المؤلفون: Lowe, Katherine E, Regan, Elizabeth A, Anzueto, Antonio, Austin, Erin, Austin, John HM, Beaty, Terri H, Benos, Panayiotis V, Benway, Christopher J, Bhatt, Surya P, Bleecker, Eugene R, Bodduluri, Sandeep, Bon, Jessica, Boriek, Aladin M, Boueiz, Adel Re, Bowler, Russell P, Budoff, Matthew, Casaburi, Richard, Castaldi, Peter J, Charbonnier, Jean-Paul, Cho, Michael H, Comellas, Alejandro, Conrad, Douglas, Costa Davis, Corinne, Criner, Gerard J, Curran-Everett, Douglas, Curtis, Jeffrey L, DeMeo, Dawn L, Diaz, Alejandro A, Dransfield, Mark T, Dy, Jennifer G, Fawzy, Ashraf, Fleming, Margaret, Flenaugh, Eric L, Foreman, Marilyn G, Fortis, Spyridon, Gebrekristos, Hirut, Grant, Sarah, Grenier, Philippe A, Gu, Tian, Gupta, Abhya, Han, MeiLan K, Hanania, Nicola A, Hansel, Nadia N, Hayden, Lystra P, Hersh, Craig P, Hobbs, Brian D, Hoffman, Eric A, Hogg, James C, Hokanson, John E, Hoth, Karin F, Hsiao, Albert, Humphries, Stephen, Jacobs, Kathleen, Jacobson, Francine L, Kazerooni, Ella A, Kim, Victor, Kim, Woo Jin, Kinney, Gregory L, Koegler, Harald, Lutz, Sharon M, Lynch, David A, MacIntye, Neil R, Make, Barry J, Marchetti, Nathaniel, Martinez, Fernando J, Maselli, Diego J, Mathews, Anne M, McCormack, Meredith C, McDonald, Merry-Lynn N, McEvoy, Charlene E, Moll, Matthew, Molye, Sarah S, Murray, Susan, Nath, Hrudaya, Newell, John D, Occhipinti, Mariaelena, Paoletti, Matteo, Parekh, Trisha, Pistolesi, Massimo, Pratte, Katherine A, Putcha, Nirupama, Ragland, Margaret, Reinhardt, Joseph M, Rennard, Stephen I, Rosiello, Richard A, Ross, James C, Rossiter, Harry B, Ruczinski, Ingo, San Jose Estepar, Raul, Sciurba, Frank C, Sieren, Jessica C, Singh, Harjinder, Soler, Xavier, Steiner, Robert M, Strand, Matthew J, Stringer, William W, Tal-Singer, Ruth, Thomashow, Byron, Vegas Sánchez-Ferrero, Gonzalo, Walsh, John W

المصدر: Chronic obstructive pulmonary diseases (Miami, Fla.). 6(5)

مصطلحات موضوعية: COPD Genetic Epidemiology study, preserved ratio-impaired spirometry, COPD diagnosis, COPD diagnosis, COPDGene, GOLD, Global initiative for chronic Obstructive Lung Dis, PRISm, chronic obstructive pulmonary disease, copd, preserved ratio-impaired spirometry, spirometry, Prevention, Tobacco Smoke and Health, Tobacco, Lung, Chronic Obstructive Pulmonary Disease, Biomedical Imaging, Clinical Research, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, Respiratory, Good Health and Well Being, COPD, COPD Genetic Epidemiology study, Global initiative for chronic Obstructive Lung Disease

الوصف: BackgroundChronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality. Present-day diagnostic criteria are largely based solely on spirometric criteria. Accumulating evidence has identified a substantial number of individuals without spirometric evidence of COPD who suffer from respiratory symptoms and/or increased morbidity and mortality. There is a clear need for an expanded definition of COPD that is linked to physiologic, structural (computed tomography [CT]) and clinical evidence of disease. Using data from the COPD Genetic Epidemiology study (COPDGene®), we hypothesized that an integrated approach that includes environmental exposure, clinical symptoms, chest CT imaging and spirometry better defines disease and captures the likelihood of progression of respiratory obstruction and mortality.MethodsFour key disease characteristics - environmental exposure (cigarette smoking), clinical symptoms (dyspnea and/or chronic bronchitis), chest CT imaging abnormalities (emphysema, gas trapping and/or airway wall thickening), and abnormal spirometry - were evaluated in a group of 8784 current and former smokers who were participants in COPDGene® Phase 1. Using these 4 disease characteristics, 8 categories of participants were identified and evaluated for odds of spirometric disease progression (FEV1 > 350 ml loss over 5 years), and the hazard ratio for all-cause mortality was examined.ResultsUsing smokers without symptoms, CT imaging abnormalities or airflow obstruction as the reference population, individuals were classified as Possible COPD, Probable COPD and Definite COPD. Current Global initiative for obstructive Lung Disease (GOLD) criteria would diagnose 4062 (46%) of the 8784 study participants with COPD. The proposed COPDGene® 2019 diagnostic criteria would add an additional 3144 participants. Under the new criteria, 82% of the 8784 study participants would be diagnosed with Possible, Probable or Definite COPD. These COPD groups showed increased risk of disease progression and mortality. Mortality increased in patients as the number of their COPD characteristics increased, with a maximum hazard ratio for all cause-mortality of 5.18 (95% confidence interval [CI]: 4.15-6.48) in those with all 4 disease characteristics.ConclusionsA substantial portion of smokers with respiratory symptoms and imaging abnormalities do not manifest spirometric obstruction as defined by population normals. These individuals are at significant risk of death and spirometric disease progression. We propose to redefine the diagnosis of COPD through an integrated approach using environmental exposure, clinical symptoms, CT imaging and spirometric criteria. These expanded criteria offer the potential to stimulate both current and future interventions that could slow or halt disease progression in patients before disability or irreversible lung structural changes develop.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/8qm9s0t0Test

المؤلفون: Han, Seong Kyu, McNulty, Michelle T., Benway, Christopher J., Wen, Pei, Greenberg, Anya, Onuchic-Whitford, Ana C., Jang, Dongkeun, Flannick, Jason, Burtt, Noël P., Wilson, Parker C., Humphreys, Benjamin D., Wen, Xiaoquan, Han, Zhe, Lee, Dongwon, Sampson, Matthew G.

المساهمون: U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases, U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute

المصدر: Nature Communications ; volume 14, issue 1 ; ISSN 2041-1723

مصطلحات موضوعية: General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry, Multidisciplinary

الوصف: Expression quantitative trait locus (eQTL) studies illuminate genomic variants that regulate specific genes and contribute to fine-mapped loci discovered via genome-wide association studies (GWAS). Efforts to maximize their accuracy are ongoing. Using 240 glomerular (GLOM) and 311 tubulointerstitial (TUBE) micro-dissected samples from human kidney biopsies, we discovered 5371 GLOM and 9787 TUBE genes with at least one variant significantly associated with expression (eGene) by incorporating kidney single-nucleus open chromatin data and transcription start site distance as an “integrative prior” for Bayesian statistical fine-mapping. The use of an integrative prior resulted in higher resolution eQTLs illustrated by (1) smaller numbers of variants in credible sets with greater confidence, (2) increased enrichment of partitioned heritability for GWAS of two kidney traits, (3) an increased number of variants colocalized with the GWAS loci, and (4) enrichment of computationally predicted functional regulatory variants. A subset of variants and genes were validated experimentally in vitro and using a Drosophila nephrocyte model. More broadly, this study demonstrates that tissue-specific eQTL maps informed by single-nucleus open chromatin data have enhanced utility for diverse downstream analyses.

الإتاحة: https://doi.org/10.1038/s41467-023-37691-7Test
https://www.nature.com/articles/s41467-023-37691-7.pdfTest
https://www.nature.com/articles/s41467-023-37691-7Test

المؤلفون: Moll, Matthew, Jackson, Victoria E., Yu, Bing, Grove, Megan L., London, Stephanie J., Gharib, Sina A., Bartz, Traci M., Sitlani, Colleen M., Dupuis, Josee, O'Connor, George T., Xu, Hanfei, Cassano, Patricia A., Kaufmann Patchen, Bonnie, Jin Kim, Woo, Park, Jinkyeong, Hee Kim, Kun, Han, Buhm, Barr, R. Graham, Manichaikul, Ani, Nguyen, Jennifer N., Rich, Stephen S., Lahousse, Lies, Terzikhan, Natalie, Brusselle, Guy, Sakornsakolpat, Phuwanat, Liu, Jiangyuan, Benway, Christopher J., Hall, Ian P., Tobin, Martin D., Wain, Louise V., Silverman, Edwin K., Cho, Michael H., Hobbs, Brian D.

المصدر: AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY ; ISSN: 1040-0605 ; ISSN: 1522-1504

مصطلحات موضوعية: Medicine and Health Sciences, Physiology (medical), Cell Biology, Physiology, Pulmonary and Respiratory Medicine, chronic obstructive pulmonary disease, exome, exon, functional, genomics, GENOME-WIDE ASSOCIATION, ZINC-FINGER PROTEIN, LUNG-FUNCTION, GENETIC ASSOCIATION, GENOTYPE, DESIGN, COPD, ATHEROSCLEROSIS, EXPRESSION, SMOKING

الوصف: Genome-wide association studies (GWASs) have identified regions associated with chronic obstructive pulmonary disease (COPD). GWASs of other diseases have shown an approximately 10-fold overrepresentation of nonsynonymous variants, despite limited exonic coverage on genotyping arrays. We hypothesized that a large-scale analysis of coding variants could discover novel genetic associations with COPD, including rare variants with large effect sizes. We performed a meta-analysis of exome arrays from 218,399 controls and 33,851 moderate-to-severe COPD cases. All exome-wide significant associations were present in regions previously identified by GWAS. We did not identify any novel rare coding variants with large effect sizes. Within GWAS regions on chromosomes 5q, 6p, and 15q, four coding variants were conditionally significant (p < 0.00015) when adjusting for lead GWAS SNPs. A common GSDMB splice variant (rs11078928) previously associated with decreased risk for asthma, was nominally associated with decreased risk for COPD (MAF = 0.46, p=1.8e-4). Two stop variants in CCHCR1, a gene involved in regulating cell proliferation, were associated with COPD (both p < 0.0001). The SERPINA1 Z allele was associated with a random effects odds ratio of 1.43 for COPD (95% CI: 1.17-1.74), though with marked heterogeneity across studies. Overall, COPD-associated exonic variants were identified in genes involved in DNA methylation, cell-matrix interactions, cell proliferation, and cell death. In conclusion, we performed the largest exome array meta-analysis of COPD to date and identified potential functional coding variants. Future studies are needed to identify rarer variants, and further define the role of coding variants in COPD pathogenesis.

وصف الملف: application/pdf

العلاقة: https://biblio.ugent.be/publication/8710108Test; http://hdl.handle.net/1854/LU-8710108Test; http://dx.doi.org/10.1152/ajplung.00009.2021Test; https://biblio.ugent.be/publication/8710108/file/8710110Test

الإتاحة: https://doi.org/10.1152/ajplung.00009.2021Test
https://biblio.ugent.be/publication/8710108Test
http://hdl.handle.net/1854/LU-8710108Test
https://biblio.ugent.be/publication/8710108/file/8710110Test

المؤلفون: Benway, Christopher J., Iacomini, John

المساهمون: Tufts University School of Medicine

المصدر: American Journal of Transplantation ; volume 18, issue 4, page 796-809 ; ISSN 1600-6135

مصطلحات موضوعية: Pharmacology (medical), Transplantation, Immunology and Allergy

الإتاحة: https://doi.org/10.1111/ajt.14503Test
https://api.elsevier.com/content/article/PII:S1600613522094874?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S1600613522094874?httpAccept=text/plainTest

المؤلفون: Lowe, Katherine E., Regan, Elizabeth A., Anzueto, Antonio, Austin, Erin, Austin, John H. M., Beaty, Terri H., Benos, Panayiotis V., Benway, Christopher J., Bhatt, Surya P., Bleecker, Eugene R., Bodduluri, Sandeep, Bon, Jessica, Boriek, Aladin M., Boueiz, Adel RE., Bowler, Russell P., Budoff, Matthew, Casaburi, Richard, Castaldi, Peter J., Charbonnier, Jean-Paul, Cho, Michael H., Comellas, Alejandro, Conrad, Douglas, Costa Davis, Corinne, Criner, Gerard J., Curran-Everett, Douglas, Curtis, Jeffrey L., DeMeo, Dawn L., Diaz, Alejandro A., Dransfield, Mark T., Dy, Jennifer G., Fawzy, Ashraf, Fleming, Margaret, Flenaugh, Eric L., Foreman, Marilyn G., Fortis, Spyridon, Gebrekristos, Hirut, Grant, Sarah, Grenier, Philippe A., Gu, Tian, Gupta, Abhya, Han, MeiLan K., Hanania, Nicola A., Hansel, Nadia N., Hayden, Lystra P., Hersh, Craig P., Hobbs, Brian D., Hoffman, Eric A., Hogg, James C., Hokanson, John E., Hoth, Karin F.

مصطلحات موضوعية: Original Research, envir, psy

الوصف: Background: Chronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality. Present-day diagnostic criteria are largely based solely on spirometric criteria. Accumulating evidence has identified a substantial number of individuals without spirometric evidence of COPD who suffer from respiratory symptoms and/or increased morbidity and mortality. There is a clear need for an expanded definition of COPD that is linked to physiologic, structural (computed tomography [CT]) and clinical evidence of disease. Using data from the COPD Genetic Epidemiology study (COPDGene(®)), we hypothesized that an integrated approach that includes environmental exposure, clinical symptoms, chest CT imaging and spirometry better defines disease and captures the likelihood of progression of respiratory obstruction and mortality. Methods: Four key disease characteristics – environmental exposure (cigarette smoking), clinical symptoms (dyspnea and/or chronic bronchitis), chest CT imaging abnormalities (emphysema, gas trapping and/or airway wall thickening), and abnormal spirometry – were evaluated in a group of 8784 current and former smokers who were participants in COPDGene(®) Phase 1. Using these 4 disease characteristics, 8 categories of participants were identified and evaluated for odds of spirometric disease progression (FEV(1) > 350 ml loss over 5 years), and the hazard ratio for all-cause mortality was examined. Results: Using smokers without symptoms, CT imaging abnormalities or airflow obstruction as the reference population, individuals were classified as Possible COPD, Probable COPD and Definite COPD. Current Global initiative for obstructive Lung Disease (GOLD) criteria would diagnose 4062 (46%) of the 8784 study participants with COPD. The proposed COPDGene(®) 2019 diagnostic criteria would add an additional 3144 participants. Under the new criteria, 82% of the 8784 study participants would be diagnosed with Possible, Probable or Definite COPD. These COPD groups showed increased risk of .

العلاقة: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020846Test/

الإتاحة: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020846Test/

المؤلفون: Benway, Christopher J., Jiangyuan Liu, Feng Guo, Fei Du, Randell, Scott H., Cho, Michael H., Silverman, Edwin K., Xiaobo Zhou

المصدر: American Journal of Respiratory Cell & Molecular Biology; Jul2021, Vol. 65 Issue 1, p92-102, 11p

مصطلحات موضوعية: GENOME-wide association studies, MOLECULAR epidemiology, OBSTRUCTIVE lung diseases, LUNG diseases, CHROMATIN

مستخلص: Genome-wide association studies (GWASs) have identified dozens of loci associated with risk of chronic obstructive pulmonary disease (COPD). However, identifying the causal variants and their functional role in the appropriate cell type remains a major challenge. We aimed to identify putative causal variants in 82 GWAS loci associated with COPD susceptibility and predict the regulatory impact of these variants in lung-cell types. We used an integrated approach featuring statistical fine mapping, open chromatin profiling, and machine learning to identify functional variants. We generated chromatin accessibility data using the Assay for Transposase-Accessible Chromatin with High-Throughput Sequencing (ATAC-seq) for human primary lung-cell types implicated in COPD pathobiology. We then evaluated the enrichment of COPD risk variants in lung-specific open chromatin regions and generated cell type-specific regulatory predictions for .6,500 variants corresponding to 82 COPD GWAS loci. Integration of the fine-mapped variants with lung open chromatin regions helped prioritize 22 variants in putative regulatory elements with potential functional effects. Comparison with functional predictions from 222 Encyclopedia of DNA Elements (ENCODE) cell samples revealed cell type-specific regulatory effects of COPD variants in the lung epithelium, endothelium, and immune cells. We identified potential causal variants for COPD risk by integrating fine mapping in GWAS loci with cell-specific regulatory profiling, highlighting the importance of leveraging the chromatin status in relevant cell types to predict the molecular effects of risk variants in lung disease. [ABSTRACT FROM AUTHOR]

: Copyright of American Journal of Respiratory Cell & Molecular Biology is the property of American Thoracic Society and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Yuan Hao, Bates, Samuel, Hongmei Mou, Yun, Jeong H., Betty Pham, Jiangyuan Liu, Weiliang Qiu, Feng Guo, Morrow, Jarrett D., Hersh, Craig P., Benway, Christopher J., Lu Gong, Yihan Zhang, Rosas, Ivan O., Cho, Michael H., Jin-Ah Park, Castaldi, Peter J., Fei Du, Xiaobo Zhou, Hao, Yuan

المصدر: American Journal of Respiratory & Critical Care Medicine; 11/1/2020, Vol. 202 Issue 9, p1225-1236, 12p

مصطلحات موضوعية: EPITHELIAL cells, GENE expression, CELL migration, CELL proliferation, IMMUNOPRECIPITATION, RESEARCH, SEQUENCE analysis, IDIOPATHIC pulmonary fibrosis, GENETICS, RESEARCH methodology, CYTOSKELETAL proteins, EVALUATION research, MEDICAL cooperation, COMPARATIVE studies, RESEARCH funding

مستخلص: Rationale: Genetic association studies have identified rs2076295 in association with idiopathic pulmonary fibrosis (IPF). We hypothesized that rs2076295 is the functional variant regulating DSP (desmoplakin) expression in human bronchial epithelial cells, and DSP regulates extracellular matrix-related gene expression and cell migration, which is relevant to IPF development.Objectives: To determine whether rs2076295 regulates DSP expression and the function of DSP in airway epithelial cells.Methods: Using CRISPR (clustered regularly interspaced short palindromic repeat)/Cas9 editing (including regional deletion, indel, CRISPR interference, and single-base editing), we modified rs2076295 and measured DSP expression in edited 16HBE14o- and primary airway epithelial cells. Cellular integrity, migration, and genome-wide gene expression changes were examined in 16HBE14o- single colonies with DSP knockout. The expression of DSP and its relevant matrix genes was measured by quantitative PCR and also analyzed in single-cell RNA-sequencing data from control and IPF lungs.Measurements and Main Results:DSP is expressed predominantly in bronchial and alveolar epithelial cells, with reduced expression in alveolar epithelial cells in IPF lungs. The deletion of the DNA region-spanning rs2076295 led to reduced expression of DSP, and the edited rs2076295GG 16HBE14o- line has lower expression of DSP than the rs2076295TT lines. Knockout of DSP in 16HBE14o- cells decreased transepithelial resistance but increased cell migration, with increased expression of extracellular matrix-related genes, including MMP7 and MMP9. Silencing of MMP7 and MMP9 abolished increased migration in DSP-knockout cells.Conclusions: rs2076295 regulates DSP expression in human airway epithelial cells. The loss of DSP enhances extracellular matrix-related gene expression and promotes cell migration, which may contribute to the pathogenesis of IPF. [ABSTRACT FROM AUTHOR]

: Copyright of American Journal of Respiratory & Critical Care Medicine is the property of American Thoracic Society and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Ragland, Margaret F., Benway, Christopher J., Lutz, Sharon M., Bowler, Russell P., Hecker, Julian, Hokanson, John E., Crapo, James D., Castaldi, Peter J., DeMeo, Dawn L., Hersh, Craig P., Hobbs, Brian D., Lange, Christoph, Beaty, Terri H., Cho, Michael H., Silverman, Edwin K.

المصدر: American Journal of Respiratory & Critical Care Medicine; 9/15/2019, Vol. 200 Issue 6, p677-690, 14p

مصطلحات موضوعية: OBSTRUCTIVE lung diseases, BRONCHITIS, EPIDEMIOLOGY, HYPOXEMIA, DISEASE susceptibility, GENETIC epidemiology

مستخلص: Chronic obstructive pulmonary disease (COPD) is a common and progressive disease that is influenced by both genetic and environmental factors. For many years, knowledge of the genetic basis of COPD was limited to Mendelian syndromes, such as alpha-1 antitrypsin deficiency and cutis laxa, caused by rare genetic variants. Over the past decade, the proliferation of genome-wide association studies, the accessibility of whole-genome sequencing, and the development of novel methods for analyzing genetic variation data have led to a substantial increase in the understanding of genetic variants that play a role in COPD susceptibility and COPD-related phenotypes. COPDGene (Genetic Epidemiology of COPD), a multicenter, longitudinal study of over 10,000 current and former cigarette smokers, has been pivotal to these breakthroughs in understanding the genetic basis of COPD. To date, over 20 genetic loci have been convincingly associated with COPD affection status, with additional loci demonstrating association with COPD-related phenotypes such as emphysema, chronic bronchitis, and hypoxemia. In this review, we discuss the contributions of the COPDGene study to the discovery of these genetic associations as well as the ongoing genetic investigations of COPD subtypes, protein biomarkers, and post-genome-wide association study analysis. [ABSTRACT FROM AUTHOR]

: Copyright of American Journal of Respiratory & Critical Care Medicine is the property of American Thoracic Society and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)