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Integrative Genomics Analysis Identifies ACVR1B as a Candidate Causal Gene of Emphysema Distribution

2018; American Thoracic Society; Volume: 60; Issue: 4 Linguagem: Inglês

10.1165/rcmb.2018-0110oc

1535-4989

Adel Boueiz, Betty Pham, Robert Chase, Andrew Lamb, Sool Lee, Zun Zar Chi Naing, Michael H. Cho, Margaret M. Parker, Phuwanat Sakornsakolpat, Craig P. Hersh, James D. Crapo, Andrew B. Stergachis, Ruth Tal‐Singer, Dawn L. DeMeo, Edwin K. Silverman, Xiaobo Zhou, Peter J. Castaldi, James D. Crapo, Edwin K. Silverman, Barry J. Make, Elizabeth A. Regan, Terri H. Beaty, Ferdouse Begum, Peter J. Castaldi, Michael H. Cho, Dawn L. DeMeo, Adel Boueiz, Marilyn G. Foreman, Eitan Halper-Stromberg, Lystra P. Hayden, Craig P. Hersh, Jacqueline B. Hetmanski, Brian D. Hobbs, John E. Hokanson, Nan M. Laird, Christoph Lange, Sharon M. Lutz, Merry‐Lynn McDonald, Margaret M. Parker, Dandi Qiao, Elizabeth A. Regan, Edwin K. Silverman, Emily S. Wan, Sungho Won, Phuwanat Sakornsakolpat, Dmitry Prokopenko, Mustafa Al Qaisi, Harvey O. Coxson, Teresa Gray, MeiLan K. Han, Eric A. Hoffman, Stephen M. Humphries, Francine L. Jacobson, Philip F. Judy, Ella A. Kazerooni, Alex Kluiber, David A. Lynch, John D. Newell, Elizabeth A. Regan, James C. Ross, Raúl San Jośe Estépar, Joyce Schroeder, Jered Sieren, Douglas R. Stinson, Berend C. Stoel, Juerg Tschirren, Edwin J.R. van Beek, Bram van Ginneken, Eva M. van Rikxoort, George R. Washko, Carla G. Wilson, Robert L. Jensen, Douglas Curran‐Everett, Jim Crooks, Camille M. Moore, Matthew Strand, Carla G. Wilson, John E. Hokanson, John Hughes, Gregory L. Kinney, Sharon M. Lutz, Katherine Pratte, Kendra A. Young, Surya P. Bhatt, Jessica Bon, MeiLan K. Han, Barry J. Make, Cristina Martínez, Susan Murray, Elizabeth A. Regan, Xavier Soler, Carla G. Wilson, Russell P. Bowler, Katerina Kechris, Farnoush Banaei‐Kashani, Yavor Ivanov, Kosta Kostov, Jean Bourbeau, Mark Fitzgerald, Paul Hernandez, K. J. Killian, RobertD. Levy, F. Maltais, Denis O’Donnell, J. Krepelka, Jørgen Vestbo, Emiel F.�M. Wouters, David I. Quinn, Per Bakke, Mitja Košnik, Àlvar Agustí, Jaume Sauleda, Y. I. Feschenko, V. Gavrisyuk, L. P. Yashina, Nadiya Monogarova, Peter M.A. Calverley, David A. Lomas, William MacNee, D. Singh, J A Wedzicha, Antonio Anzueto, Sidney S. Braman, Richard Casaburi, Bartolomé R. Celli, G. Giessel, Mark H. Gotfried, Gilbert S. Greenwald, Rancho Mirage, Nicola A. Hanania, D.A. Mahler, Barry J. Make, Stephen I. Rennard, Carolyn L. Rochester, Paul Scanlon, Dan Schuller, Frank C. Sciurba, Amir Sharafkhaneh, Thomas Siler, Edwin K. Silverman, Adam Wanner, Robert A. Wise, Richard ZuWallack, Harvey O. Coxson, Courtney Crim, Lisa Edwards, David A. Lomas, William MacNee, Edwin K. Silverman, Ruth Tal‐Singer, Jørgen Vestbo, Julie Yates, Àlvar Agustí, Peter M.A. Calverley, Bartolomé R. Celli, Courtney Crim, Brian C. Miller, William MacNee, Stephen I. Rennard, Ruth Tal‐Singer, Emiel F.�M. Wouters, Julie Yates, Per Bakke, Amund Gulsvik,

RNA modifications and cancer

Genome-wide association studies (GWAS) have identified multiple associations with emphysema apicobasal distribution (EABD), but the biological functions of these variants are unknown. To characterize the functions of EABD-associated variants, we integrated GWAS results with 1) expression quantitative trait loci (eQTL) from the Genotype Tissue Expression (GTEx) project and subjects in the COPDGene (Genetic Epidemiology of COPD) study and 2) cell type epigenomic marks from the Roadmap Epigenomics project. On the basis of these analyses, we selected a variant near ACVR1B (activin A receptor type 1B) for functional validation. SNPs from 168 loci with P values less than 5 × 10-5 in the largest GWAS meta-analysis of EABD were analyzed. Eighty-four loci overlapped eQTL, with 12 of these loci showing greater than 80% likelihood of harboring a single, shared GWAS and eQTL causal variant. Seventeen cell types were enriched for overlap between EABD loci and Roadmap Epigenomics marks (permutation P < 0.05), with the strongest enrichment observed in CD4+, CD8+, and regulatory T cells. We selected a putative causal variant, rs7962469, associated with ACVR1B expression in lung tissue for additional functional investigation, and reporter assays confirmed allele-specific regulatory activity for this variant in human bronchial epithelial and Jurkat immune cell lines. ACVR1B expression levels exhibit a nominally significant association with emphysema distribution. EABD-associated loci are preferentially enriched in regulatory elements of multiple cell types, most notably T-cell subsets. Multiple EABD loci colocalize to regulatory elements that are active across multiple tissues and cell types, and functional analyses confirm the presence of an EABD-associated functional variant that regulates ACVR1B expression, indicating that transforming growth factor-β signaling plays a role in the EABD phenotype. Clinical trial registered with www.clinicaltrials.gov (NCT00608764).