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1. Unique and shared systemic biomarkers for emphysema in Alpha-1 Antitrypsin deficiency and chronic obstructive pulmonary disease

Author

K.A. Serban, K.A. Pratte, C. Strange, R.A. Sandhaus, A.M. Turner, T. Beiko, D.A. Spittle, L. Maier, N. Hamzeh, E.K. Silverman, B.D. Hobbs, C.P. Hersh, D.L. DeMeo, M.H. Cho, and R.P. Bowler

Subjects
SomaScan, Protein score, Emphysema, Plasma biomarker, Alpha-1 antitrypsin deficiency, Medicine, Medicine (General), R5-920
Abstract

Summary: Background: Alpha-1 Antitrypsin (AAT) deficiency (AATD), the most common genetic cause of emphysema presents with unexplained phenotypic heterogeneity in affected subjects. Our objectives to identify unique and shared AATD plasma biomarkers with chronic obstructive pulmonary disease (COPD) may explain AATD phenotypic heterogeneity. Methods: The plasma or serum of 5,924 subjects from four AATD and COPD cohorts were analyzed on SomaScan V4.0 platform. Using multivariable linear regression, inverse variance random-effects meta-analysis, and Least Absolute Shrinkage and Selection Operator (LASSO) regression we tested the association between 4,720 individual proteins or combined in a protein score with emphysema measured by 15th percentile lung density (PD15) or diffusion capacity (DLCO) in distinct AATD genotypes (Pi*ZZ, Pi*SZ, Pi*MZ) and non-AATD, PiMM COPD subjects. AAT SOMAmer accuracy for identifying AATD was tested using receiver operating characteristic curve analysis. Findings: In PiZZ AATD subjects, 2 unique proteins were associated with PD15 and 98 proteins with DLCO. Of those, 68 were also associated with DLCO in COPD also and enriched for three cellular component pathways: insulin-like growth factor, lipid droplet, and myosin complex. PiMZ AATD subjects shared similar proteins associated with DLCO as COPD subjects. Our emphysema protein score included 262 SOMAmers and predicted emphysema in AATD and COPD subjects. SOMAmer AAT level

Published
2022
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14. Race-Based Spirometry Under-Diagnoses COPD in African-American Smokers

Author

E.A. Regan, M.E. Lowe, J.L. Curtis, C. Wilson, R. Casaburi, A.K. Baldomero, A. Balasubramanian, M.C. Mccormack, K.A. Young, G.L. Kinney, G.R. Oates, K.F. Hoth, A.A. Diaz, Q.G. Chen, V. Kim, B.J. Make, J.K. O'Brien, J. Crooks, G.E. Westney, K. Lowe, N.A. Hanania, S. Watts, D.J. Conrad, H. Amaza, S.P. Bhatt, S. Fortis, A.J. Mamary, N. Putcha, M.G. Foreman, M.T. Dransfield, N.N. Hansel, D.L. Demeo, E.K. Silverman, J.D. Crapo, R.A. Wise, and null for the COPDGene Investigators

Published
2022
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16. gpuZoo: Cost-effective estimation of gene regulatory networks using the Graphics Processing Unit

Author

John Quackenbush, Ben Guebila M, Daniel Morgan, Kimberly Glass, Marieke L. Kuijjer, and D.L. DeMeo

Subjects
Regulation of gene expression, education.field_of_study, Computer science, Distributed computing, Population, Gene regulatory network, Graphics processing unit, Python (programming language), Gene regulatory network inference, MATLAB, education, computer, Implementation, computer.programming_language
Abstract

Gene regulatory network inference allows for the study of transcriptional control to identify the alteration of cellular processes in human diseases. Our group has developed several tools to model a variety of regulatory processes, including transcriptional (PANDA, SPIDER) and post-transcriptional (PUMA) gene regulation, and gene regulation in individual samples (LIONESS). These methods work by performing repeated operations on data matrices in order to integrate information across multiple lines of biological evidence. This limits their use for large-scale genomic studies due to the associated high computational burden. To address this limitation, we developed gpuZoo, which includes GPU-accelerated implementations of these algorithms. The runtime of the gpuZoo implementation in MATLAB and Python is up to 61 times faster and 28 times less expensive than the multi-core CPU implementation of the same methods. gpuZoo takes advantage of the modern multi-GPU device architecture to build a population of sample-specific gene regulatory networks with similar runtime and cost improvements by combining GPU acceleration with an efficient on-line derivation. Taken together, gpuZoo allows parallel and on-line gene regulatory network inference in large-scale genomic studies with cost-effective performance.gpuZoo is available in MATLAB through the netZooM package https://github.com/netZoo/netZooM and in Python through the netZooPy package https://github.com/netZoo/netZooPy.

Published
2021
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20. Mortality, Chronic Pain, and Opiate Use in the COPDGene Cohort

Author

G.L. Kinney, John E. Hokanson, Karin F. Hoth, B.J. Make, J.D. Crapo, D.L. DeMeo, Kendra A. Young, E.A. Regan, M.F. Ragland, and Katherine E Lowe

Subjects
medicine.medical_specialty, business.industry, Internal medicine, Cohort, medicine, Chronic pain, Opiate, business, medicine.disease
Published
2020
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24. Risk for Cognitive Impairment in Smokers with Preserved Ratio Impaired Spirometry- An Analysis of the COPDGene Cohort

Author

K. Hoth, C. Linkenmeyer, A.P. Comellas, P. Ten Eyck, J. Fiedorowicz, B.J. Make, E.A. Regan, E.A. Hoffman, J.D. Newell, G.L. Kinney, F.S. Wamboldt, N.A. Hanania, V. Kim, A.S. Iyer, S. Fortis, S.P. Bhatt, D.L. DeMeo, K.M. Kunisaki, B.E. Henkle, M.G. Foreman, A.M. Yohannes, E.K. Silverman, J.D. Crapo, and null For the COPDGene Investigators

Subjects
Spirometry, medicine.medical_specialty, medicine.diagnostic_test, business.industry, Internal medicine, Cohort, medicine, Cognitive impairment, business
Published
2020
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28. Genome-Wide Discovery of Modifiers of Lung Function in Severe Alpha-1 Antitrypsin Deficiency

Author

James K. Stoller, D.L. DeMeo, Mark L. Brantly, Auyon J. Ghosh, Alice M Turner, Stephen I. Rennard, Michael H. Cho, Edward K. Silverman, Robert A. Stockley, Brian D. Hobbs, C Strange, Gerard M. Turino, Noel G. McElvaney, Edward Eden, Dandi Qiao, E.J. Campbell, Alan F. Barker, and Robert A. Sandhaus

Subjects
Alpha 1-antitrypsin deficiency, Immunology, medicine, Biology, medicine.disease, Genome, Lung function
Published
2020
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32. X Chromosome Genetic Associations in COPD

Author

Christian E. Lange, Amund Gulsvik, David A. Lomas, Michael H. Cho, Lystra P. Hayden, Edward K. Silverman, Per Bakke, D.L. DeMeo, Nan M. Laird, and T.H. Beaty

Subjects
Genetics, COPD, medicine, Biology, medicine.disease, X chromosome
Published
2019
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36. Integrative Omics to Discover Novel Subtypes in a Chronic Obstructive Pulmonary Disease Lung Tissue Cohort

Author

Brian D. Hobbs, L. Chimakurthi, Yang-Yu Liu, Jarrett D. Morrow, D.L. DeMeo, Edward K. Silverman, Bartholome Celli, G.J. Criner, Raphael Bueno, Craig P. Hersh, Xiaoyun Wang, and Michael H. Cho

Subjects
Oncology, medicine.medical_specialty, Integrative omics, business.industry, Internal medicine, Cohort, medicine, Pulmonary disease, Lung tissue, business
Published
2019
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37. The Nasal Methylome as Biomarker of PM2.5 Exposure in Children

Author

Brent A. Coull, Diane R. Gold, Emily Oken, Joanne E. Sordillo, Andrea A. Baccarelli, D.L. DeMeo, Marie-France Hivert, Andres Cardenas, Kasey J. Brennan, Heike Luttmann-Gibson, Sheryl L. Rifas-Shiman, and Elena Colicino

Subjects
Oncology, medicine.medical_specialty, business.industry, Internal medicine, DNA methylation, medicine, General Earth and Planetary Sciences, Biomarker (medicine), business, General Environmental Science
Published
2018
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38. Integrative genomics analysis identifies ACVR1B as a candidate causal gene of emphysema distribution in non-alpha 1-antitrypsin deficient smokers

Author

Craig P. Hersh, Andrew Lamb, James D. Crapo, Adel El Boueiz, P. Castaldi, Margaret M. Parker, Michael H. Cho, E.K. Silverman, Robert P. Chase, Sool Lee, Naing Zzc, Andrew B. Stergachis, Ruth Tal-Singer, and D.L. DeMeo

Subjects
Genetics, 0303 health sciences, Colocalization, Genomics, Genome-wide association study, Single-nucleotide polymorphism, Biology, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Expression quantitative trait loci, Gene, 030304 developmental biology, Epigenomics, Genetic association
Abstract

BackgroundSeveral genetic risk loci associated with emphysema apico-basal distribution (EABD) have been identified through genome-wide association studies (GWAS), but the biological functions of these variants are unknown. To characterize gene regulatory functions of EABD-associated variants, we integrated EABD GWAS results with 1) a multi-tissue panel of expression quantitative trait loci (eQTL) from subjects with COPD and the GTEx project and 2) epigenomic marks from 127 cell types in the Roadmap Epigenomics project. Functional validation was performed for a variant near ACVR1B.ResultsSNPs from 168 loci with P-values-5 in the largest GWAS meta-analysis of EABD (Boueiz A. et al, AJRCCM 2017) were analyzed. 54 loci overlapped eQTL regions from our multi-tissue panel, and 7 of these loci showed a high probability of harboring a single, shared GWAS and eQTL causal variant (colocalization posterior probability≥0.9). 17 cell types exhibited greater than expected overlap between EABD loci and DNase-I hypersensitive peaks, DNaseI hotspots, enhancer marks, or digital DNaseI footprints (permutation P-value < 0.05), with the strongest enrichment observed in CD4+, CD8+, and regulatory T cells. A region near ACVR1B demonstrated significant colocalization with a lung eQTL and overlapped DNase-I hypersensitive regions in multiple cell types, and reporter assays in human bronchial epithelial cells confirmed allele-specific regulatory activity for the lead variant, rs7962469.ConclusionsIntegrative analysis highlights candidate causal genes, regulatory variants, and cell types that may contribute to the pathogenesis of emphysema distribution. These findings will enable more accurate functional validation studies and better understanding of emphysema distribution biology.

Published
2017
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39. Maternal alcohol consumption during pregnancy and offspring epigenome-wide DNA methylation: findings from six general population-based birth cohorts

Author

Sarah E. Reese, Sheryl L. Rifas-Shiman, Marie-France Hivert, Oken E, Liesbeth Duijts, Andrea A. Baccarelli, Gemma C Sharp, Luisa Zuccolo, Nystad W, Augusto A. Litonjua, Kimberley Burrows, Ryan Arathimos, Ching-Ti Liu, Leanne K. Küpers, Jaddoe, Magnus Mc, Christian M. Page, Harold Snieder, Shanshan Zhao, Corpeleijn E, London Sj, Caroline L Relton, D.L. DeMeo, and Janine F. Felix

Subjects
Genetics, Pregnancy, education.field_of_study, Offspring, Population, Physiology, Epigenome, Biology, medicine.disease, Differentially methylated regions, CpG site, DNA methylation, medicine, Epigenetics, education
Abstract

Some evidence suggests that light-to-moderate alcohol consumption during pregnancy is associated with adverse outcomes in the offspring, but the precise biological mechanisms underlying such associations are currently unknown. Epigenetic modifications have been suggested as one potential explanation.Within the Pregnancy and Childhood Epigenetics (PACE) consortium, we performed meta-analysis to combine information from six population-based birth cohort studies to investigate DNA methylation at over 450,000 sites in the cord blood of newborns differentially exposed to alcohol in utero. We were primarily interested in the effects of sustained consumption throughout pregnancy (data available for five cohorts, 3,075 mother-child pairs), which represents a prolonged prenatal exposure to alcohol, but we also explored binge-drinking and timing-specific exposures. In addition to looking for differential methylation at individual CpG sites, we also used two different methods, Comb-P and DMRcate, to identify differentially methylated regions (DMRs).We found no strong evidence of association between any of our alcohol exposure measures and DNA methylation at any individual CpG site. Using Comb-P, we identified 19 DMRs in the offspring of mothers who drank throughout pregnancy compared to the offspring of mothers who gave up drinking at the start of pregnancy, but these were not validated using DMRcate.In this multi-cohort study of the general population we found no evidence that maternal alcohol consumption during pregnancy is associated with offspring cord blood DNA methylation, which is in stark contrast to the multiple, strong associations that previous studies have found for maternal smoking. However, it is possible that a combination of a larger sample size, higher doses, different timings of exposure and a more global assessment of genomic DNA methylation might show evidence of association.

Published
2017
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40. Persistent DNA methylation changes link prenatal mercury exposure and cognitive performance in childhood

Author

Xihong Lin, D.L. DeMeo, Marie-France Hivert, Augusto A. Litonjua, Andrea A. Baccarelli, Andres Cardenas, Emily Oken, Matthew W. Gillman, Sheryl L. Rifas-Shiman, and Golareh Agha

Subjects
Fetus, business.industry, Physiology, chemistry.chemical_element, Cognition, MERCURY EXPOSURE, Mercury (element), chemistry.chemical_compound, fluids and secretions, chemistry, parasitic diseases, mental disorders, DNA methylation, General Earth and Planetary Sciences, Medicine, Epigenetics, Effects of sleep deprivation on cognitive performance, business, reproductive and urinary physiology, General Environmental Science, Toxicant
Abstract

Introduction: Prenatal exposure to mercury, a known neurodevelopmental toxicant, is associated with lower cognitive scores. Fetal epigenetic programming events could explain neurodevelopmental effe...

Published
2016
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41. Genome-wide association study of smoking behaviours in patients with COPD

Author

Byron Thomashow, John D. Newell, Philip Alapat, Timothy Bresnahan, Matt Budoff, Richard Casaburi, Julie C. Yates, Amund Gulsvik, Kalpalatha K. Guntupalli, Elizabeth Guy, Paul J. Friedman, Venkata Bandi, Ella A. Kazerooni, Lisa D. Edwards, Adam L. Friedlander, Mark T. Dransfield, Amir Sharafkhaneh, Jørgen Vestbo, Robert Brown, Charlene McEvoy, Wayne H. Anderson, John E. Hokanson, Geoffrey McLennan, Dennis E. Niewoehner, A. James Mamary, David A. Lomas, Fernando J. Martinez, Roham Darvishi, H. Page McAdams, Antonio Anzueto, Terri H. Beaty, Hirani Kamal, Michael H. Cho, Brad H. Thompson, Aditi Satti, Nicola A. Hanania, Christine H. Wendt, Nadia Hansel, Harvey O. Coxson, Tadashi Allen, Ruth Tal-Singer, Mateusz Siedlinski, Robert M. Steiner, Russell P. Bowler, Sandra G. Adams, Katharine Knobil, Per Bakke, Hrudaya Nath, D.L. DeMeo, Joel L. Weissfeld, Gloria Westney, Janos Porszasz, Kathryn L. Rice, Edwin J. R. van Beek, Graham Barr, John H.M. Austin, Stephen I. Rennard, William MacNee, Quentin Anderson, Eugene Berkowitz, Dwight C. Look, Carlos Orozco, William C. Bailey, Nathaniel Marchetti, Carl R. Fuhrman, James D. Crapo, Hans Fischer, Victor Kim, Xiangyang Kong, Charles Trinh, Joe Ramsdell, George Washko, Richard Rosiello, Joyce Schroeder, Joseph H. Tashjian, Frank C. Sciurba, Mustafa A. Atik, Gerard J. Criner, Edwin K. Silverman, MeiLan K. Han, Marilyn Foreman, Jeffrey L. Curtis, Antara Mallampalli, Mario E. Ruiz, Robert Wise, C.P. Hersh, Lacey Washington, Gregory Diette, Neil R. MacIntyre, David A. Lynch, Francine Jacobson, Jessica Bon, Chandra Dass, Pulmonologie, RS: CAPHRI School for Public Health and Primary Care, and RS: NUTRIM - R3 - Chronic inflammatory disease and wasting

Subjects
Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Genotype, medicine.medical_treatment, Genome-wide association study, Single-nucleotide polymorphism, Dopamine beta-Hydroxylase, Polymorphism, Single Nucleotide, Article, Cytochrome P-450 CYP2A6, Pulmonary Disease, Chronic Obstructive, Internal medicine, Epidemiology, medicine, Humans, SNP, Comparative Study, Genetic Predisposition to Disease, Aged, Genetic association, Genetics, COPD, clinical trial, phase II, business.industry, Incidence, Smoking, Age Factors, DNA, Middle Aged, medicine.disease, United States, Obstructive lung disease, multicenter study, Randomized controlled trial, Smoking cessation, Female, Smoking Cessation, Aryl Hydrocarbon Hydroxylases, business, Genome-Wide Association Study
Abstract

Background Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease (COPD) and COPD severity. Previous genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with the number of cigarettes smoked per day (CPD) and a dopamine beta-hydroxylase (DBH) locus associated with smoking cessation in multiple populations. Objective To identify SNPs associated with lifetime average and current CPD, age at smoking initiation, and smoking cessation in patients with COPD. Methods GWAS were conducted in four independent cohorts encompassing 3441 ever-smoking patients with COPD (Global Initiative for Obstructive Lung Disease stage II or higher). Untyped SNPs were imputed using the HapMap (phase II) panel. Results from all cohorts were meta-analysed. Results Several SNPs near the HLA region on chromosome 6p21 and in an intergenic region on chromosome 2q21 showed associations with age at smoking initiation, both with the lowest p=2x10(-7). No SNPs were associated with lifetime average CPD, current CPD or smoking cessation with p

Published
2011
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47. Familial Aggregation of Augmentation Therapy Use in Severe Alpha-1-Antitrypsin (AAT) Deficiency

Author

C Strange, Divay Chandra, Edward K. Silverman, E.J. Campbell, Edward Eden, Stephen I. Rennard, James M. Stocks, James K. Stoller, Mark L. Brantly, D.L. DeMeo, Noel G. McElvaney, Alan F. Barker, Gerard M. Turino, and Robert A. Sandhaus

Subjects
medicine.medical_specialty, Endocrinology, business.industry, Internal medicine, AAT deficiency, medicine, Alpha (ethology), Family aggregation, business
Published
2009
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