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1. Dietary nutrients associated with preservation of lung function in Hispanic and non-Hispanic white smokers from New Mexico

Author

Leng S, Picchi MA, Tesfaigzi Y, Wu G, Gauderman WJ, Xu F, Gilliland FD, and Belinsky SA

Subjects
Nutrientomics, spirometry, ethnic disparity, Diseases of the respiratory system, RC705-779
Abstract

Shuguang Leng,1,2 Maria A Picchi,1 Yohannes Tesfaigzi,3 Guodong Wu,1 W James Gauderman,4 Fadi Xu,5 Frank D Gilliland,4 Steven A Belinsky1,2,6 1The Lung Cancer Program, Lovelace Respiratory Research Institute, 2Cancer Control Research Program, University of New Mexico Comprehensive Cancer Center, 3COPD Program, Lovelace Respiratory Research Institute, Albuquerque, NM, 4Keck School of Medicine, University of Southern California, Los Angeles, CA, 5Pathophysiology Program, Lovelace Respiratory Research Institute, 6Cancer Genetics and Epigenetics Program, University of New Mexico Comprehensive Cancer Center, Albuquerque, NM, USA Background: COPD is the third leading cause of death in the United States. Cigarette smoking accelerates the age-related forced expiratory volume in 1 s (FEV1) decline, an important determinant for the genesis of COPD. Hispanic smokers have lower COPD prevalence and FEV1 decline than non-Hispanic whites (NHWs). Patients and methods: A nutritional epidemiological study was conducted in the Lovelace Smokers cohort (LSC; n=1,829) and the Veterans Smokers cohort (n=508) to identify dietary nutrients (n=139) associated with average FEV1 and its decline and to assess whether nutrient intakes could explain ethnic disparity in FEV1 decline between Hispanics and NHW smokers. Results: Nutrients discovered and replicated to be significantly associated with better average FEV1 included magnesium, folate, niacin, vitamins A and D, eicosenoic fatty acid (20:1n9), eicosapentaenoic acid (20:5n3), docosapentaenoic acid (DPA; 22:5n3), docosahexaenoic acid (22:6n3), and fiber. In addition, greater intakes of eicosenoic fatty acid and DPA were associated with slower FEV1 decline in the LSC. Among omega 3 polyunsaturated fatty acids, DPA is the most potent nutrient associated with better average FEV1 and slower FEV1 decline. Adverse effect of continuous current smoking on FEV1 decline was completely negated in LSC members with high DPA intake (>20 mg/day). Slower FEV1 decline in Hispanics compared to NHWs may be due to the greater protection of eicosenoic fatty acid and DPA for FEV1 decline rather than greater intake of protective nutrients in this ethnic group. Conclusion: The protective nutrients for the preservation of FEV1 in ever smokers could lay foundation for designing individualized nutritional intervention targeting “optimal physiological levels” in human to improve lung function in ever smokers. Ethnic disparity in FEV1 decline may be explained by difference in magnitude of protection of dietary intakes of eicosenoic fatty acid and DPA between Hispanics and NHWs. Keywords: nutrientomics, spirometry, ethnic disparity

Published
2017

14. Genetic Associations and Architecture of Asthma-COPD Overlap:Chest

Author

John, C., Guyatt, A. L., Shrine, N., Packer, R., Olafsdottir, T. A., Liu, J., Hayden, L. P., Chu, S. H., Koskela, J. T., Luan, J., Li, X., Terzikhan, N., Xu, H., Bartz, T. M., Petersen, H., Leng, S., Belinsky, S. A., Cepelis, A., Hernández Cordero, A. I., Obeidat, M., Thorleifsson, G., Meyers, D. A., Bleecker, E. R., Sakoda, L. C., Iribarren, C., Tesfaigzi, Y., Gharib, S. A., Dupuis, J., Brusselle, G., Lahousse, L., Ortega, V. E., Jonsdottir, I., Sin, D. D., Bossé, Y., van den Berge, M., Nickle, D., Quint, J. K., Sayers, I., Hall, I. P., Langenberg, C., Ripatti, S., Laitinen, T., Wu, A. C., Lasky-Su, J., Bakke, P., Gulsvik, A., Hersh, C. P., Hayward, C., Langhammer, A., Brumpton, B., Stefansson, K., Cho, M. H., Wain, L. V., Tobin, M. D., John, C., Guyatt, A. L., Shrine, N., Packer, R., Olafsdottir, T. A., Liu, J., Hayden, L. P., Chu, S. H., Koskela, J. T., Luan, J., Li, X., Terzikhan, N., Xu, H., Bartz, T. M., Petersen, H., Leng, S., Belinsky, S. A., Cepelis, A., Hernández Cordero, A. I., Obeidat, M., Thorleifsson, G., Meyers, D. A., Bleecker, E. R., Sakoda, L. C., Iribarren, C., Tesfaigzi, Y., Gharib, S. A., Dupuis, J., Brusselle, G., Lahousse, L., Ortega, V. E., Jonsdottir, I., Sin, D. D., Bossé, Y., van den Berge, M., Nickle, D., Quint, J. K., Sayers, I., Hall, I. P., Langenberg, C., Ripatti, S., Laitinen, T., Wu, A. C., Lasky-Su, J., Bakke, P., Gulsvik, A., Hersh, C. P., Hayward, C., Langhammer, A., Brumpton, B., Stefansson, K., Cho, M. H., Wain, L. V., and Tobin, M. D.

Abstract

Background: Some people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone. Research Question: What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma? Study Design and Methods: We conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P < 5 × 10 –6) that remained associated in analyses comparing (1) asthma-COPD overlap vs asthma-only control subjects, and (2) asthma-COPD overlap vs COPD-only control subjects. These variants were analyzed in 12 independent cohorts (stage 2). Results: We selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P < 5 × 10 –8) for asthma-COPD overlap (meta-analysis of stage 1 and 2 studies). These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent. Interpretation: We identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma.

Published
2022

24. Identification of novel epigenetic abnormalities as sputum biomarkers for lung cancer risk among smokers and COPD patients

Author

Picchi, M.A., Randell, S., Tesfaigzi, Y., Tessema, M., Petersen, H., Yingling, C.M., Wu, G., Belinsky, S.A., Lin, Y., Do, K., and Tassew, D.D.

Subjects
respiratory tract diseases
Abstract

Objectives: Smoking is a common risk factor for chronic obstructive pulmonary disease (COPD) and lung cancer. Although COPD patients have higher risk of lung cancer compared to non-COPD smokers, the molecular links between these diseases are not well-defined. This study aims to identify genes that are downregulated by cigarette smoke and commonly repressed in COPD and lung cancer. Materials and methods: Primary human airway epithelial cells (HAEC) were exposed to cigarette-smoke-extract (CSE) for 10-weeks and significantly suppressed genes were identified by transcriptome array. Epigenetic abnormalities of these genes in lung adenocarcinoma (LUAD) from patients with or without COPD were determined using genome-wide and gene-specific assays and by in vitro treatment of cell lines with trichostatin-A or 5-aza-2-deoxycytidine. Results: The ten most commonly downregulated genes following chronic CSE exposure of HAEC and show promoter hypermethylation in LUAD were selected. Among these, expression of CCNA1, SNCA, and ZNF549 was significantly reduced in lung tissues from COPD compared with non-COPD cases while expression of CCNA1 and SNCA was further downregulated in tumors with COPD. The promoter regions of all three genes were hypermethylated in LUAD but not normal or COPD lungs. The reduced expression and aberrant promoter hypermethylation of these genes in LUAD were independently validated using data from the Cancer Genome Atlas project. Importantly, SNCA and ZNF549 methylation detected in sputum DNA from LUAD (52% and 38%) cases were more prevalent compared to cancer-free smokers (26% and 15%), respectively (p < 0.02). Conclusions: Our data show that suppression of CCNA1, SNCA, and ZNF549 in lung cancer and COPD occurs with or without promoter hypermethylation, respectively. Detecting methylation of these and previously identified genes in sputum of cancer-free smokers may serve as non-invasive biomarkers for early detection of lung cancer among high risk smokers including COPD patients.

Published
2020
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25. Paradoxical effects of cigarette smoke and COPD on SARS-CoV2 infection and disease

Author

Tomchaney, M., primary, Contoli, M., additional, Mayo, J., additional, Baraldo, S., additional, Shuaizhi, L., additional, Cabel, CR., additional, Bull, DA., additional, Lick, S., additional, Malo, J., additional, Knoper, S., additional, Kim, SS., additional, Tram, J., additional, Rojas-Quintero, J., additional, Kraft, M., additional, Ledford, J., additional, Tesfaigzi, Y., additional, Martinez, F.D., additional, Thorne, C. A., additional, Kheradmand, F., additional, Campos, S. K., additional, Papi, A., additional, and Polverino, F., additional

Published
2020
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26. Genetic associations and architecture of asthma-chronic obstructive pulmonary disease overlap

Author

John, C., primary, Guyatt, A.L., additional, Shrine, N., additional, Packer, R., additional, Olafsdottir, T.A., additional, Liu, J., additional, Hayden, L.P., additional, Chu, S.H., additional, Koskela, J.T., additional, Luan, J., additional, Li, X., additional, Terzikhan, N., additional, Xu, H., additional, Bartz, T.M., additional, Petersen, H., additional, Leng, S., additional, Belinsky, S.A., additional, Cepelis, A., additional, Hernández Cordero, A.I., additional, Obeidat, M., additional, Thorleifsson, G., additional, Meyers, D.A., additional, Bleecker, E.R., additional, Sakoda, L.C., additional, Iribarren, C., additional, Tesfaigzi, Y., additional, Gharib, S.A., additional, Dupuis, J., additional, Brusselle, G., additional, Lahousse, L., additional, Ortega, V.E., additional, Jonsdottir, I., additional, Sin, D. D., additional, Bossé, Y., additional, van den Berge, M., additional, Nickle, D., additional, Quint, J.K., additional, Sayers, I., additional, Hall, I.P., additional, Langenberg, C., additional, Ripatti, S., additional, Laitinen, T., additional, Wu, A.C., additional, Lasky-Su, J., additional, Bakke, P., additional, Gulsvik, A., additional, Hersh, C.P., additional, Hayward, C., additional, Langhammer, A., additional, Brumpton, B., additional, Stefansson, K., additional, Cho, M.H., additional, Wain, L.V., additional, and Tobin, M.D., additional

Published
2020
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27. Systemic Biomarkers of Lung Function and FEV1 Decline Across Multiple Cohorts

Author

Ngo, D., primary, Pratte, K.A., additional, Flexeder, C., additional, Petersen, H., additional, Dang, H., additional, Ma, Y., additional, Keyes, M.J., additional, Peterson, B.D., additional, Sitar, V., additional, Gillenwater, L.A., additional, Xu, H., additional, Emson, C., additional, Gieger, C., additional, Suhre, K., additional, Graumann, J., additional, Jain, D., additional, Conomos, M.P., additional, Tracy, R.P., additional, Guo, X., additional, Liu, Y., additional, Johnson, W.C., additional, Cornell, E., additional, Durda, P., additional, Taylor, K.D., additional, Papanicolaou, G.J., additional, Rich, S.S., additional, Rotter, J.I., additional, Rennard, S.I., additional, Curtis, J.L., additional, Woodruff, P., additional, Comellas, A.P., additional, Silverman, E.K., additional, Crapo, J.D., additional, Larson, M.G., additional, Ramachandran, V., additional, Wang, T.J., additional, Gerszten, R.E., additional, O'Connor, G.T., additional, Barr, R.G., additional, Couper, D., additional, Dupuis, J., additional, Manichaikul, A., additional, O'Neal, W.K., additional, Tesfaigzi, Y., additional, Schulz, H., additional, and Bowler, R.P., additional

Published
2020
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31. CD14

Author

Tesfaigzi, Y., primary and Daheshia, M., additional

Published
2006
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32. A Disintegrin and A Metalloproteinase Domain-8 (ADAM8): a novel protective Proteinase in COPD

Author

Polverino, F, Rojas-Quintero, J, Wang, X, Petersen, H, Zhang, L, Gai, X, Higham, A, Zhang, D, Gupta, K, Rout, A, Yambayev, I, Pinto-Plata, V, Sholl, LM, Cunoosamy, D, Celli, BR, Goldring, J, Singh, D, Tesfaigzi, Y, Wedzicha, J, Olsson, H, Owen, CA, and Medical Research Council (MRC)

Subjects
ADAM8 EXPRESSION, Science & Technology, AIRWAY INFLAMMATION, Respiratory System, lung inflammation, NECROSIS-FACTOR-ALPHA, macrophage, respiratory system, BETA-CATENIN, respiratory tract diseases, airway mucus cell metaplasia, EGFR shedding, MICE, Critical Care Medicine, FACTOR RECEPTOR, MONOCYTES, General & Internal Medicine, intrinsic apoptosis pathway, SMOKE-INDUCED EMPHYSEMA, CELLS, Life Sciences & Biomedicine, LUNG INJURY, 11 Medical and Health Sciences
Abstract

RATIONALE: A disintegrin and metalloproteinase-8 (ADAM8) is expressed by leukocytes and epithelial cells in health, but its contribution to the pathogenesis of COPD is unknown. OBJECTIVES: ADAM8 levels were measured in lung, sputum, plasma, and/or bronchoalveolar lavage fluid (BALF) samples from COPD patients, smokers, and non-smokers, and wild-type (WT) mice exposed to cigarette smoke (CS) versus air. COPD-like lung pathologies were compared in CS-exposed WT versus Adam8-/- mice. RESULTS: ADAM8 expression was reduced in macrophages, and alveolar and bronchial epithelial cells in the lungs of COPD patients versus controls, and CS- versus air-exposed WT mice. ADAM8 levels were similar in plasma, sputum, and BALF samples from COPD patients and controls. CS-exposed Adam8-/- mice had greater airspace enlargement and airway mucus cell metaplasia than WT mice, but similar small airway fibrosis. CS-exposed Adam8-/- mice had higher lung macrophage counts, oxidative stress levels, and alveolar septal cell death rates, but lower alveolar septal cell proliferation rates and soluble EGF receptor BALF levels than WT mice. Adam8 deficiency increased lung inflammation by reducing CS-induced activation of the intrinsic apoptosis pathway in macrophages. Human ADAM8 proteolytically shed the EGF receptor from bronchial epithelial cells to reduce mucin expression in vitro. Adam8 bone marrow chimera studies revealed that Adam8 deficiency in leukocytes and lung parenchymal cells contributed to the exaggerated COPD-like disease in Adam8-/- mice. CONCLUSIONS: Adam8 deficiency increases CS-induced lung inflammation, emphysema, and airway mucus cell metaplasia. Strategies that increase or prolong ADAM8's expression in the lung may have therapeutic efficacy in COPD.

Published
2018

37. Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis

Author

Hobbs, BD, de Jong, K, Lamontagne, M, Bossé, Y, Shrine, N, Artigas, MS, Wain, LV, Hall, IP, Jackson, VE, Wyss, AB, London, SJ, North, KE, Franceschini, N, Strachan, DP, Beaty, TH, Hokanson, JE, Crapo, JD, Castaldi, PJ, Chase, RP, Bartz, TM, Heckbert, SR, Psaty, BM, Gharib, SA, Zanen, P, Lammers, JW, Oudkerk, M, Groen, HJ, Locantore, N, Tal-Singer, R, Rennard, SI, Vestbo, J, Timens, W, Paré, PD, Latourelle, JC, Dupuis, J, O'Connor, GT, Wilk, JB, Kim, WJ, Lee, MK, Oh, Y-M, Vonk, JM, de Koning, HJ, Leng, S, Belinsky, SA, Tesfaigzi, Y, Manichaikul, A, Wang, X-Q, Rich, SS, Barr, RG, Sparrow, D, Litonjua, AA, Bakke, P, Gulsvik, A, Lahousse, L, Brusselle, GG, Stricker, BH, Uitterlinden, AG, Ampleford, EJ, Bleecker, ER, Woodruff, PG, Meyers, DA, Qiao, D, Lomas, DA, Yim, J-J, Kim, DK, Hawrylkiewicz, I, Sliwinski, P, Hardin, M, Fingerlin, TE, Schwartz, DA, Postma, DS, MacNee, W, Tobin, MD, Silverman, EK, Boezen, HM, Cho, MH, COPDGene Investigators, ECLIPSE Investigators, LifeLines Investigators, SPIROMICS Research Group, International COPD Genetics Network Investigators, UK BiLEVE Investigators, and International COPD Genetics Consortium

Subjects
respiratory tract diseases
Abstract

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10(-6)) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.

Published
2017

38. Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis

Author

Hobbs, B.D. (Brian D.), Jong, K. (Kim) de, Lamontagne, M. (Maxime), Bossé, Y. (Yohan), Shrine, N.R.G. (Nick), Artigas, M.S., Wain, L.V. (Louise V), Hall, I.P. (Ian), Jackson, V.E. (Victoria E.), Wyss, A.B. (Annah B.), London, S.J. (Stephanie J), North, K.E. (Kari), Franceschini, N. (Nora), Strachan, D.P. (David), Beaty, T.H. (Terri), Hokanson, J.E. (John E.), Crapo, R.O. (Robert), Castaldi, P.J. (Peter J.), Chase, R.P. (Robert P.), Bartz, T.M. (Traci M.), Heckbert, S.R. (Susan), Psaty, B.M. (Bruce M.), Gharib, S.A. (Sina), Zanen, P. (Pieter), Lammers, J.-W.J. (Jan-Willem), Oudkerk, M. (Matthijs), Groen, H.J.M. (Henk), Locantore, N. (Nicholas), Tal-Singer, R. (Ruth), Rennard, S.I., Vestbo, J. (Jorgen), Timens, W. (Wim), Paré, P.D. (Peter), Latourelle, J.C. (Jeanne), Dupuis, J. (Josée), O'Connor, G.T. (George), Wilk, J.B. (Jemma), Kim, W.J. (Woo Jin), Lee, M.K. (Mi Kyeong), Oh, Y.-M. (Yeon-Mok), Vonk, J.M. (Judith), Koning, H.J. (Harry) de, Leng, S. (Shuguang), Belinsky, S.A. (Steven A.), Tesfaigzi, Y. (Yohannes), Manichaikul, A. (Ani), Wang, X.-Q. (Xin-Qun), Rich, S.S. (Stephen), Barr, R.G. (Graham), Sparrow, D. (David), Litonjua, A.A. (Augusto), Bakke, A.B. (Arnold B.), Gulsvik, A. (Amund), Lahousse, L. (Lies), Brusselle, G.G. (Guy), Stricker, B.H.Ch. (Bruno), Uitterlinden, A.G. (André), Ampleford, E.J. (Elizabeth J.), Bleecker, E.R. (E.), Woodruff, P.G. (Prescott G.), Meyers, D.A. (Deborah A.), Qiao, D. (Dandi), Lomas, D.A. (David A.), Yim, J.-J. (Jae-Joon), Kim, D.K. (Deog Kyeom), Hawrylkiewicz, I. (Iwona), Sliwinski, P. (Pawel), Hardin, M. (Megan), Fingerlin, T.E. (Tasha E.), Schwartz, D.A. (David A.), Postma, D.S. (Dirkje S.), MacNee, W., Tobin, M.D. (Martin), Silverman, E. (Edwin), Boezen, H.M. (Marike), Cho, M.H. (Michael), Hobbs, B.D. (Brian D.), Jong, K. (Kim) de, Lamontagne, M. (Maxime), Bossé, Y. (Yohan), Shrine, N.R.G. (Nick), Artigas, M.S., Wain, L.V. (Louise V), Hall, I.P. (Ian), Jackson, V.E. (Victoria E.), Wyss, A.B. (Annah B.), London, S.J. (Stephanie J), North, K.E. (Kari), Franceschini, N. (Nora), Strachan, D.P. (David), Beaty, T.H. (Terri), Hokanson, J.E. (John E.), Crapo, R.O. (Robert), Castaldi, P.J. (Peter J.), Chase, R.P. (Robert P.), Bartz, T.M. (Traci M.), Heckbert, S.R. (Susan), Psaty, B.M. (Bruce M.), Gharib, S.A. (Sina), Zanen, P. (Pieter), Lammers, J.-W.J. (Jan-Willem), Oudkerk, M. (Matthijs), Groen, H.J.M. (Henk), Locantore, N. (Nicholas), Tal-Singer, R. (Ruth), Rennard, S.I., Vestbo, J. (Jorgen), Timens, W. (Wim), Paré, P.D. (Peter), Latourelle, J.C. (Jeanne), Dupuis, J. (Josée), O'Connor, G.T. (George), Wilk, J.B. (Jemma), Kim, W.J. (Woo Jin), Lee, M.K. (Mi Kyeong), Oh, Y.-M. (Yeon-Mok), Vonk, J.M. (Judith), Koning, H.J. (Harry) de, Leng, S. (Shuguang), Belinsky, S.A. (Steven A.), Tesfaigzi, Y. (Yohannes), Manichaikul, A. (Ani), Wang, X.-Q. (Xin-Qun), Rich, S.S. (Stephen), Barr, R.G. (Graham), Sparrow, D. (David), Litonjua, A.A. (Augusto), Bakke, A.B. (Arnold B.), Gulsvik, A. (Amund), Lahousse, L. (Lies), Brusselle, G.G. (Guy), Stricker, B.H.Ch. (Bruno), Uitterlinden, A.G. (André), Ampleford, E.J. (Elizabeth J.), Bleecker, E.R. (E.), Woodruff, P.G. (Prescott G.), Meyers, D.A. (Deborah A.), Qiao, D. (Dandi), Lomas, D.A. (David A.), Yim, J.-J. (Jae-Joon), Kim, D.K. (Deog Kyeom), Hawrylkiewicz, I. (Iwona), Sliwinski, P. (Pawel), Hardin, M. (Megan), Fingerlin, T.E. (Tasha E.), Schwartz, D.A. (David A.), Postma, D.S. (Dirkje S.), MacNee, W., Tobin, M.D. (Martin), Silverman, E. (Edwin), Boezen, H.M. (Marike), and Cho, M.H. (Michael)

Abstract

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10-6) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.

Published
2017
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39. COPD Subtype Identification In The International COPD Genetics Consortium: Collaborative Subtyping Results Across Ten Cohorts

Author

Castaldi, P. J., Benet-Mora, M., Petersen, H., Boorgula, M. Preethi, Finigan, J., Paoletti, M., Boezen, M., Vonk, J. M., Bowler, R. P., Agusti, A., Pistolesi, M., Puhan, M. A., Ter Riet, G., Wauters, E., Anto, J., Cho, M. H., Hersh, C. P., Barnes, K., Rennard, S. I., Rafaels, N., Crapo, J. D., Tesfaigzi, Y., Silverman, E. K., Garcia-Aymerich, J., Groningen Research Institute for Asthma and COPD (GRIAC), and Life Course Epidemiology (LCE)

Published
2016

40. Identification of FGF7 as a novel susceptibility locus for chronic obstructive pulmonary disease

Author

Brehm, J. M., primary, Hagiwara, K., additional, Tesfaigzi, Y., additional, Bruse, S., additional, Mariani, T. J., additional, Bhattacharya, S., additional, Boutaoui, N., additional, Ziniti, J. P., additional, Soto-Quiros, M. E., additional, Avila, L., additional, Cho, M. H., additional, Himes, B., additional, Litonjua, A. A., additional, Jacobson, F., additional, Bakke, P., additional, Gulsvik, A., additional, Anderson, W. H., additional, Lomas, D. A., additional, Forno, E., additional, Datta, S., additional, Silverman, E. K., additional, and Celedon, J. C., additional

Published
2011
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41. Role of alpha(2)-macroglobulin in fever and cytokine responses induced by lipopolysaccharide in mice

Author

UCL, Gourine, AV, Gourine, VN, Tesfaigzi, Y, Caluwaerts, N, Van Leuven, F, Kluger, MJ, UCL, Gourine, AV, Gourine, VN, Tesfaigzi, Y, Caluwaerts, N, Van Leuven, F, and Kluger, MJ

Abstract

alpha(2)-Macroglobulin (alpha(2)M) is not only a proteinase inhibitor in mammals, but it is also a specific cytokine carrier that binds pro- and anti-inflammatory cytokines implicated in fever, including interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha). To define the role of alpha(2)M in regulation of febrile and cytokine responses, wild-type mice and mice deficient in alpha(2)M (alpha(2)M-/-) were injected with lipopolysaccharide (LPS). Changes in body temperature as well as plasma levels of IL-1beta, IL-6, and TNF-alpha and hepatic TNF-alpha mRNA level during fever in alpha(2)M-/- mice were compared with those in wild-type control mice. The alpha(2)M-/- mice developed a short-term markedly attenuated (ANOVA, P < 0.05) fever in response to LPS (2.5 mg/kg ip) compared with the wild-type mice. At 1.5 h after injection of LPS, the plasma concentration of TNF-alpha, but not IL-1 beta or IL-6, was significantly lower (by 58%) in the alpha M-2-/- mice compared with their wild-type controls (ANOVA, P < 0.05). There was no difference in hepatic TNF-alpha mRNA levels between alpha(2)M -/- and wild-type mice 1.5 h after injection of LPS. These data support the hypotheses that 1) alpha(2)M is important for the normal development of LPS-induced fever and 2) a putative mechanism of alpha(2)M involvement in fever is through the inhibition of TNF-alpha clearance. These findings indicate a novel physiological role for alpha(2)M.

Published
2002

45. A Functional MMP12 Polymorphism Is Associated with Lung Function throughout Life and Delayed Onset of COPD.

Author

Hunninghake, GM, primary, Cho, MH, additional, Tesfaigzi, Y, additional, Soto-Quiros, ME, additional, Avila, L, additional, Lasky-Su, J, additional, Lange, C, additional, Demeo, DL, additional, Hersh, CP, additional, Klanderman, BJ, additional, Raby, BA, additional, Sparrow, D, additional, Shapiro, SD, additional, Silverman, EK, additional, Litonjua, AA, additional, Weiss, ST, additional, and Celedon, JC, additional

Published
2009
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48. LPS PRIMING OF PULMONARY EPITHELIUM AFFECTS THE RESPONSE TO A SECONDARY CHALLENGE.

Author

Daheshia, M., Harris, J. F., Johnson, N., and Tesfaigzi, Y.

Subjects
MEDICAL personnel, BASIC proteins, INSULIN derivatives, FUNCTIONAL magnetic resonance imaging, FEEDBACK control systems, IMMUNOGLOBULIN E
Abstract

The first document discusses the effects of exposure to LPS on the airway epithelium in rats, finding that the changes in the epithelium resolved after 16 days but left an immunological footprint that altered the inflammatory response and development of mucous cell metaplasia. The second document describes a study on mice that established a standard morphometric procedure for quantifying pulmonary emphysema, finding that mice exposed to elastase had increased lung volume and alveolar surface area, confirming the diagnosis of elastase-induced emphysema. The third document compares serum IgE and ECP levels in elderly asthmatics and non-asthmatics, finding that elderly asthmatics were more likely to have elevated total IgE and specific IgE to D. pteronyssinus. The fourth document presents a new method for mapping ventilation-perfusion ratios (VA/Q) in patients using inert fluorinated gas MRI, demonstrated by imaging the lungs of a live laboratory rat with obstructed ventilation. The final document discusses the importance of enhancing activity levels for older adults with respiratory problems and presents various research projects related to respiratory health, including the development of an artificial muscle to assist with mobility, correlation between skin and nasal tests for allergens, a proteomic core facility for disease management, and the investigation of inhaled pegylated-insulin for increased bioavailability. These projects aim to improve the quality of life for individuals with respiratory issues and advance understanding in the field of respiratory health. [Extracted from the article]

Published
2005
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50. Adam8 Limits the Development of Allergic Airway Inflammation in Mice

Author

Knolle, M. D., Nakajima, T., Hergrueter, A., Gupta, K., Polverino, Francesca, Craig, V, Fyfe, S. E., Zahid, M., Permaul, Perdita, Cernadas, Manuela, Montano, Giancarlo Vengco, Tesfaigzi, Y., Sholl, Lynette Marie, Kobzik, Lester, Israel, Elliot, and Owen, Caroline Ann

Abstract

To determine whether a disintegrin and a metalloproteinase-8 (Adam8) regulates allergic airway inflammation (AAI) and airway hyper-responsiveness (AHR), we compared AAI and AHR in wild type (WT) versus Adam8−/− mice in different genetic backgrounds sensitized and challenged with ovalbumin (OVA) or house dust mite protein extract (HDM). OVA- and HDM-treated Adam8−/− mice had higher lung leukocyte counts, more airway mucus metaplasia, greater lung levels of some TH2 cytokines, and higher methacholine-induced increases in central airway resistance than allergen-treated WT mice. Studies of OVA-treated Adam8 bone marrow chimeric mice confirmed that leukocyte-derived Adam8 predominantly mediated Adam8’s anti-inflammatory activities in murine airways. Airway eosinophils and macrophages both expressed Adam8 in WT mice with AAI. Adam8 limited AAI and AHR in mice by reducing leukocyte survival because: 1) Adam8−/− mice with AAI had fewer apoptotic eosinophils and macrophages in their airways than WT mice with AAI; and 2) Adam8−/− macrophages and eosinophils had reduced rates of apoptosis compared with WT leukocytes when the intrinsic (but not the extrinsic) apoptosis pathway was triggered in the cells in vitro. ADAM8 was robustly expressed by airway granulocytes in lung sections from human asthma patients but, surprisingly, airway macrophages had less ADAM8 staining than airway eosinophils. Thus, ADAM8 has anti-inflammatory activities during AAI in mice by activating the intrinsic apoptosis pathway in myeloid leukocytes. Strategies that increase ADAM8 levels in myeloid leukocytes may have therapeutic efficacy in asthma.

Published
2013
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