Divya Chhabra - Academia.edu (original) (raw)

Papers by Divya Chhabra

Table S1. List of the core set of 262 genes from differential expression analysis and GSEA. (DOCX... more Table S1. List of the core set of 262 genes from differential expression analysis and GSEA. (DOCX 15Â kb)

Pediatric Research, 2021

Background: Chronic lung disease (CLD) is the most common pulmonary morbidity in extremely preter... more Background: Chronic lung disease (CLD) is the most common pulmonary morbidity in extremely preterm infants. It is unclear to what extent prenatal exposures influence the risk of CLD. Epigenetic variation in placenta DNA methylation may be associated with differential risk of CLD, and these association may be dependent upon sex. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Respiratory Medicine, 2021

Background Previous gene expression studies have identified genes IFNγ, TNFα, RNase 3, CXCL9, and... more Background Previous gene expression studies have identified genes IFNγ, TNFα, RNase 3, CXCL9, and CD55 as potential biomarkers for sarcoidosis and/or chronic beryllium disease (CBD). We hypothesized that differential expression of these genes could function as diagnostic biomarkers for sarcoidosis and CBD, and prognostic biomarkers for sarcoidosis. Study Design/Methods We performed RT-qPCR on whole blood samples from CBD (n = 132), beryllium sensitized (BeS) (n = 109), and sarcoidosis (n = 99) cases and non-diseased controls (n = 97) to determine differential expression of target genes. We then performed logistic regression modeling and generated ROC curves to determine which genes could most accurately differentiate: 1) CBD versus sarcoidosis 2) CBD versus BeS 3) sarcoidosis versus controls 4) non-progressive versus progressive sarcoidosis. Results CD55 and TNFα were significantly upregulated, while CXCL9 was significantly downregulated in CBD compared to sarcoidosis (p < 0.05). The ROC curve from the logistic regression model demonstrated high discriminatory ability of the combination of CD55, TNFα, and CXCL9 to distinguish between CBD and sarcoidosis with an AUC of 0.98. CD55 and TNFα were significantly downregulated in sarcoidosis compared to controls (p < 0.05). The ROC curve from the model showed a reasonable discriminatory ability of CD55 and TNFα to distinguish between sarcoidosis and controls with an AUC of 0.86. There was no combination of genes that could accurately differentiate between CBD and BeS or sarcoidosis phenotypes. Interpretation CD55, TNFα and CXCL9 expression levels can accurately differentiate between CBD and sarcoidosis, while CD55 and TNFα expression levels can accurately differentiate sarcoidosis and controls.

Healthcare, 2020

Background: In utero smoke (IUS) exposure is associated with asthma susceptibility. Objective: We... more 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-conceptio...

Biological systems are increasingly being studied by high throughput profiling of molecular data ... more Biological systems are increasingly being studied by high throughput profiling of molecular data over time. Determining the set of time points to sample in studies that profile several different types of molecular data is still challenging. Here we present the Time Point Selection (TPS) method that solves this combinatorial problem in a principled and practical way. TPS utilizes expression data from a small set of genes sampled at a high rate. As we show by applying TPS to study mouse lung development, the points selected by TPS can be used to reconstruct an accurate representation for the expression values of the non selected points. Further, even though the selection is only based on gene expression, these points are also appropriate for representing a much larger set of protein, miRNA and DNA methylation changes over time. TPS can thus serve as a key design strategy for high throughput time series experiments. Supporting Website: www.sb.cs.cmu.edu/TPS

American Journal of Physiology-Lung Cellular and Molecular Physiology, 2019

A comprehensive understanding of the dynamic regulatory networks that govern postnatal alveolar l... more A comprehensive understanding of the dynamic regulatory networks that govern postnatal alveolar lung development is still lacking. To construct such a model, we profiled mRNA, microRNA, DNA methylation, and proteomics of developing murine alveoli isolated by laser capture microdissection at 14 predetermined time points. We developed a detailed comprehensive and interactive model that provides information about the major expression trajectories, the regulators of specific key events, and the impact of epigenetic changes. Intersecting the model with single-cell RNA-Seq data led to the identification of active pathways in multiple or individual cell types. We then constructed a similar model for human lung development by profiling time-series human omics data sets. Several key pathways and regulators are shared between the reconstructed models. We experimentally validated the activity of a number of predicted regulators, leading to new insights about the regulation of innate immunity d...

Environmental health : a global access science source, Nov 3, 2016

Exposure to air pollution, including traffic-related pollutants, has been associated with a varie... more Exposure to air pollution, including traffic-related pollutants, has been associated with a variety of adverse health outcomes, including increased cardiopulmonary morbidity and mortality, and increased lung cancer risk. To better understand the cellular responses induced by air pollution exposures, we performed genome-wide gene expression microarray analysis using whole blood RNA sampled at three time-points across the work weeks of 63 non-smoking employees at 10 trucking terminals in the northeastern US. We defined genes and gene networks that were differentially activated in response to PM2.5 (particulate matter ≤ 2.5 microns in diameter) and elemental carbon (EC) and organic carbon (OC). Multiple transcripts were strongly associated (padj < 0.001) with pollutant levels (48, 260, and 49 transcripts for EC, OC, and PM2.5, respectively), including 63 that were statistically significantly correlated with at least two out of the three exposures. These genes included many that have...

The Journal of clinical investigation, Dec 1, 2016

Low vitamin D status in pregnancy was proposed as a risk factor of preeclampsia. We assessed the ... more Low vitamin D status in pregnancy was proposed as a risk factor of preeclampsia. We assessed the effect of vitamin D supplementation (4,400 vs. 400 IU/day), initiated early in pregnancy (10-18 weeks), on the development of preeclampsia. The effects of serum vitamin D (25-hydroxyvitamin D [25OHD]) levels on preeclampsia incidence at trial entry and in the third trimester (32-38 weeks) were studied. We also conducted a nested case-control study of 157 women to investigate peripheral blood vitamin D-associated gene expression profiles at 10 to 18 weeks in 47 participants who developed preeclampsia. Of 881 women randomized, outcome data were available for 816, with 67 (8.2%) developing preeclampsia. There was no significant difference between treatment (N = 408) or control (N = 408) groups in the incidence of preeclampsia (8.08% vs. 8.33%, respectively; relative risk: 0.97; 95% CI, 0.61-1.53). However, in a cohort analysis and after adjustment for confounders, a significant effect of su...

PLOS ONE, 2016

The role of Vitamin D in the transcriptional program of human pregnancy Supporting Information (S... more The role of Vitamin D in the transcriptional program of human pregnancy Supporting Information (S1 Table) S1 Table Maternal differentially expressed genes between 1st and 3rd trimester of pregnancy (FDR < 0.05) Probe_ID uFlO1F07cIGqFJNTSU GENE SYMBOL

American journal of respiratory cell and molecular biology, Jun 19, 2015

The fetal origins of disease hypothesis suggests that variations in the course of prenatal lung d... more The fetal origins of disease hypothesis suggests that variations in the course of prenatal lung development may affect lifelong pulmonary function growth, decline and pathobiology. Many studies support the existence of differences in the developing lung trajectory in males and females, and sex specific differences in the prevalence of chronic lung diseases such as asthma and bronchopulmonary dysplasia (BPD). To investigate the early developing fetal lung for transcriptomic correlates of post conception age (maturity) and sex, and their associations with chronic lung diseases. We analyzed whole lung transcriptome profiles of 61 females and 78 males at 54-127 days post conception (dpc) from non-smoking mothers using unsupervised principal component analysis and supervised linear regression models. We identified dominant transcriptomic correlates for post conception age and sex with corresponding gene sets that were enriched for developing lung structural and functional ontologies. We ...

D51. STRANGE RANGERS IN THE ICU: SELECTED CASE REPORTS, 2010

B60. CARING FOR THE CRITICALLY ILL INFANT AND CHILD, 2011

A32. ASTHMA GENETICS AND GENOMICS, 2010

American Journal of Respiratory Cell and Molecular Biology, 2015

Antenatal corticosteroids enhance lung maturation. However, the importance of glucocorticoid gene... more Antenatal corticosteroids enhance lung maturation. However, the importance of glucocorticoid genes on early lung development, asthma susceptibility, and treatment response remains unknown. We investigated whether glucocorticoid genes are important during lung development and their role in asthma susceptibility and treatment response. We identified genes that were differentially expressed by corticosteroids in two of three genomic datasets: lymphoblastoid cell lines of participants in the Childhood Asthma Management Program, a glucocorticoid chromatin immunoprecipitation/RNA sequencing experiment, or a murine model; these genes made up the glucocorticoid gene set (GCGS). Using gene expression profiles from 38 human fetal lungs and C57BL/6J murine fetal lungs, we identified developmental genes that were in the top 5% of genes contributing to the top three principal components (PCs) most highly associated with post-conceptional age. Glucocorticoid genes that were enriched in this set of developmental genes were then included in the developmental glucocorticoid gene set (DGGS). We then investigated whether glucocorticoid genes are important during lung development, and their role in asthma susceptibility and treatment response. A total of 232 genes were included in the GCGS. Analysis of gene expression demonstrated that glucocorticoid genes were enriched in lung development (P = 7.02 3 10 226). The developmental GCGS was enriched for genes that were differentially expressed between subjects with asthma and control subjects (P = 4.26 3 10 23) and were enriched after treatment of subjects with asthma with inhaled corticosteroids (P , 2.72 3 10 24). Our results show that glucocorticoid genes are overrepresented among genes implicated in fetal lung development. These genes influence asthma susceptibility and treatment response, suggesting their involvement in the early ontogeny of asthma.

B106. RESPIRATORY FAILURE IN CHILDREN, 2010

BMC medical genomics, Jan 13, 2015

BackgroundExacerbations of chronic obstructive pulmonary disease (COPD), characterized by acute d... more BackgroundExacerbations of chronic obstructive pulmonary disease (COPD), characterized by acute deterioration in symptoms, may be due to bacterial or viral infections, environmental exposures, or unknown factors. Exacerbation frequency may be a stable trait in COPD patients, which could imply genetic susceptibility. Observing the genes, networks, and pathways that are up- and down-regulated in COPD patients with differing susceptibility to exacerbations will help to elucidate the molecular signature and pathogenesis of COPD exacerbations.MethodsGene expression array and plasma biomarker data were obtained using whole-blood samples from subjects enrolled in the Treatment of Emphysema With a Gamma-Selective Retinoid Agonist (TESRA) study. Linear regression, weighted gene co-expression network analysis (WGCNA), and pathway analysis were used to identify signatures and network sub-modules associated with the number of exacerbations within the previous year; other COPD-related phenotypes...

Epigenetics, 2014

In utero smoke exposure has been shown to have detrimental effects on lung function and to be ass... more In utero smoke exposure has been shown to have detrimental effects on lung function and to be associated with persistent wheezing and asthma in children. One potential mechanism of IUS effects could be alterations in DNA methylation, which may have lifelong implications. The goal of this study was to examine the association between DNA methylation and nicotine exposure in fetal lung and placental tissue in early development; nicotine exposure in this analysis represents a likely surrogate for in-utero smoke. We performed an epigenome-wide analysis of DNA methylation in fetal lung tissue (n D 85, 41 smoke exposed (48%), 44 controls) and the corresponding placental tissue samples (n D 80, 39 smoke exposed (49%), 41 controls) using the Illumina HumanMethylation450 BeadChip array. Differential methylation analyses were conducted to evaluate the variation associated with nicotine exposure. The most significant CpG sites in the fetal lung analysis mapped to the PKP3 (P D 2.94 £ 10 ¡03), ANKRD33B (P D 3.12 £ 10 ¡03), CNTD2 (P D 4.9 £ 10 ¡03) and DPP10 (P D 5.43 £ 10 ¡03) genes. In the placental methylome, the most significant CpG sites mapped to the GTF2H2C and GTF2H2D genes (P D 2.87 £ 10 ¡06 ¡ 3.48 £ 10 ¡05). One hundred and one unique CpG sites with P-values < 0.05 were concordant between lung and placental tissue analyses. Gene Set Enrichment Analysis demonstrated enrichment of specific disorders, such as asthma and immune disorders. Our findings demonstrate an association between in utero nicotine exposure and variable DNA methylation in fetal lung and placental tissues, suggesting a role for DNA methylation variation in the fetal origins of chronic diseases.

A28. LUNG DEVELOPMENT: BENCH TO BEDSIDE, 2012

Thorax, 2014

Lung function tracks from the earliest age that it can be reliably measured. Genome wide associat... more Lung function tracks from the earliest age that it can be reliably measured. Genome wide association studies suggest that most variants identified for common complex traits are regulatory in function and active during fetal development. Fetal programming of gene expression during development is critical to the formation of a normal lung. An understanding of how fetal developmental genes related to diseases of the lungs and airways is a critical area for research. This review article considers the developmental origins hypothesis, the stages of normal lung development and a variety of environmental exposures that might influence the developmental process: in utero cigarette smoke exposure, vitamin D and folate. We conclude with some information on developmental genes and asthma.

Free Radical Research, 2007

Oxidative stress and mitochondrial damage occur in sepsis. Manganese superoxide dismutase (MnSOD)... more Oxidative stress and mitochondrial damage occur in sepsis. Manganese superoxide dismutase (MnSOD) provides the main defence against oxidative stress within mitochondria. Ala9Val is a single nucleotide polymorphism (SNP) in the MnSOD gene, predicted to affect intra-mitochondrial transport of the enzyme. We found a significant difference in the genotype frequency between healthy subjects (n = 100) and patients with sepsis (n = 40, p = 0.009). For assessment of functionality ten healthy subjects of each homozygous genotype (A/A or V/V) were studied. Peripheral blood mononuclear cells were separated and incubated for 18 h with lipopolysaccharide (LPS), followed by analysis of mitochondrial and cytosolic fractions. There was no difference between genotypes in MnSOD activity and cytochrome c concentration, and minor differences in total antioxidant capacity (TAC) and mitochondrial membrane potential, which did not affect response to LPS. Despite predictions from structural enzyme studies that mitochondrial trafficking would be affected by the Ala9Val polymorphism of the MnSOD gene had little functional effect.