Search Results (32)

Background/Objectives: Vitamin D is essential for bone health, immune function, and overall well-being. Numerous ecological, observational, and prospective studies, including randomized controlled clinical trials (RCTs), report an inverse association between higher serum 25-hydroxyvitamin D [25(OH)D; calcifediol] levels in various conditions, including cardiovascular disease, metabolic disorders such as diabetes and obesity, susceptibility to infection-related complications, autoimmune diseases, and all-cause mortality. Results: Vitamin D operates through two distinct systems. The endocrine system comprises the renal tubular cell-derived circulatory calcitriol, which primarily regulates calcium homeostasis and muscular functions. In contrast, intracellularly generated calcitriol in peripheral target cells is responsible for intracrine/paracrine system signaling and calcitriol–vitamin D receptor-mediated genomic effects. Government-appointed committees and health organizations have developed various clinical practice guidelines for vitamin D supplementation and management. However, these guidelines heavily relied on the 2011 Institute of Medicine (IoM) report, which focused solely on the skeletal effects of vitamin D, ignoring other body systems. Thus, they do not represent maintaining good overall health and aspects of disease prevention. Additionally, the IoM report was intended as a public health recommendation for the government and is not a clinical guideline. Discussion: New country- and regional-specific guidelines must focus on healthy nations through disease prevention and reducing healthcare costs. They should not be restricted to bone effect and must encompass all extra-skeletal benefits. Nevertheless, due to misunderstandings, medical societies and other governments have used faulty IoM report as a foundation for creating vitamin D guidelines. Consequently, they placed disproportionate emphasis on bone health while largely overlooking its benefits for other bodily systems, making current guidelines, including 2024, the Endocrine Society less applicable to the public. As a result, the utility of published guidelines has been significantly reduced for clinical practice and RCTs that designed on bone-centric are generate misleading information and remain suboptimal for public health and disease prevention. Conclusions: This review and its recommendations address the gaps in current vitamin D clinical practice guidelines and propose a framework for developing more effective, country and region-specific recommendations that capture the extra-skeletal benefits of vitamin D to prevent multiple diseases and enhance public health. Full article

Background: Although inhaled corticosteroids (ICS) are the first-line therapy for patients with persistent asthma, many patients continue to have exacerbations. We developed machine learning models to predict the ICS response in patients with asthma. Methods: The subjects included asthma patients of European ancestry (n = 1371; 448 children; 916 adults). A genome-wide association study was performed to identify the SNPs associated with ICS response. Using the SNPs identified, two machine learning models were developed to predict ICS response: (1) least absolute shrinkage and selection operator (LASSO) regression and (2) random forest. Results: The LASSO regression model achieved an AUC of 0.71 (95% CI 0.67–0.76; sensitivity: 0.57; specificity: 0.75) in an independent test cohort, and the random forest model achieved an AUC of 0.74 (95% CI 0.70–0.78; sensitivity: 0.70; specificity: 0.68). The genes contributing to the prediction of ICS response included those associated with ICS responses in asthma (TPSAB1, FBXL16), asthma symptoms and severity (ABCA7, CNN2, PTRN3, and BSG/CD147), airway remodeling (ELANE, FSTL3), mucin production (GAL3ST), leukotriene synthesis (GPX4), allergic asthma (ZFPM1, SBNO2), and others. Conclusions: An accurate risk prediction of ICS response can be obtained using machine learning methods, with the potential to inform personalized treatment decisions. Further studies are needed to examine if the integration of richer phenotype data could improve risk prediction. Full article

Background: Asthmatic patients’ responses to inhaled corticosteroids (ICS) are variable and difficult to quantify. We have previously defined a Cross-sectional Asthma STEroid Response (CASTER) measure of ICS response. MicroRNAs (miRNAs) have shown strong effects on asthma and inflammatory processes. Objective: The purpose of this study was to identify key associations between circulating miRNAs and ICS response in childhood asthma. Methods: Small RNA sequencing in peripheral blood serum from 580 children with asthma on ICS treatment from The Genetics of Asthma in Costa Rica Study (GACRS) was used to identify miRNAs associated with ICS response using generalized linear models. Replication was conducted in children on ICS from the Childhood Asthma Management Program (CAMP) cohort. The association between replicated miRNAs and the transcriptome of lymphoblastoid cell lines in response to a glucocorticoid was assessed. Results: The association study on the GACRS cohort identified 36 miRNAs associated with ICS response at 10% false discovery rate (FDR), three of which (miR-28-5p, miR-339-3p, and miR-432-5p) were in the same direction of effect and significant in the CAMP replication cohort. In addition, in vitro steroid response lymphoblastoid gene expression analysis revealed 22 dexamethasone responsive genes were significantly associated with three replicated miRNAs. Furthermore, Weighted Gene Co-expression Network Analysis (WGCNA) revealed a significant association between miR-339-3p and two modules (black and magenta) of genes associated with immune response and inflammation pathways. Conclusion: This study highlighted significant association between circulating miRNAs miR-28-5p, miR-339-3p, and miR-432-5p and ICS response. miR-339-3p may be involved in immune dysregulation, which leads to a poor response to ICS treatment. Full article

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. Full article

Shifts in the maternal gut microbiome and vitamin D deficiency during pregnancy have been associated, separately, with health problems for both the mother and the child. Yet, they have rarely been studied simultaneously. Here, we analyzed the gut microbiome (from stool samples obtained in late pregnancy) and vitamin D level (from blood samples obtained both in early and late pregnancy) data of pregnant women in the Vitamin D Antenatal Asthma Reduction Trial (VDAART), a randomized controlled trial of vitamin D supplementation during pregnancy, to investigate the association of vitamin D status on the pregnant women’s microbiome. To find associations, we ran linear regressions on alpha diversity measures, PERMANOVA tests on beta diversity distances, and used the ANCOM-BC and Maaslin2 algorithms to find differentially abundant taxa. Analyses were deemed significant using a cut-off p-value of 0.05. We found that gut microbiome composition is associated with the vitamin D level in early pregnancy (baseline), the maternal gut microbiome does not show a shift in response to vitamin D supplementation during pregnancy, and that the genus Desulfovibrio is enriched in women without a substantial increase in vitamin D level between the first and the third trimesters of pregnancy. We conclude that increasing the vitamin D level during pregnancy could be protective against the growth of sulfate-reducing bacteria such as Desulfovibrio, which has been associated with chronic intestinal inflammatory disorders. More in-depth investigations are needed to confirm this hypothesis. Full article

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. Full article

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 (P_interaction = 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. Full article

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. Full article

Recurrent respiratory infections are a leading cause of morbidity and mortality in early life, but there is no broadly accepted means to identify infection-prone children during this highly vulnerable period. In this study, we investigated associations between steroid metabolites and incident respiratory infections in two pre-birth cohorts to identify novel metabolomic signatures of early infection proneness. Children from the Vitamin D Antenatal Asthma Reduction Trial and the Copenhagen Prospective Studies on Asthma in Childhood were included, and profiling was performed on plasma samples collected at ages 1 and 6 years. Both cohorts recorded incidence of lower respiratory infections, upper respiratory infections, ear infections, and colds. Poisson regression analysis assessed the associations between 18 steroid metabolites and the total number of respiratory infections that occurred in offspring during follow-up. We found that steroid metabolites across androgenic, corticosteroid, pregnenolone, and progestin classes were reduced in children that suffered more infections, and these patterns persisted at age 6 years, generally reflecting consistency in direction of effect and significance. Our analysis suggested steroid metabolite measurement may be useful in screening for infection proneness during this critical developmental period. Future studies should clinically evaluate their potential utility as a clinical screening tool. Full article

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. Full article

Aberrant remodeling of the asthmatic airway is not well understood but is thought to be attributable in part to mechanical compression of airway epithelial cells. Here, we examine compression-induced expression and secretion of the extracellular matrix protein tenascin C (TNC) from well-differentiated primary human bronchial epithelial (HBE) cells grown in an air–liquid interface culture. We measured TNC mRNA expression using RT-qPCR and secreted TNC protein using Western blotting and ELISA. To determine intracellular signaling pathways, we used specific inhibitors for either ERK or TGF-β receptor, and to assess the release of extracellular vesicles (EVs) we used a commercially available kit and Western blotting. At baseline, secreted TNC protein was significantly higher in asthmatic compared to non-asthmatic cells. In response to mechanical compression, both TNC mRNA expression and secreted TNC protein was significantly increased in both non-asthmatic and asthmatic cells. TNC production depended on both the ERK and TGF-β receptor pathways. Moreover, mechanically compressed HBE cells released EVs that contain TNC. These data reveal a novel mechanism by which mechanical compression, as is caused by bronchospasm, is sufficient to induce the production of ECM protein in the airway and potentially contribute to airway remodeling. Full article

Vitamin D deficiency and elevated high sensitivity C-reactive protein (hs-CRP) have been associated with several health outcomes, but knowledge on early life trajectories and association between 25 hydroxyvitamin D (25(OH)D) and hs-CRP is lacking. We investigated the association between longitudinal measurements of 25(OH)D and hs-CRP, respectively, from pregnancy to childhood and throughout childhood in two Danish mother–child cohorts—the COPSAC₂₀₁₀ and COPSAC₂₀₀₀. In COPSAC₂₀₁₀, there was an association between 25(OH)D concentrations at week 24 in pregnancy and at age 6 months in childhood (n = 633): estimate (95% CI); 0.114 (0.041;0.187), p = 0.002, and between 25(OH)D at age 6 months and 6 years (n = 475): 0.155 (0.083;0.228), p < 0.001. This was also demonstrated in the COPSAC₂₀₀₀ cohort between 25(OH)D concentrations in cord blood and at age 4 years (n = 188): 0.294 (0.127;0.461), p < 0.001 and at age 6 months and 4 years (n = 264): 0.260 (0.133;0.388), p < 0.001. In COPSAC₂₀₀₀, we also found an association between hs-CRP at age 6 months and 12 years in childhood (n = 232): 0.183 (0.076;0.289), p < 0.001. Finally, we found a negative association between the cross-sectional measurements of 25(OH)D and hs-CRP at age 6 months (n = 613) in COPSAC₂₀₁₀: −0.004 (−0.008;−0.0004), p = 0.030, but this was not replicated in COPSAC₂₀₀₀. In this study, we found evidence of associations across timepoints of 25(OH)D concentrations from mid-pregnancy to infancy and through childhood and associations between hs-CRP levels during childhood, although with weak correlations. We also found a negative cross-sectional association between 25(OH)D and hs-CRP concentrations in COPSAC₂₀₁₀ proposing a role of vitamin D in systemic low-grade inflammation, though this association was not present in COPSAC₂₀₀₀. Full article

Metabolomic indicators of asthma treatment responses have yet to be identified. In this study, we aimed to uncover plasma metabolomic profiles associated with asthma exacerbations while on inhaled corticosteroid (ICS) treatment. We determined whether these profiles change with age from adolescence to adulthood. We utilized data from 170 individuals with asthma on ICS from the Mass General Brigham Biobank to identify plasma metabolites associated with asthma exacerbations while on ICS and examined potential effect modification of metabolite-exacerbation associations by age. We used liquid chromatography–high-resolution mass spectrometry-based metabolomic profiling. Sex-stratified analyses were also performed for the significant associations. The age range of the participating individuals was 13–43 years with a mean age of 33.5 years. Of the 783 endogenous metabolites tested, eight demonstrated significant associations with exacerbation after correction for multiple comparisons and adjusting for potential confounders (Bonferroni p value < 6.2 × 10⁻⁴). Potential effect modification by sex was detected for fatty acid metabolites, with males showing a greater reduction in their metabolite levels with ICS exacerbation. Thirty-eight metabolites showed suggestive interactions with age on exacerbation (nominal p-value < 0.05). Our findings demonstrate that plasma metabolomic profiles differ for individuals who experience asthma exacerbations while on ICS. The differentiating metabolites may serve as biomarkers of ICS response and may highlight metabolic pathways underlying ICS response variability. Full article

Genome-wide association studies (GWAS) of response to asthma medications have primarily focused on Caucasian populations, with findings that may not be generalizable to minority populations. We derived a polygenic risk score (PRS) for response to albuterol as measured by bronchodilator response (BDR), and examined the PRS in a cohort of Hispanic school-aged children with asthma. We leveraged a published GWAS of BDR to identify relevant genetic variants, and ranked the top variants according to their Combined Annotation Dependent Depletion (CADD) scores. Variants with CADD scores greater than 10 were used to compute the PRS. Once we derived the PRS, we determined the association of the PRS with BDR in a cohort of Hispanic children with asthma (the Genetics of Asthma in Costa Rica Study (GACRS)) in adjusted linear regression models. Mean BDR in GACRS participants was5.6% with a standard deviation of 10.2%. We observed a 0.63% decrease in BDR in response to albuterol for a standard deviation increase in the PRS (p = 0.05). We also observed decreased odds of a BDR response at or above the 12% threshold for a one standard deviation increase in the PRS (OR = 0.80 (95% CI 0.67 to 0.95)). Our findings show that combining variants from a pharmacogenetic GWAS into a PRS may be useful for predicting medication response in asthma. Full article

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. Full article