Showing papers by "National Jewish Health published in 2017"

Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets

Abstract: Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (∼6 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 × 10(-49)), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.

Cognitive Behavioral Insomnia Therapy for Those With Insomnia and Depression: A Randomized Controlled Clinical Trial

Abstract: Study objective To compare cognitive behavioral therapy for insomnia (CBT-I) + antidepressant medication (AD) against treatments that target solely depression or solely insomnia. Design A blinded, randomized split-plot experimental study. Setting Two urban academic clinical centers. Participants 107 participants (68% female, mean age 42 ± 11) with major depressive disorder and insomnia. Interventions Randomization was to one of three groups: antidepressant (AD; escitalopram) + CBT-I (4 sessions), CBT-I + placebo pill, or AD + 4-session sleep hygiene control (SH). Measurements and results Subjective sleep was assessed via 2 weeks of daily sleep diaries (use of medication was covaried in all analyses); although there were no statistically significant group differences detected, all groups improved from baseline to posttreatment on subjective sleep efficiency (SE) and total wake time (TWT) and the effect sizes were large. Objective sleep was assessed via overnight polysomnographic monitoring at baseline and posttreatment; analyses revealed both CBT groups improved on TWT (p = .03), but the AD + SH group worsened. There was no statistically significant effect for PSG SE (p = .07). There was a between groups medium effect observed for the AD + SH and CBT + placebo group differences on diary TWT and both PSG variables. All groups improved significantly from baseline to posttreatment on the Hamilton Rating Scale for Depression (HAMD-17); the groups did not differ. Conclusions Although all groups self-reported sleeping better after treatment, only the CBT-I groups improved on objective sleep, and AD + SH's sleep worsened. This suggests that we should be treating sleep in those with depression with an effective insomnia treatment and relying on self-report obscures sleep worsening effects. All groups improved on depression, even a group with absolutely no depression-focused treatment component (CBT-I + placebo). The depression effect in CBT-I only group has been reported in other studies, suggesting that we should further investigate the antidepressant properties of CBT-I.

Helicity and Vorticity of Pulmonary Arterial Flow in Patients With Pulmonary Hypertension: Quantitative Analysis of Flow Formations.

Abstract: BackgroundQualitative and quantitative flow hemodynamic indexes have been shown to reflect right ventricular (RV) afterload and function in pulmonary hypertension (PH). We aimed to quantify flow he...

A Genome-wide Association and Admixture Mapping Study of Bronchodilator Drug Response in African Americans with Asthma

Abstract: Background: Short-acting B2-adrenergic receptor agonists (SABAs) are the most commonly prescribed asthma medications worldwide. Response to SABAs is measured as bronchodilator drug response (BDR), which varies among racial/ethnic groups in the U.S. However, the genetic variation that contributes to BDR is largely undefined in African Americans with asthma. Objective: To identify genetic variants that may contribute to differences in BDR in African Americans with asthma. Methods: We performed a genome-wide association study of BDR in 949 African American children with asthma, genotyped with the Axiom World Array 4 (Affymetrix, Santa Clara, CA) followed by imputation using 1000 Genomes phase 3 genotypes. We used linear regression models adjusting for age, sex, body mass index and genetic ancestry to test for an association between BDR and genotype at single nucleotide polymorphisms (SNPs). To increase power and distinguish between shared vs. population-specific associations with BDR in children with asthma, we performed a meta-analysis across 949 African Americans and 1,830 Latinos (Total=2,779). Lastly, we performed genome-wide admixture mapping to identify regions whereby local African or European ancestry is associated with BDR in African Americans. Two additional populations of 416 Latinos and 1,325 African Americans were used to replicate significant associations. Results: We identified a population-specific association with an intergenic SNP on chromosome 9q21 that was significantly associated with BDR (rs73650726, p=7.69x10-9). A trans-ethnic meta-analysis across African Americans and Latinos identified three additional SNPs within the intron of PRKG1 that were significantly associated with BDR (rs7903366, rs7070958, and rs7081864, p≤5x10-8). Conclusions: Our findings indicate that both population specific and shared genetic variation contributes to differences in BDR in minority children with asthma, and that the genetic underpinnings of BDR may differ between racial/ethnic groups.

Alternative pre-mRNA splicing of Toll-like receptor signaling components in peripheral blood mononuclear cells from patients with ARDS.

Abstract: A key physiological feature of acute respiratory distress syndrome (ARDS) is inflammation. Toll-like receptor (TLR) signaling is required to combat the infection that underlies many ARDS cases but ...

Genetic architecture drives seasonal onset of hibernation in the 13-lined ground squirrel

Abstract: Hibernation is a highly dynamic phenotype whose timing, for many mammals, is controlled by a circannual clock and accompanied by rhythms in body mass and food intake. When housed in an animal facility, 13-lined ground squirrels exhibit individual variation in the seasonal onset of hibernation, which is not explained by environmental or biological factors, such as body mass and sex. We hypothesized that underlying genetic architecture instead drives variation in this timing. After first increasing the contiguity of the genome assembly, we therefore employed a genotype-by-sequencing approach to characterize genetic variation in 153 13-lined ground squirrels. Combining this with datalogger records, we estimated high heritability (61-100%) for the seasonal onset of hibernation. After applying a genome-wide scan with 46,996 variants, we also identified 21 loci significantly associated with hibernation immergence, which alone accounted for 54% of the variance in the phenotype. The most significant marker (SNP 15, p=3.81x10−6) was located near prolactin-releasing hormone receptor (PRLHR), a gene that regulates food intake and energy homeostasis. Other significant loci were located near genes functionally related to hibernation physiology, including muscarinic acetylcholine receptor M2 (CHRM2), involved in the control of heart rate, exocyst complex component 4 (EXOC4) and prohormone convertase 2 (PCSK2), both of which are involved in insulin signaling and processing. Finally, we applied an expression quantitative loci (eQTL) analysis using existing transcriptome datasets, and we identified significant (q

MUC18 regulates IL-13-mediated airway inflammatory response

Abstract: To evaluate the effects of MUC18 on IL-13-mediated airway inflammatory responses in human airway epithelial cells and in mice. Primary normal human tracheobronchial epithelial (HTBE) cells, wild-type (WT) and Muc18 knockout (KO) mice, and mouse tracheal epithelial cells (mTECs) were utilized. Cultured HTBE cells treated with MUC18 siRNA or MUC18 expressing lentivirus were incubated with IL-13 (10 ng/mL) for 24 h. Mice were intranasally instilled with 500 ng of IL-13 for 3 days. mTECs were treated with IL-13 (10 ng/mL) for 3 days. PCR was used to measure mRNA expression. Western Blot and ELISAs were used to quantify protein expression. Cytospins of bronchoalveolar lavage (BAL) cells were used to obtain leukocyte differentials. MUC18 siRNA reduced IL-13-mediated eotaxin-3 (183 ± 44 vs. 380 ± 59 pg/mL, p < 0.05), while MUC18 overexpression increased IL-13-mediated eotaxin-3 (95 ± 3 vs. 58 ± 3 pg/mL, p < 0.05) in HTBE cells. IL-13-treated Muc18 KO mice had a lower percentage of neutrophils in BAL than WT mice (25 ± 3 vs. 35 ± 3%, p = 0.0565). These results implicate MUC18 as a potential enhancer of airway inflammation in a type 2 cytokine (e.g., IL-13) milieu.

Sox4 drives intestinal secretory differentiation toward tuft and enteroendocrine fates

Abstract: Intestinal stem cells (ISCs) undergo differentiation following reduction of Notch signaling and activation of Atoh1, a master regulator of secretory fate. However, recent evidence suggests that rare tuft cells may differentiate via alternative mechanisms. Here, we examine the role of Sox4 in ISC fate decisions. Loss of Sox4 results in disruption of ISC function and secretory differentiation, including decreased numbers of enteroendocrine and tuft cells. Sox4 is activated following reduction of Notch signaling and required for response to signals that induce tuft cell hyperplasia, including IL-13 and parasitic helminth infection. Subsets of Sox4+ progenitors are transcriptomically similar to both actively dividing and mature tuft cells, and dissimilar from other secretory progenitors expressing Atoh1. Our data suggest that Sox4 drives an alternative, Notch-repressed secretory differentiation pathway independently of Atoh1, and challenge the status of Atoh1 as the sole initiator of secretory fate in the intestine.

Systems and methods for automatic detection and quantification of pathology using dynamic feature classification

Abstract: Methods, devices, and systems are provided for quantifying an extent of various pathology patterns in scanned subject images. The detection and quantification of pathology is performed automatically and unsupervised via a trained system. The methods, devices, and systems described herein generate unique dictionaries of elements based on actual image data scans to automatically identify pathology of new image data scans of subjects. The automatic detection and quantification system can detect a number of pathologies including a usual interstitial pneumonia pattern on computed tomography images, which is subject to high inter-observer variation, in the diagnosis of idiopathic pulmonary fibrosis.

Integrative genomics analysis identifies ACVR1B as a candidate causal gene of emphysema distribution in non-alpha 1-antitrypsin deficient smokers

Abstract: Background: Upper lobe predominant emphysema is an important predictor of the response to lung volume reduction procedures. Several genetic risk loci associated with emphysema distribution have been identified through genome-wide association studies (GWAS). To further characterize these associations, we performed functional evaluations of the identified SNPs using available resources of expression quantitative trait loci (eQTL) and cell-type-specific epigenomic annotations. Results: SNPs with P-values <5x10-5 in the largest current GWAS meta-analysis of emphysema distribution in smokers (Boueiz A. et al, AJRCCM 2017) were analyzed. 99 distinct emphysema distribution-associated loci had significant associations with multi-tissue eQTL from the Genotype-Tissue Expression (GTEx) project and whole blood eQTL from the COPDGene study at FDR 10%. 14 of these loci showed strong evidence of one shared causal variant for emphysema distribution and an eQTL in multiple tissues (colocalization posterior probability ≥ 0.9). 17 Roadmap cell types exhibited enrichment in DNase-I hypersensitive peaks, DNaseI hotspots, enhancer marks, or digital DNaseI footprinting (P-value < 0.05), with the strongest enrichment observed in CD4+, CD8+, and regulatory T cells. A region near the ACVR1B gene demonstrated significant colocalization in lung eQTL and DNase-I hypersensitive region that is active in multiple cell types. Reporter assays confirmed allele-specific regulatory activity for the emphysema distribution-associated variant, rs7962469, near ACVR1B. Conclusions: This integrative analysis highlights candidate causal genes, regulatory variations, and specific cell types that may contribute to the pathogenesis of emphysema distribution. These findings will enable more accurate functional validation studies, better understanding of emphysema distribution biology, and ultimately, personalized patient care.

Systemic Markers of Adaptive and Innate Immunity Are Associated with COPD Severity and Spirometric Disease Progression

Abstract: The progression of chronic obstructive pulmonary disease (COPD) is associated with marked alterations in circulating immune cell populations, but no studies have characterized alterations in these cell types across the full spectrum of lung function impairment in current and former smokers. In 6,299 subjects from the COPDGene and ECLIPSE studies, we related Coulter blood counts and proportions to cross-sectional FEV1 adjusting for current smoking status. We also related cell count measures to three-year change in FEV1 in ECLIPSE subjects. In a subset of subjects with blood gene expression data, we used cell type deconvolution methods to infer the proportions of immune cell subpopulations, and we related these to COPD clinical status. We observed that FEV1 levels are positively correlated with lymphocytes and negatively correlated with myeloid populations such as neutrophils and monocytes. In multivariate models, cell counts and proportions were significantly associated with FEV1. We also observed that lymphocytes, monocytes, and eosinophil counts were predictive of three year change in lung function. Using cell type deconvolution to study immune cell subpopulations, we observed that subjects with COPD had a lower proportion of CD4+ resting memory cells and naive B cells compared to non-COPD smokers. Alterations in circulating immune cells in COPD support a mixed pattern of lymphocyte suppression and an enhanced myeloid cell immune response. Cell counts and proportions contribute independent information to models predicting lung function suggesting a critical role for immune response in long-term COPD outcomes. Cell type deconvolution is a promising method for immunophenotyping in large cohorts.

Post-GWAS Prioritization Through Data Integration Provides Novel Insights on Chronic Obstructive Pulmonary Disease.

Abstract: Rich collections of genomic and epigenomic annotations, availabilities of large population cohorts for genome-wide association studies (GWAS), and advancements in data integration techniques provide the unprecedented opportunity to accelerate discoveries in complex disease studies through integrative analyses. In this paper, we apply a variety of approaches to integrate GWAS summary statistics of chronic obstructive pulmonary disease (COPD) with functional annotations to illustrate how data integration could help researchers understand complex human diseases. We show that incorporating functional annotations can better prioritize GWAS signals at both the global and the local levels. Signal prioritization on severe COPD GWAS reveals multiple potential risk loci that are linked with pulmonary functions. Enrichment analysis provides novel insights on the pathogenesis of COPD and hints the existence of genetic contributions to muscle dysfuncion and chronic lung inflammation, two symptoms that are often co-morbid with COPD. Our results suggest that rich signals for COPD genetics are still buried under the Bonferroni-corrected genome-wide significance threshold. Many more biological findings are expected to emerge as more samples are recruited for COPD studies.

Methods of detecting and preventing atopic allergic diseases

Abstract: The present invention is related to novel methods for identifying a population of subjects that are at risk for developing of atopic allergic diseases, and to the prevention of these allergic diseases.

The Spectrum of Pulmonary Disease in COPD

Abstract: The pulmonary vascular disease component in COPD/emphysema has initially been described by A. Liebow at the dawn of emphysema research [1], and radiologists pointed out that vessel loss on the routine chest X-ray films was the best indicator of emphysema. Benjamin Burrows published the first systematic hemodynamic evaluation of patients with COPD and illustrated the great variability of pulmonary hypertension at rest and during exercise in these patients [2]. Since these early investigations, there have been additional remarkable observations. J. Barbera and coworkers [3] demonstrated histologically the presence of vascular abnormalities in chronic smokers without evidence of pulmonary hypertension (PH); the group of E. Weitzenblum reported severe PH in a subgroup of COPD patients [4] and H.J. Bogaard et al. described a severe reduction in the DLCO in their Dutch cohort of cigarette-smoking patients with idiopathic PH [5]. Finally, it has been recognized that a subset of patients with COPD and with interstitial pulmonary fibrosis has significant PH [6]. It thus appears that chronic cigarette abuse is the common denominator, which can explain an element—or “the element”—of the vascular disease component in a large number of patients with PH, and also that there is a spectrum of severity of PH and of lung vessel pathology.

The somatically generated T cell receptor CDR3a contributes to the MHC allele specificity of the T cell receptor

Abstract: Mature T cells bearing ab T cell receptors react with foreign antigens bound to alleles of major histocompatibility complex proteins (MHC) that they were exposed to during their development in the thymus, a phenomenon known as positive selection. The structural basis for positive selection has long been debated. Here, using mice expressing one of two different T cell receptor b chains and various MHC alleles, we show that positive selection-induced MHC bias of T cell receptors is affected both by the germline encoded elements of the T cell receptor a and b chain and, surprisingly, dramatically affected by the non germ line encoded CDR3 of the T cell receptor a chain. Thus, in addition to determining specificity for antigen, the non germline encoded elements of T cell receptors may help the proteins cope with the extremely polymorphic nature of major histocompatibility complex products within the species.

Methods for diagnosing and treating subjects for pulmonary exacerbation

Abstract: The present invention is related to novel methods for diagnosing and treating acute pulmonary exacerbation in subjects in need thereof.

Drug Resistance Assays for Mycobacterium tuberculosis

Abstract: Timely detection of patients harboring drug-resistant Mycobacterium tuberculosis strains is of paramount importance for effective treatment and also for preventing epidemics of drug-resistant tuberculosis. Bacteriologic methods currently in use for detection of drug resistance are the agar proportion method and the use of automated liquid medium systems. In addition, genotypic methods are increasingly employed as screening tests and complement conventional antimicrobial susceptibility testing. Accurate detection of clinically meaningful minimal inhibitory concentrations is the prerequisite for pharmacokinetic and pharmacodynamic correlations.

ICU complications of hematopoietic stem cell transplantation including graft versus host disease

Abstract: Hematopoietic stem cell transplant (HSCT) is a common procedure with an array of indications. While in the appropriate patient this therapy can be life-saving, it does come with a risk of significant complications, many of which might require intensive care unit (ICU) admission. Shock, altered mental status, renal failure and respiratory therapy can all occur. From a pulmonary standpoint, a host of etiologies for respiratory therapy have been observed. The common causes of pulmonary dysfunction include infection with bacteria, viruses, fungi or Mycobacteria as well as noninfectious conditions such as hemorrhage, Idiopathic Pneumonia Syndrome, and Broniolitis Obliterans Syndrome. The following chapter outlines in detail the common ICU complications of HSCT including presentation, diagnosis and therapy.

Methods for treating and preventing allergies and acute allergic responses

Abstract: The present invention relates to methods and compositions for treating and/or preventing allergic diseases and/or conditions, as well as for preventing acute allergic responses by administering a therapeutically effective amount of 1,25-dihydroxy vitamin D3 (1,25D3).

Treatment of Interstitial Lung Disease

Abstract: Pulmonary disease is the leading cause of hospitalizations and mortality in patients with systemic sclerosis (SSc). This chapter will discuss the management of ILD in SSc with a focus on whom to treat, what pharmacological therapies to use, and how long to use them. Previous chapters in this textbook have discussed the pathogenesis of SSc-ILD in detail.