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  • 1
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    Association of Severe Bronchiolitis during Infancy with Childhood Asthma Development: An Analysis of the ECHO Consortium
    MDPI AG ; 2022
    In:  Biomedicines Vol. 11, No. 1 ( 2022-12-22), p. 23-
    Details
    In: Biomedicines, MDPI AG, Vol. 11, No. 1 ( 2022-12-22), p. 23-
    Abstract: Objective: Many studies have shown that severe (hospitalized) bronchiolitis during infancy is a risk factor for developing childhood asthma. However, the population subgroups at the highest risk remain unclear. Using large nationwide pediatric cohort data, namely the NIH Environmental influences on Child Health Outcomes (ECHO) Program, we aimed to quantify the longitudinal relationship of bronchiolitis hospitalization during infancy with asthma in a generalizable dataset and to examine potential heterogeneity in terms of major demographics and clinical factors. Methods: We analyzed data from infants (age 〈 12 months) enrolled in one of the 53 prospective cohort studies in the ECHO Program during 2001–2021. The exposure was bronchiolitis hospitalization during infancy. The outcome was a diagnosis of asthma by a physician by age 12 years. We examined their longitudinal association and determined the potential effect modifications of major demographic factors. Results: The analytic cohort consisted of 11,762 infants, 10% of whom had bronchiolitis hospitalization. Overall, 15% subsequently developed asthma. In the Cox proportional hazards model adjusting for 10 patient-level factors, compared with the no-bronchiolitis hospitalization group, the bronchiolitis hospitalization group had a significantly higher rate of asthma (14% vs. 24%, HR = 2.77, 95%CI = 2.24–3.43, p 〈 0.001). There was significant heterogeneity by race and ethnicity (Pinteraction = 0.02). The magnitude of the association was greater in non-Hispanic White (HR = 3.77, 95%CI = 2.74–5.18, p 〈 0.001) and non-Hispanic Black (HR = 2.39, 95%CI = 1.60–3.56; p 〈 0.001) infants, compared with Hispanic infants (HR = 1.51, 95%CI = 0.77–2.95, p = 0.23). Conclusions: According to the nationwide cohort data, infants hospitalized with bronchiolitis are at a higher risk for asthma, with quantitative heterogeneity in different racial and ethnic groups.
    Type of Medium: Online Resource
    ISSN: 2227-9059
    URL: Article
    DOI: 10.3390/biomedicines11010023
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2720867-9
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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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    Omega-3 Fatty Acids Interact with DPP10 Region Genotype in Association with Childhood Atopy
    MDPI AG ; 2023
    In:  Nutrients Vol. 15, No. 10 ( 2023-05-22), p. 2416-
    Details
    In: Nutrients, MDPI AG, Vol. 15, No. 10 ( 2023-05-22), p. 2416-
    Abstract: Associations of omega-3 fatty acids (n-3) with allergic diseases are inconsistent, perhaps in part due to genetic variation. We sought to identify and validate genetic variants that modify associations of n-3 with childhood asthma or atopy in participants in the Vitamin D Antenatal Asthma Reduction Trial (VDAART) and the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC). Dietary n-3 was derived from food frequency questionnaires and plasma n-3 was measured via untargeted mass spectrometry in early childhood and children aged 6 years old. Interactions of genotype with n-3 in association with asthma or atopy at age 6 years were sought for six candidate genes/gene regions and genome-wide. Two SNPs in the region of DPP10 (rs958457 and rs1516311) interacted with plasma n-3 at age 3 years in VDAART (p = 0.007 and 0.003, respectively) and with plasma n-3 at age 18 months in COPSAC (p = 0.01 and 0.02, respectively) in associationwith atopy. Another DPP10 region SNP, rs1367180, interacted with dietary n-3 at age 6 years in VDAART (p = 0.009) and with plasma n-3 at age 6 years in COPSAC (p = 0.004) in association with atopy. No replicated interactions were identified for asthma. The effect of n-3 on reducing childhood allergic disease may differ by individual factors, including genetic variation in the DPP10 region.
    Type of Medium: Online Resource
    ISSN: 2072-6643
    URL: Article
    DOI: 10.3390/nu15102416
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2518386-2
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  • 4
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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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  • 5
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    Effect of Intrauterine Smoke Exposure on microRNA-15a Expression in Human Lung Development and Subsequent Asthma Risk
    MDPI AG ; 2020
    In:  Healthcare Vol. 8, No. 4 ( 2020-12-04), p. 536-
    Details
    In: Healthcare, MDPI AG, Vol. 8, No. 4 ( 2020-12-04), p. 536-
    Abstract: Background: In utero smoke (IUS) exposure is associated with asthma susceptibility. Objective: We sought to test the hypothesis that changes in miRNA expression by IUS exposure during human lung development is associated with asthma susceptibility. Methods: Gene expression was profiled from 53 IUS unexposed and 51 IUS exposed human fetal lung tissues. We tested for the differential expression of miRNAs across post-conception age and by IUS using linear models with covariate adjustment. We tested the IUS-associated miRNAs for association with their gene expression targets using pair-wise inverse correlation. Using our mouse model, we investigated the persistence of the IUS-associated miRNA signature using RT-PCR from the lungs of mouse pups with and without IUS at postnatal day 14. MiRNAs were then tested for association with asthma and exacerbations using whole blood gene expression profiles from Asthma BRIDGE. Results: Five miRNAs were differentially expressed across post-conception age (adjusted p 〈 0.0002) including two that were differentially expressed by IUS exposure in human fetal lung (p 〈 0.05). MiR-15a was differentially expressed by post-conception age (p = 0.00002), IUS exposure in human fetal lung (p = 0.005), and in the post-natal mouse lung (p = 0.01). MiR-15a was also associated with the in utero expression of GSDMB (adjusted p = 0.0002), a known childhood asthma gene and with asthma exacerbations (p = 0.0009) in Asthma BRIDGE. Thus, miR-15a is expressed during human lung development, is impacted by IUS exposure, regulates the intrauterine expression of asthma genes, and is associated with asthma severity. Conclusions: These results provide evidence for the role of miR-15a in the fetal origin of asthma.
    Type of Medium: Online Resource
    ISSN: 2227-9032
    URL: Article
    DOI: 10.3390/healthcare8040536
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2721009-1
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  • 6
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    CASTER: Cross-Sectional Asthma STEroid Response Measurement
    MDPI AG ; 2020
    In:  Journal of Personalized Medicine Vol. 10, No. 3 ( 2020-08-20), p. 95-
    Details
    In: Journal of Personalized Medicine, MDPI AG, Vol. 10, No. 3 ( 2020-08-20), p. 95-
    Abstract: Asthma patient response to inhaled corticosteroids (ICS) is variable and difficult to quantify. We aimed to define a measure of steroid response suitable for pharmacogenetic research in longitudinal and cross-sectional cohorts. Using longitudinal data from the Childhood Asthma Management Program (CAMP) asthma cohort, we defined the Cross-sectional Asthma STEroid Response (CASTER) measure in cross-sectional data. We then applied this to cross-sectional slices of four independent asthma cohorts: The Improving Asthma Control Trial (IMPACT), the Salmeterol or Corticosteroids Study (SOCS), the Pediatric Asthma Controller Trial (PACT), and the Genetics of Asthma in Costa Rica Study (GACRS). CASTER achieved high accuracy on the childhood asthma cohorts: GACRS, PACT, and also on cross-sectional data from CAMP (AUCs 82%, 71%, 63%, respectively). This demonstrates that select cross-sectional clinical information is sufficient to identify good and poor responders to ICS treatment in childhood asthma. Thus, CASTER represents a major improvement in the usability and applicability of steroid response measures in asthma research.
    Type of Medium: Online Resource
    ISSN: 2075-4426
    URL: Article
    DOI: 10.3390/jpm10030095
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2662248-8
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  • 7
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    Drug Repurposing to Treat Glucocorticoid Resistance in Asthma
    MDPI AG ; 2021
    In:  Journal of Personalized Medicine Vol. 11, No. 3 ( 2021-03-03), p. 175-
    Details
    In: Journal of Personalized Medicine, MDPI AG, Vol. 11, No. 3 ( 2021-03-03), p. 175-
    Abstract: Corticosteroid resistance causes significant morbidity in asthma, and drug repurposing may identify timely and cost-effective adjunctive treatments for corticosteroid resistance. In 95 subjects from the Childhood Asthma Management Program (CAMP) and 19 subjects from the Severe Asthma Research Program (SARP), corticosteroid response was measured by the change in percent predicted forced expiratory volume in one second (FEV1). In each cohort, differential gene expression analysis was performed comparing poor (resistant) responders, defined as those with zero to negative change in FEV1, to good responders, followed by Connectivity Map (CMap) analysis to identify inversely associated (i.e., negatively connected) drugs that reversed the gene expression profile of poor responders to resemble that of good responders. Mean connectivity scores weighted by sample size were calculated. The top five drug compound candidates underwent in vitro validation in NF-κB-based luciferase reporter A549 cells stimulated by IL-1β ± dexamethasone. In CAMP and SARP, 134 and 178 respective genes were differentially expressed in poor responders. CMap analysis identified 46 compounds in common across both cohorts with connectivity scores 〈 −50. γ-linolenic acid, ampicillin, exemestane, brinzolamide, and INCA-6 were selected for functional validation. γ-linolenic acid, brinzolamide, and INCA-6 significantly reduced IL-1β induced luciferase activity and potentiated the anti-inflammatory effect of dexamethasone in A549/NF-κB-luc reporter cells. These results demonstrate how existing drugs, including γ-linolenic acid, brinzolamide, and INCA-6, may be repurposed to improve corticosteroid response in asthmatics.
    Type of Medium: Online Resource
    ISSN: 2075-4426
    URL: Article
    DOI: 10.3390/jpm11030175
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
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  • 8
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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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  • 9
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    Delayed Motor Milestones Achievement in Infancy Associates with Perturbations of Amino Acids and Lipid Metabolic Pathways
    MDPI AG ; 2020
    In:  Metabolites Vol. 10, No. 9 ( 2020-08-19), p. 337-
    Details
    In: Metabolites, MDPI AG, Vol. 10, No. 9 ( 2020-08-19), p. 337-
    Abstract: The relationship between developmental milestone achievement in infancy and later cognitive function and mental health is well established, but underlying biochemical mechanisms are poorly described. Our study aims to discover pathways connected to motor milestone achievement during infancy by using untargeted plasma metabolomic profiles from 571 six-month-old children in connection with age of motor milestones achievement (Denver Developmental Index) in the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010) mother–child cohort. We used univariate regression models and multivariate modelling (Partial Least Squares Discriminant Analysis: PLS-DA) to examine the associations and the VDAART (Vitamin D Antenatal Asthma Reduction Trial) cohort for validation. The univariate analyses showed 62 metabolites associated with gross-motor milestone achievement (p 〈 0.05) as well as the PLS-DA significantly differentiated between slow and fast milestone achievers (AUC = 0.87, p = 0.01). Higher levels of tyramine-O-sulfate in the tyrosine pathway were found in the late achievers in COPSAC (p = 0.0002) and in VDAART (p = 0.02). Furthermore, we observed that slow achievers were characterized by higher levels of fatty acids and products of fatty acids metabolism including acyl carnitines. Finally, we also observed changes in the lysine, histidine, glutamate, creatine and tryptophan pathways. Observing these metabolic changes in relation to gross-motor milestones in the first year of life, may be of importance for later cognitive function and mental health.
    Type of Medium: Online Resource
    ISSN: 2218-1989
    URL: Article
    DOI: 10.3390/metabo10090337
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2662251-8
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  • 10
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    Maternal Inflammatory Biomarkers during Pregnancy and Early Life Neurodevelopment in Offspring: Results from the VDAART Study
    MDPI AG ; 2022
    In:  International Journal of Molecular Sciences Vol. 23, No. 23 ( 2022-12-03), p. 15249-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 23, No. 23 ( 2022-12-03), p. 15249-
    Abstract: Maternal infection and stress during the prenatal period have been associated with adverse neurodevelopmental outcomes in offspring, suggesting that biomarkers of increased inflammation in the mothers may associate with poorer developmental outcomes. In 491 mother–child pairs from the Vitamin D Antenatal Asthma Reduction Trial (VDAART), we investigated the association between maternal levels of two inflammatory biomarkers; interleukin-8 (IL-8) and C-Reactive Protein (CRP) during early (10–18 wks) and late (32–38 wks) pregnancy with offspring scores in the five domains of the Ages and Stages Questionnaire, a validated screening tool for assessing early life development. We identified a robust association between early pregnancy IL-8 levels and decreased fine-motor (β: −0.919, 95%CI: −1.425, −0.414, p = 3.9 × 10−4) and problem-solving skills at age two (β: −1.221, 95%CI: −1.904, −0.414, p = 4.9 × 10−4). Associations between IL-8 with other domains of development and those for CRP did not survive correction for multiple testing. Similarly, while there was some evidence that the detrimental effects of early pregnancy IL-8 were strongest in boys and in those who were not breastfed, these interactions were not robust to correction for multiple testing. However, further research is required to determine if other maternal inflammatory biomarkers associate with offspring neurodevelopment and work should continue to focus on the management of factors leading to increases in IL-8 levels in pregnant women.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms232315249
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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