrogate the full small RNA’ome, a prerequisite for down-stream data analysis. We present COMPSRA, a comprehensive modular stand-alone platform for identifying and quantifying small RNAs from small RNA sequencing data. COMPSRA contains prebuilt customizable standard RNA databases and sequence processing tools to enable turnkey basic small RNA analysis. We evaluated COMPSRA against comparable existing tools on small RNA sequencing data set from serum samples of 12 healthy human controls, and COMPSRA identified a greater diversity and abundance of small RNA molecules. COMPSRA is modular, stand-alone and integrates multiple customizable RNA databases and sequence processing tool and is distributed under the GNU General Public License free to non-commercial registered users at https://github.com/cougarlj/COMPSRA .
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-020-61495-0
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2615211-3
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  • 6
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    Online Resource
    Expression of SMARCD1 interacts with age in association with asthma control on inhaled corticosteroid therapy
    Springer Science and Business Media LLC ; 2020
    In:  Respiratory Research Vol. 21, No. 1 ( 2020-12)
    Details
    In: Respiratory Research, Springer Science and Business Media LLC, Vol. 21, No. 1 ( 2020-12)
    Abstract: Global 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. Methods We 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 & 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. Results The 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. Conclusion Focusing 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.
    Type of Medium: Online Resource
    ISSN: 1465-993X
    URL: Article
    DOI: 10.1186/s12931-020-1295-4
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2041675-1
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  • 7
    Online Resource
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    Enhancing the prediction of childhood asthma remission: Integrating clinical factors with microRNAs
    Elsevier BV ; 2021
    In:  Journal of Allergy and Clinical Immunology Vol. 147, No. 3 ( 2021-03), p. 1093-1095.e1
    Details
    In: Journal of Allergy and Clinical Immunology, Elsevier BV, Vol. 147, No. 3 ( 2021-03), p. 1093-1095.e1
    Type of Medium: Online Resource
    ISSN: 0091-6749
    URL: Article
    DOI: 10.1016/j.jaci.2020.08.019
    RVK:
    XA 52000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 2006613-2
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  • 8
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    Intrauterine Smoke Exposure, microRNA Expression during Human Lung Development, and Childhood Asthma
    MDPI AG ; 2023
    In:  International Journal of Molecular Sciences Vol. 24, No. 9 ( 2023-04-23), p. 7727-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 24, No. 9 ( 2023-04-23), p. 7727-
    Abstract: Intrauterine smoke (IUS) exposure during early childhood has been associated with a number of negative health consequences, including reduced lung function and asthma susceptibility. The biological mechanisms underlying these associations have not been established. MicroRNAs regulate the expression of numerous genes involved in lung development. Thus, investigation of the impact of IUS on miRNA expression during human lung development may elucidate the impact of IUS on post-natal respiratory outcomes. We sought to investigate the effect of IUS exposure on miRNA expression during early lung development. We hypothesized that miRNA–mRNA networks are dysregulated by IUS during human lung development and that these miRNAs may be associated with future risk of asthma and allergy. Human fetal lung samples from a prenatal tissue retrieval program were tested for differential miRNA expression with IUS exposure (measured using placental cotinine concentration). RNA was extracted and miRNA-sequencing was performed. We performed differential expression using IUS exposure, with covariate adjustment. We also considered the above model with an additional sex-by-IUS interaction term, allowing IUS effects to differ by male and female samples. Using paired gene expression profiles, we created sex-stratified miRNA–mRNA correlation networks predictive of IUS using DIABLO. We additionally evaluated whether miRNAs were associated with asthma and allergy outcomes in a cohort of childhood asthma. We profiled pseudoglandular lung miRNA in n = 298 samples, 139 (47%) of which had evidence of IUS exposure. Of 515 miRNAs, 25 were significantly associated with intrauterine smoke exposure (q-value 〈 0.10). The IUS associated miRNAs were correlated with well-known asthma genes (e.g., ORM1-Like Protein 3, ORDML3) and enriched in disease-relevant pathways (oxidative stress). Eleven IUS-miRNAs were also correlated with clinical measures (e.g., Immunoglobulin E andlungfunction) in children with asthma, further supporting their likely disease relevance. Lastly, we found substantial differences in IUS effects by sex, finding 95 significant IUS-miRNAs in male samples, but only four miRNAs in female samples. The miRNA–mRNA correlation networks were predictive of IUS (AUC = 0.78 in males and 0.86 in females) and suggested that IUS-miRNAs are involved in regulation of disease-relevant genes (e.g., A disintegrin and metalloproteinase domain 19 (ADAM19), LBH regulator of WNT signaling (LBH)) and sex hormone signaling (Coactivator associated methyltransferase 1(CARM1)). Our study demonstrated differential expression of miRNAs by IUS during early prenatal human lung development, which may be modified by sex. Based on their gene targets and correlation to clinical asthma and atopy outcomes, these IUS-miRNAs may be relevant for subsequent allergy and asthma risk. Our study provides insight into the impact of IUS in human fetal lung transcriptional networks and on the developmental origins of asthma and allergic disorders.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms24097727
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 9
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    Blood miRNAs Are Linked to Frequent Asthma Exacerbations in Childhood Asthma and Adult COPD
    MDPI AG ; 2022
    In:  Non-Coding RNA Vol. 8, No. 2 ( 2022-04-03), p. 27-
    Details
    In: Non-Coding RNA, MDPI AG, Vol. 8, No. 2 ( 2022-04-03), p. 27-
    Abstract: MicroRNAs have been independently associated with asthma and COPD; however, it is unclear if microRNA associations will overlap when evaluating retrospective acute exacerbations. Objective: We hypothesized that peripheral blood microRNAs would be associated with retrospective acute asthma exacerbations in a pediatric asthma cohort and that such associations may also be relevant to acute COPD exacerbations. Methods: We conducted small-RNA sequencing on 374 whole-blood samples from children with asthma ages 6–14 years who participated in the Genetics of Asthma in Costa Rica Study (GACRS) and 450 current and former adult smokers with and without COPD who participated in the COPDGene study. Measurements and Main Results: After QC, we had 351 samples and 649 microRNAs for Differential Expression (DE) analysis between the frequent (n = 183) and no or infrequent exacerbation (n = 168) groups in GACRS. Fifteen upregulated miRs had odds ratios (OR) between 1.22 and 1.59 for a doubling of miR counts, while five downregulated miRs had ORs between 0.57 and 0.8. These were assessed for generalization in COPDGene, where three of the upregulated miRs (miR-532-3p, miR-296-5p, and miR-766-3p) and two of the downregulated miRs (miR-7-5p and miR-451b) replicated. Pathway enrichment analysis showed MAPK and PI3K-Akt signaling pathways were strongly enriched for target genes of DE miRNAs and miRNAs generalizing to COPD exacerbations, as well as infection response pathways to various pathogens. Conclusion: miRs (451b; 7-5p; 532-3p; 296-5p and 766-3p) associated with both childhood asthma and adult COPD exacerbations may play a vital role in airflow obstruction and exacerbations and point to shared genomic regulatory machinery underlying exacerbations in both diseases.
    Type of Medium: Online Resource
    ISSN: 2311-553X
    URL: Article
    DOI: 10.3390/ncrna8020027
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2813993-8
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  • 10
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    Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age
    Springer Science and Business Media LLC ; 2020
    In:  Genome Medicine Vol. 12, No. 1 ( 2020-12)
    Details
    In: Genome Medicine, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2020-12)
    Abstract: Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. Methods We performed meta-analysis of Illumina’s HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4–18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. Results We identified 8899 CpGs in cord blood that were associated with gestational age (range 27–42 weeks), at Bonferroni significance, P   〈  1.06 × 10 − 7 , of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. Conclusions We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.
    Type of Medium: Online Resource
    ISSN: 1756-994X
    URL: Article
    DOI: 10.1186/s13073-020-0716-9
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2484394-5
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