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2. Respiratory Exacerbations and Lung Function Decline in People With Normal Spirometry and Smoking Exposure

Author

Fortis, S., primary, Strand, M., additional, Bhatt, S.P., additional, Tel Eyck, P., additional, Wendt, L., additional, Parekh, T.M., additional, Han, M.K., additional, Hokanson, J.E., additional, Kinney, G.L., additional, Curtis, J.L., additional, Bowler, R.P., additional, Wan, E.S., additional, Kunisaki, K.M., additional, Wendt, C.H., additional, Regan, E.A., additional, Dransfield, M.T., additional, Crapo, J.D., additional, Silverman, E.K., additional, and Comellas, A.P., additional

Published
2023
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4. Prevalence of Abnormal Spirometry in Ever Smokers with No Known Obstructive Lung Disease

Author

Tran, T., primary, Kinney, G.L., additional, Comellas, A.P., additional, Hoth, K.F., additional, Baldomero, A.K., additional, Wilson, C., additional, Strand, M., additional, Demeo, D.L., additional, Putcha, N., additional, Hokanson, J.E., additional, Crapo, J.D., additional, Hanania, N.A., additional, Wan, E.S., additional, Dransfield, M.T., additional, Mamary, A.J., additional, Curtis, J.L., additional, Casaburi, R., additional, Young, K., additional, Kim, V., additional, Make, B.J., additional, Diaz, A.A., additional, Silverman, E.K., additional, Bhatt, S.P., additional, Regan, E.A., additional, and Fortis, S., additional

Published
2022
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8. Pulmonary Arterial Pruning and Longitudinal Change in Percent Emphysema and Lung Function

Author

Pistenmaa, Carrie L., primary, Nardelli, P., additional, Ash, S.Y., additional, Come, C.E., additional, Diaz, A.A., additional, Rahaghi, F.N., additional, Barr, R.G., additional, Young, K.A., additional, Kinney, G.L., additional, Simmons, J.P., additional, Wade, R.C., additional, Wells, J.M., additional, Hokanson, J.E., additional, Washko, G.R., additional, San José Estépar, R., additional, Crapo, James D., additional, Silverman, Edwin K., additional, Make, Barry J., additional, Regan, Elizabeth A., additional, Beaty, Terri H., additional, Castaldi, Peter J., additional, Cho, Michael H., additional, DeMeo, Dawn L., additional, El Boueiz, Adel, additional, Foreman, Marilyn G., additional, Ghosh, Auyon, additional, Hayden, Lystra P., additional, Hersh, Craig P., additional, Hetmanski, Jacqueline, additional, Hobbs, Brian D., additional, Hokanson, John E., additional, Kim, Wonji, additional, Laird, Nan, additional, Lange, Christoph, additional, Lutz, Sharon M., additional, McDonald, Merry-Lynn, additional, Prokopenko, Dmitry, additional, Moll, Matthew, additional, Morrow, Jarrett, additional, Qiao, Dandi, additional, Saferali, Aabida, additional, Sakornsakolpat, Phuwanat, additional, Wan, Emily S., additional, Yun, Jeong, additional, Centeno, Juan Pablo, additional, Charbonnier, Jean-Paul, additional, Coxson, Harvey O., additional, Galban, Craig J., additional, Han, MeiLan K., additional, Hoffman, Eric A., additional, Humphries, Stephen, additional, Jacobson, Francine L., additional, Judy, Philip F., additional, Kazerooni, Ella A., additional, Kluiber, Alex, additional, Lynch, David A., additional, Nardelli, Pietro, additional, Newell, John D., additional, Notary, Aleena, additional, Oh, Andrea, additional, Ross, James C., additional, San Jose Estepar, Raul, additional, Schroeder, Joyce, additional, Sieren, Jered, additional, Stoel, Berend C., additional, Tschirren, Juerg, additional, Van Beek, Edwin, additional, Ginneken, Bramvan, additional, van Rikxoort, Eva, additional, Sanchez- Ferrero, Gonzalo Vegas, additional, Veitel, Lucas, additional, Washko, George R., additional, Wilson, Carla G., additional, Jensen, Robert, additional, Everett, Douglas, additional, Crooks, Jim, additional, Pratte, Katherine, additional, Strand, Matt, additional, Austin, Erin, additional, Kinney, Gregory, additional, Young, Kendra A., additional, Bhatt, Surya P., additional, Bon, Jessica, additional, Diaz, Alejandro A., additional, Make, Barry, additional, Murray, Susan, additional, Regan, Elizabeth, additional, Soler, Xavier, additional, Bowler, Russell P., additional, Kechris, Katerina, additional, Banaei-Kashani, Farnoush, additional, Curtis, Jeffrey L., additional, Pernicano, Perry G., additional, Hanania, Nicola, additional, Atik, Mustafa, additional, Boriek, Aladin, additional, Guntupalli, Kalpatha, additional, Guy, Elizabeth, additional, Parulekar, Amit, additional, Hersh, Craig, additional, Washko, George, additional, Barr, R. Graham, additional, Austin, John, additional, D’Souza, Belinda, additional, Thomashow, Byron, additional, MacIntyre, Neil, additional, McAdams, H. Page, additional, Washington, Lacey, additional, McEvoy, Charlene, additional, Tashjian, Joseph, additional, Wise, Robert, additional, Brown, Robert, additional, Hansel, Nadia N., additional, Horton, Karen, additional, Lambert, Allison, additional, Putcha, Nirupama, additional, Casaburi, Richard, additional, Adami, Alessandra, additional, Budoff, Matthew, additional, Fischer, Hans, additional, Porszasz, Janos, additional, Rossiter, Harry, additional, Stringer, William, additional, Sharafkhaneh, Amir, additional, Lan, Charlie, additional, Wendt, Christine, additional, Bell, Brian, additional, Kunisaki, Ken M., additional, Flenaugh, Eric L., additional, Gebrekristos, Hirut, additional, Ponce, Mario, additional, Terpenning, Silanath, additional, Westney, Gloria, additional, Bowler, Russell, additional, Rosiello, Richard, additional, Pace, David, additional, Criner, Gerard, additional, Ciccolella, David, additional, Cordova, Francis, additional, Dass, Chandra, additional, D’Alonzo, Gilbert, additional, Desai, Parag, additional, Jacobs, Michael, additional, Kelsen, Steven, additional, Kim, Victor, additional, Mamary, A. James, additional, Marchetti, Nathaniel, additional, Satti, Aditi, additional, Shenoy, Kartik, additional, Steiner, Robert M., additional, Swift, Alex, additional, Swift, Irene, additional, Vega-Sanchez, Maria Elena, additional, Dransfield, Mark, additional, Bailey, William, additional, Iyer, Anand, additional, Nath, Hrudaya, additional, Wells, J. Michael, additional, Conrad, Douglas, additional, Yen, Andrew, additional, Comellas, Alejandro P., additional, Hoth, Karin F., additional, Newell, John, additional, Thompson, Brad, additional, Kazerooni, Ella, additional, Labaki, Wassim, additional, Galban, Craig, additional, Vummidi, Dharshan, additional, Billings, Joanne, additional, Begnaud, Abbie, additional, Allen, Tadashi, additional, Sciurba, Frank, additional, Chandra, Divay, additional, and Weissfeld, Joel, additional

Published
2021
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12. Longitudinal Association Between Skeletal Muscle Mass and All-Cause Mortality in Ever-Smokers

Author

Mason, S., primary, Moreta-Martinez, R., additional, Labaki, W.W., additional, Strand, M.J., additional, Regan, E.A., additional, Bon, J., additional, San Jose Estepar, R., additional, Casaburi, R., additional, Mcdonald, M.-L.N., additional, Rossiter, H.B., additional, Make, B.J., additional, Dransfield, M.T., additional, Han, M.K., additional, Young, K.A., additional, Kinney, G.L., additional, Hokanson, J.E., additional, and Washko, G.R., additional

Published
2021
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14. Increased Bone and Muscle Measures Derived from Chest CT Are Markers of Improved Quality of Life, Function, and Survival in COPD

Author

Wilson, A.C., primary, Bon, J., additional, Mason, S., additional, Diaz, A.A., additional, Lutz, S.M., additional, San Jose Estepar, R., additional, Kinney, G.L., additional, Hokanson, J.E., additional, Rennard, S.I., additional, Casaburi, R., additional, Bhatt, S.P., additional, Irvin, M.R., additional, Hersh, C.P., additional, Dransfield, M.T., additional, Washko, G.R., additional, Regan, E.A., additional, and Mcdonald, M.-L.N., additional

Published
2021
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18. Machine Learning Characterization of COPD Subtypes: Insights From the COPDGene Study

Author

Castaldi, P.J., Boueiz, A., Yun, J., Estepar, R.S.J., Ross, J.C., Washko, G., Cho, M.H., Hersh, C.P., Kinney, G.L., Young, K.A., Regan, E.A., Lynch, D.A., Criner, G.J., Dy, J.G., Rennard, S.I., Casaburi, R., Make, B.J., Crapo, J., Ginneken, B. van, Silverman, E.K., and Hokanson, J.E.

Subjects
Diagnostic Imaging, Chronic Obstructive, Molecular Epidemiology, COPDGene Investigators, Chronic Obstructive Pulmonary Disease, Clinical Sciences, Respiratory System, Respiratory Function Tests, respiratory tract diseases, Pulmonary Disease, Machine Learning, Phenotype, emphysema, Disease Progression, Genetics, Respiratory, Humans, Cluster Analysis, COPD, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Aetiology, Lung, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Genome-Wide Association Study
Abstract

Contains fulltext : 220804.pdf (Publisher’s version ) (Open Access) COPD is a heterogeneous syndrome. Many COPD subtypes have been proposed, but there is not yet consensus on how many COPD subtypes there are and how they should be defined. The COPD Genetic Epidemiology Study (COPDGene), which has generated 10-year longitudinal chest imaging, spirometry, and molecular data, is a rich resource for relating COPD phenotypes to underlying genetic and molecular mechanisms. In this article, we place COPDGene clustering studies in context with other highly cited COPD clustering studies, and summarize the main COPD subtype findings from COPDGene. First, most manifestations of COPD occur along a continuum, which explains why continuous aspects of COPD or disease axes may be more accurate and reproducible than subtypes identified through clustering methods. Second, continuous COPD-related measures can be used to create subgroups through the use of predictive models to define cut-points, and we review COPDGene research on blood eosinophil count thresholds as a specific example. Third, COPD phenotypes identified or prioritized through machine learning methods have led to novel biological discoveries, including novel emphysema genetic risk variants and systemic inflammatory subtypes of COPD. Fourth, trajectory-based COPD subtyping captures differences in the longitudinal evolution of COPD, addressing a major limitation of clustering analyses that are confounded by disease severity. Ongoing longitudinal characterization of subjects in COPDGene will provide useful insights about the relationship between lung imaging parameters, molecular markers, and COPD progression that will enable the identification of subtypes based on underlying disease processes and distinct patterns of disease progression, with the potential to improve the clinical relevance and reproducibility of COPD subtypes.

Published
2020

19. Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts

Author

Moll, M., Sakornsakolpat, P., Shrine, N., Hobbs, B.D., Demeo, D.L. (Dawn), John, C, Guyatt, A.L., McGeachie, M.J., Gharib, S.A. (Sina), Obeidat, M. (Ma'en), Lahousse, L. (Lies), Wijnant, S.R.A., Brusselle, G.G. (Guy), Meyers, DA, Bleecker, E.R. (E.), Li, X. (Xinna), Tal-Singer, R., Manichaikul, A. (Ani), Rich, S.S. (Stephen), Won, S, Kim, WJ, Do, A.R., Washko, G.R., Barr, R.G. (Graham), Psaty, B.M. (Bruce), Bartz, TM, Hansel, C.R.W. (Christian), Barnes, K. (Kelly), Hokanson, J.E., Crapo, R.O. (Robert), Lynch, D., Bakke, A.B. (Arnold B.), Gulsvik, A. (Amund), Hall, I.P. (Ian), Wain, L., Weiss, ST, Silverman, E.K. (Edwin), Dudbridge, F. (Frank), Tobin, M.D. (Martin), Cho, M.H. (Michael), Moll, M., Sakornsakolpat, P., Shrine, N., Hobbs, B.D., Demeo, D.L. (Dawn), John, C, Guyatt, A.L., McGeachie, M.J., Gharib, S.A. (Sina), Obeidat, M. (Ma'en), Lahousse, L. (Lies), Wijnant, S.R.A., Brusselle, G.G. (Guy), Meyers, DA, Bleecker, E.R. (E.), Li, X. (Xinna), Tal-Singer, R., Manichaikul, A. (Ani), Rich, S.S. (Stephen), Won, S, Kim, WJ, Do, A.R., Washko, G.R., Barr, R.G. (Graham), Psaty, B.M. (Bruce), Bartz, TM, Hansel, C.R.W. (Christian), Barnes, K. (Kelly), Hokanson, J.E., Crapo, R.O. (Robert), Lynch, D., Bakke, A.B. (Arnold B.), Gulsvik, A. (Amund), Hall, I.P. (Ian), Wain, L., Weiss, ST, Silverman, E.K. (Edwin), Dudbridge, F. (Frank), Tobin, M.D. (Martin), and Cho, M.H. (Michael)

Abstract

Background Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes. Methods We constructed a polygenic risk score using a genome-wide association study of lung function (FEV1 and FEV1/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV1/FVC <0·7 and FEV1 <80% of predicted). Associations were tested using logistic regression models, adjusting for age, sex, height, smoking pack-years, and principal components of genetic ancestry. We assessed predictive performance of models by area under the curve. In a subset of studies, we also studied quantitative and qualitative CT imaging phenotypes that reflect parenchymal and airway pathology, and patterns of reduced lung growth. Findings The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81 [95% CI 1·74–1·88] and non-European (1·42 [1·34–1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56–9·72) in European ancestry and 4·83 (3·45–6·77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79–0·81] vs 0·76 [0·75–0·76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive emphysema subtypes. The polygenic risk score was associated with a reduce

Published
2020

20. Expanding the genetic architecture of nicotine dependence and its shared genetics with multiple traits

Author

Quach, B.C., Bray, M.J., Gaddis, N.C., Liu, M., Palviainen, T., Minica, C.C., Zellers, S., Sherva, R., Aliev, F., Nothnagel, M., Young, K.A., Marks, J., Young, H., Guo, Y., Waldrop, A., Sey, N., Landi, M.T., McNeil, D.W., Farrer, L.A., Markunas, C.A., Vink, J.M., Hottenga, J.J., Iacono, W.G., Kranzler, H.R., Saccone, N.L., Neale, M.C., Madden, P.A.F., Rietschel, M., Marazita, M.L., McGue, M.K., Won, H., Winterer, G., Grucza, R.A., Dick, D.M., Gelernter, J., Caporaso, N.E., Baker, T.B., Boomsma, D.I., Kaprio, J., Hokanson, J.E., Vrieze, S., Bierut, L.J., Johnson, E.O., Hancock, D.B., Quach, B.C., Bray, M.J., Gaddis, N.C., Liu, M., Palviainen, T., Minica, C.C., Zellers, S., Sherva, R., Aliev, F., Nothnagel, M., Young, K.A., Marks, J., Young, H., Guo, Y., Waldrop, A., Sey, N., Landi, M.T., McNeil, D.W., Farrer, L.A., Markunas, C.A., Vink, J.M., Hottenga, J.J., Iacono, W.G., Kranzler, H.R., Saccone, N.L., Neale, M.C., Madden, P.A.F., Rietschel, M., Marazita, M.L., McGue, M.K., Won, H., Winterer, G., Grucza, R.A., Dick, D.M., Gelernter, J., Caporaso, N.E., Baker, T.B., Boomsma, D.I., Kaprio, J., Hokanson, J.E., Vrieze, S., Bierut, L.J., Johnson, E.O., and Hancock, D.B.

Abstract

Contains fulltext : 276901.pdf (Publisher’s version ) (Open Access), Cigarette smoking is the leading cause of preventable morbidity and mortality. Genetic variation contributes to initiation, regular smoking, nicotine dependence, and cessation. We present a Fagerström Test for Nicotine Dependence (FTND)-based genome-wide association study in 58,000 European or African ancestry smokers. We observe five genome-wide significant loci, including previously unreported loci MAGI2/GNAI1 (rs2714700) and TENM2 (rs1862416), and extend loci reported for other smoking traits to nicotine dependence. Using the heaviness of smoking index from UK Biobank (N = 33,791), rs2714700 is consistently associated; rs1862416 is not associated, likely reflecting nicotine dependence features not captured by the heaviness of smoking index. Both variants influence nearby gene expression (rs2714700/MAGI2-AS3 in hippocampus; rs1862416/TENM2 in lung), and expression of genes spanning nicotine dependence-associated variants is enriched in cerebellum. Nicotine dependence (SNP-based heritability = 8.6%) is genetically correlated with 18 other smoking traits (rg = 0.40–1.09) and co-morbidities. Our results highlight nicotine dependence-specific loci, emphasizing the FTND as a composite phenotype that expands genetic knowledge of smoking

Published
2020

22. Lung Volumes Differences Across GOLD Stages of COPD in VA Electronic Health Records, COPDGene, and SPIROMICS

Author

Arjomandi, M., primary, Zeng, S., additional, Mogilnicka, I., additional, Barjaktarevic, I., additional, Barr, R.G., additional, Bhakta, N.R., additional, Bleecker, E.R., additional, Bowler, R.P., additional, Buhr, R.G., additional, Criner, G.J., additional, Comellas, A.P., additional, Cooper, C.B., additional, Couper, D., additional, Curtis, J.L., additional, Dransfield, M.T., additional, Fortis, S., additional, Han, M.K., additional, Hansel, N.N., additional, Hoffman, E.A., additional, Hokanson, J.E., additional, Kaner, R.J., additional, Kanner, R.E., additional, Krishnan, J.A., additional, Lazarus, S.C., additional, Lynch, D.A., additional, Paine, R., additional, Peters, S.P., additional, Ragland, M., additional, Regan, E.A., additional, Rennard, S.I., additional, and Woodruff, P., additional

Published
2020
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23. Polygenic Risk Scores in Chronic Obstructive Pulmonary Disease and Related Phenotypes

Author

Moll, M., primary, Sakornsakolpat, P., additional, Shrine, N., additional, Hobbs, B.D., additional, DeMeo, D.L., additional, John, C., additional, Guyatt, A., additional, McGeachie, M., additional, Gharib, S.A., additional, Obeidat, M., additional, Lahousse, L., additional, Wijnant, S., additional, Brusselle, G.G., additional, Meyers, D.A., additional, Bleecker, E.R., additional, Li, X., additional, Tal-Singer, R., additional, Manichaikul, A., additional, Rich, S., additional, Won, S., additional, Do, A.R., additional, Washko, G.R., additional, Barr, R.G., additional, Psaty, B., additional, Bartz, T., additional, Hansel, N.N., additional, Barnes, K., additional, Hokanson, J.E., additional, Crapo, J.D., additional, Lynch, D.A., additional, Bakke, P., additional, Gulsvik, A., additional, Hall, I.P., additional, Wain, L.V., additional, Kim, W.J., additional, Weiss, S.T., additional, Silverman, E.K., additional, Dudbridge, F., additional, Tobin, M.D., additional, and Cho, M.H., additional

Published
2020
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26. 10 Year Follow-Up of Cigarette Smokers with Normal Spirometry

Author

Ragland, M., primary, Kinney, G.L., additional, Austin, E., additional, Regan, E.A., additional, Strand, M., additional, Wan, E.S., additional, Young, K.A., additional, Hokanson, J.E., additional, Silverman, E.K., additional, Make, B.J., additional, and Crapo, J.D., additional

Published
2020
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27. Predictors of Mortality and Accelerated Loss of Lung Function in Smokers with FEV1/FVC 蠅 0.7: An Analysis of the COPDGene Cohort

Author

Labaki, W.W., primary, Gu, T., additional, Murray, S., additional, Ferrera, M., additional, Curtis, J.L., additional, Martinez, F.J., additional, Vummidi, D.R., additional, Kazerooni, E.A., additional, Lynch, D.A., additional, Beaty, T.H., additional, Hokanson, J.E., additional, Everett, D.C., additional, Bowler, R.P., additional, Make, B.J., additional, Regan, E.A., additional, Silverman, E.K., additional, Crapo, J.D., additional, and Han, M.K., additional

Published
2020
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33. Causes and Predictors of Death in Smokers with and Without COPD: An Analysis of the COPDGene Cohort

Author

Labaki, W.W., primary, Gu, T., additional, Murray, S., additional, Curtis, J.L., additional, Soler, X., additional, Bhatt, S.P., additional, Bon, J.M., additional, Beaty, T., additional, Hokanson, J.E., additional, Curran-Everett, D., additional, Bowler, R.P., additional, Make, B.J., additional, Regan, E.A., additional, Silverman, E.K., additional, Crapo, J.D., additional, and Han, M.K., additional

Published
2019
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36. Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence

Author

Hancock, D.B., Guo, Y., Reginsson, G.W., Gaddis, N.C., Lutz, S.M., Sherva, R., Loukola, A., Minica, C.C., Markunas, C.A., Han, Y., Young, K.A., Gudbjartsson, D.F., Gu, F., McNeil, D.W., Qaiser, B., Glasheen, C., Olson, S., Landi, M.T., Madden, P.A.F., Farrer, L.A., Vink, J.M., Saccone, N.L., Neale, M.C., Kranzler, H.R., McKay, J., Hung, R.J., Amos, C.I., Marazita, M.L., Boomsma, D.I., Baker, T.B., Gelernter, J., Kaprio, J., Caporaso, N.E., Thorgeirsson, T.E., Hokanson, J.E., Bierut, L.J., Stefansson, K., Johnson, E.O., Hancock, D.B., Guo, Y., Reginsson, G.W., Gaddis, N.C., Lutz, S.M., Sherva, R., Loukola, A., Minica, C.C., Markunas, C.A., Han, Y., Young, K.A., Gudbjartsson, D.F., Gu, F., McNeil, D.W., Qaiser, B., Glasheen, C., Olson, S., Landi, M.T., Madden, P.A.F., Farrer, L.A., Vink, J.M., Saccone, N.L., Neale, M.C., Kranzler, H.R., McKay, J., Hung, R.J., Amos, C.I., Marazita, M.L., Boomsma, D.I., Baker, T.B., Gelernter, J., Kaprio, J., Caporaso, N.E., Thorgeirsson, T.E., Hokanson, J.E., Bierut, L.J., Stefansson, K., and Johnson, E.O.

Abstract

Item does not contain fulltext, Cigarette smoking is a leading cause of preventable mortality worldwide. Nicotine dependence, which reduces the likelihood of quitting smoking, is a heritable trait with firmly established associations with sequence variants in nicotine acetylcholine receptor genes and at other loci. To search for additional loci, we conducted a genome-wide association study (GWAS) meta-analysis of nicotine dependence, totaling 38,602 smokers (28,677 Europeans/European Americans and 9925 African Americans) across 15 studies. In this largest-ever GWAS meta-analysis for nicotine dependence and the largest-ever cross-ancestry GWAS meta-analysis for any smoking phenotype, we reconfirmed the well-known CHRNA5-CHRNA3-CHRNB4 genes and further yielded a novel association in the DNA methyltransferase gene DNMT3B. The intronic DNMT3B rs910083-C allele (frequency=44-77%) was associated with increased risk of nicotine dependence at P=3.7 [times] 10-8 (odds ratio (OR)=1.06 and 95% confidence interval (CI)=1.04-1.07 for severe vs mild dependence). The association was independently confirmed in the UK Biobank (N=48,931) using heavy vs never smoking as a proxy phenotype (P=3.6 [times] 10-4, OR=1.05, and 95% CI=1.02-1.08). Rs910083-C is also associated with increased risk of squamous cell lung carcinoma in the International Lung Cancer Consortium (N=60,586, meta-analysis P=0.0095, OR=1.05, and 95% CI=1.01-1.09). Moreover, rs910083-C was implicated as a cis-methylation quantitative trait locus (QTL) variant associated with higher DNMT3B methylation in fetal brain (N=166, P=2.3 [times] 10-26) and a cis-expression QTL variant associated with higher DNMT3B expression in adult cerebellum from the Genotype-Tissue Expression project (N=103, P=3.0 [times] 10-6) and the independent Brain eQTL Almanac (N=134, P=0.028). This novel DNMT3B cis-acting QTL variant highlights the importance of genetically influenced regulation in brain on the risks of nicotine dependence, heavy smoking and consequent lung cancer.

Published
2018

37. Association between telomere length and risk of cancer and non-neoplastic diseases a mendelian randomization study

Author

Haycock, P. (Philip), Burgess, S. (Stephen), Nounu, A. (Aayah), Zheng, J. (Jie), Okoli, G.N. (George N.), Bowden, J., Wade, K.H. (Kaitlin Hazel), Timpson, N.J. (Nicholas J.), Evans, D.M. (David M.), Willeit, P. (Peter), Aviv, A. (Abraham), Gaunt, T.R. (Tom), Hemani, G., Mangino, M. (Massimo), Ellis, H.P. (Hayley Patricia), Kurian, K.M. (Kathreena M.), Pooley, K.A. (Karen A.), Eeles, R. (Rosalind), Lee, J.E. (Jeffrey E.), Fang, S. (Shenying), Chen, W.V. (Wei V.), Law, M.H. (Matthew H.), Bowdler, L.M. (Lisa M.), Iles, M.M. (Mark M.), Yang, Q. (Qiong Fang), Worrall, B.B. (Bradford B.), Markus, H.S. (Hugh), Hung, R.J. (Rayjean J.), Amos, W., Spurdle, A.B. (Amanda), Thompson, D. (Deborah), O'Mara, T.A. (Tracy A.), Wolpin, B. (Brian), Amundadottir, L. (Laufey), Stolzenberg-Solomon, R. (Rachael), Trichopoulou, A. (Antonia), Onland-Moret, N.C. (Charlotte), Lund, E. (Eiliv), Duell, E.J. (Eric), Canzian, F. (Federico), Severi, G. (Gianluca), Overvad, K. (Kim), Gunter, M.J. (Marc J.), Tumino, R. (Rosario), Svenson, U. (Ulrika), Rij, A.M. (Andre) van, Baas, A.F. (Annette), Bown, N., Samani, N.J. (Nilesh), Van t'Hof, F.N.G. (Femke N.G.), Tromp, G. (Gerard), Jones, G.T. (Gregory T.), Kuivaniemi, H. (Helena), Elmore, J.R. (James R.), Johansson, M. (Mattias), Mckay, J. (James), Scelo, G. (Ghislaine), Carreras-Torres, R. (Robert), Gaborieau, V. (Valerie), Brennan, P. (Paul), Bracci, P.M. (Paige M.), Neale, R.E. (Rachel E.), Olson, S.H. (Sara H.), Gallinger, S. (Steve), Li, D. (Donghui), Olson, S.H. (Sara), Risch, H. (Harvey), Klein, A.P. (Alison P.), Han, J., Abnet, C.C. (Christian C.), Freedman, N.D. (Neal D.), Taylor, P.R. (Phil R.), Maris, J.M. (John), Aben, K.K.H. (Katja), Kiemeney, L.A.L.M. (Bart), Vermeulen, S.H.H.M. (Sita), Wiencke, J.K. (John K.), Walsh, K.M. (Kyle M.), Wrensch, M. (Margaret), Rice, T. (Terri), Turnbull, C. (Clare), Litchfield, K. (Kevin), Paternoster, L. (Lavinia), Standl, M. (Marie), Abecasis, G.R. (Gonçalo), SanGiovanni, J.P. (John Paul), Li, Y. (Yong), Mijatovic, V. (Vladan), Sapkota, Y. (Yadav), Low, S.-K. (Siew-Kee), Zondervan, K.T. (Krina), Montgomery, G.W. (Grant W.), Nyholt, D.R. (Dale), Heel, D.A. (David) van, Hunt, K. (Karen), Arking, D.E. (Dan), Ashar, F.N. (Foram N.), Sotoodehnia, N. (Nona), Woo, D. (Daniel), Rosand, J. (Jonathan), Comeau, M.E. (Mary E.), Brown, W.M. (W. Mark), Silverman, E. (Edwin), Hokanson, J.E. (John E.), Cho, M.H. (Michael), Hui, J. (Jennie), Ferreira, M.A. (Manuel A.), Thompson, P.J. (Philip J.), Morrison, A.C. (Alanna), Felix, J.F. (Janine F.), Smith, N.L. (Nicholas L.), Christiano, A.M. (Angela), Petukhova, L. (Lynn), Betz, R.C. (Regina), Fan, X. (Xing), Zhang, X. (Xuejun), Zhu, C. (Caihong), Langefeld, C.D. (Carl), Thompson, S.D. (Susan D.), Wang, F. (Feijie), Lin, X. (Xu), Schwartz, D.A. (David A.), Fingerlin, T.E. (Tasha E.), Rotter, J.I. (Jerome I.), Cotch, M.F. (Mary Frances), Jensen, R.A. (Richard A.), Munz, M. (Matthias), Dommisch, H. (Henrik), Schaefer, A. (Antje), Han, F. (Fang), Ollila, H.M., Hillary, R.P. (Ryan P.), Albagha, O.M.E. (Omar M.), Ralston, S.H. (Stuart), Zeng, C. (Chenjie), Zheng, W. (Wei), Shu, X.-O. (Xiao-Ou), Reis, A. (André), Uebe, S. (Steffen), Hüffmeier, U. (Ulrike), Kawamura, Y. (Yoshiya), Otowa, T. (Takeshi), Sasaki, T. (Tsukasa), Hibberd, M.L. (Martin), Davila, S. (Sonia), Xie, G. (Gang), Siminovitch, K.A. (Katherine), Bei, J.-X. (Jin-Xin), Zeng, Y.X., Försti, A. (Asta), Chen, B. (Bowang), Landi, S. (Stefano), Franke, A. (Andre), Fischer, A. (Annegret), Ellinghaus, D. (David), Flores, C. (Carlos), Noth, I. (Imre), Ma, S.-F. (Shwu-Fan), Foo, J.-N. (Jia-Nee), Liu, J. (Jianjun), Kim, J.-W. (Jong-Won), Cox, D.G. (David), Delattre, O. (Olivier), Mirabeau, O. (Olivier), Skibola, C.F. (Christine F.), Tang, C.S. (Clara S.), Garcia-Barcelo, M., Chang, K.-P. (Kai-Ping), Su, W.-H. (Wen-Hui), Chang, Y.-S. (Yu-Sun), Martin, N.G. (Nicholas G.), Gordon, S.D. (Scott D.), Wade, T.D. (Tracey D.), Lee, C. (Chaeyoung), Kubo, M. (Michiaki), Cha, P.-C. (Pei-Chieng), Nakamura, Y. (Yusuke), Levy, D. (Daniel), Kimura, M. (Masayuki), Hwang, S.-J. (Shih-Jen), Hunt, S.C. (Steven), Spector, T.D. (Timothy), Soranzo, N. (Nicole), Manichaikul, A.W. (Ani W.), Barr, R.G. (Graham), Kahali, B. (Bratati), Speliotes, E.K. (Elizabeth), Yerges-Armstrong, L.M. (Laura), Cheng, C-Y. (Ching-Yu), Jonas, J.B. (Jost B.), Wong, T.Y. (Tien Yin), Fogh, I. (Isabella), Lin, K. (Kuang), Powell, J. (John), Rice, K. (Kenneth), Relton, C.L. (Caroline), Martin, R.M. (Richard M.), Smith, A.V. (Davey), Haycock, P. (Philip), Burgess, S. (Stephen), Nounu, A. (Aayah), Zheng, J. (Jie), Okoli, G.N. (George N.), Bowden, J., Wade, K.H. (Kaitlin Hazel), Timpson, N.J. (Nicholas J.), Evans, D.M. (David M.), Willeit, P. (Peter), Aviv, A. (Abraham), Gaunt, T.R. (Tom), Hemani, G., Mangino, M. (Massimo), Ellis, H.P. (Hayley Patricia), Kurian, K.M. (Kathreena M.), Pooley, K.A. (Karen A.), Eeles, R. (Rosalind), Lee, J.E. (Jeffrey E.), Fang, S. (Shenying), Chen, W.V. (Wei V.), Law, M.H. (Matthew H.), Bowdler, L.M. (Lisa M.), Iles, M.M. (Mark M.), Yang, Q. (Qiong Fang), Worrall, B.B. (Bradford B.), Markus, H.S. (Hugh), Hung, R.J. (Rayjean J.), Amos, W., Spurdle, A.B. (Amanda), Thompson, D. (Deborah), O'Mara, T.A. (Tracy A.), Wolpin, B. (Brian), Amundadottir, L. (Laufey), Stolzenberg-Solomon, R. (Rachael), Trichopoulou, A. (Antonia), Onland-Moret, N.C. (Charlotte), Lund, E. (Eiliv), Duell, E.J. (Eric), Canzian, F. (Federico), Severi, G. (Gianluca), Overvad, K. (Kim), Gunter, M.J. (Marc J.), Tumino, R. (Rosario), Svenson, U. (Ulrika), Rij, A.M. (Andre) van, Baas, A.F. (Annette), Bown, N., Samani, N.J. (Nilesh), Van t'Hof, F.N.G. (Femke N.G.), Tromp, G. (Gerard), Jones, G.T. (Gregory T.), Kuivaniemi, H. (Helena), Elmore, J.R. (James R.), Johansson, M. (Mattias), Mckay, J. (James), Scelo, G. (Ghislaine), Carreras-Torres, R. (Robert), Gaborieau, V. (Valerie), Brennan, P. (Paul), Bracci, P.M. (Paige M.), Neale, R.E. (Rachel E.), Olson, S.H. (Sara H.), Gallinger, S. (Steve), Li, D. (Donghui), Olson, S.H. (Sara), Risch, H. (Harvey), Klein, A.P. (Alison P.), Han, J., Abnet, C.C. (Christian C.), Freedman, N.D. (Neal D.), Taylor, P.R. (Phil R.), Maris, J.M. (John), Aben, K.K.H. (Katja), Kiemeney, L.A.L.M. (Bart), Vermeulen, S.H.H.M. (Sita), Wiencke, J.K. (John K.), Walsh, K.M. (Kyle M.), Wrensch, M. (Margaret), Rice, T. (Terri), Turnbull, C. (Clare), Litchfield, K. (Kevin), Paternoster, L. (Lavinia), Standl, M. (Marie), Abecasis, G.R. (Gonçalo), SanGiovanni, J.P. (John Paul), Li, Y. (Yong), Mijatovic, V. (Vladan), Sapkota, Y. (Yadav), Low, S.-K. (Siew-Kee), Zondervan, K.T. (Krina), Montgomery, G.W. (Grant W.), Nyholt, D.R. (Dale), Heel, D.A. (David) van, Hunt, K. (Karen), Arking, D.E. (Dan), Ashar, F.N. (Foram N.), Sotoodehnia, N. (Nona), Woo, D. (Daniel), Rosand, J. (Jonathan), Comeau, M.E. (Mary E.), Brown, W.M. (W. Mark), Silverman, E. (Edwin), Hokanson, J.E. (John E.), Cho, M.H. (Michael), Hui, J. (Jennie), Ferreira, M.A. (Manuel A.), Thompson, P.J. (Philip J.), Morrison, A.C. (Alanna), Felix, J.F. (Janine F.), Smith, N.L. (Nicholas L.), Christiano, A.M. (Angela), Petukhova, L. (Lynn), Betz, R.C. (Regina), Fan, X. (Xing), Zhang, X. (Xuejun), Zhu, C. (Caihong), Langefeld, C.D. (Carl), Thompson, S.D. (Susan D.), Wang, F. (Feijie), Lin, X. (Xu), Schwartz, D.A. (David A.), Fingerlin, T.E. (Tasha E.), Rotter, J.I. (Jerome I.), Cotch, M.F. (Mary Frances), Jensen, R.A. (Richard A.), Munz, M. (Matthias), Dommisch, H. (Henrik), Schaefer, A. (Antje), Han, F. (Fang), Ollila, H.M., Hillary, R.P. (Ryan P.), Albagha, O.M.E. (Omar M.), Ralston, S.H. (Stuart), Zeng, C. (Chenjie), Zheng, W. (Wei), Shu, X.-O. (Xiao-Ou), Reis, A. (André), Uebe, S. (Steffen), Hüffmeier, U. (Ulrike), Kawamura, Y. (Yoshiya), Otowa, T. (Takeshi), Sasaki, T. (Tsukasa), Hibberd, M.L. (Martin), Davila, S. (Sonia), Xie, G. (Gang), Siminovitch, K.A. (Katherine), Bei, J.-X. (Jin-Xin), Zeng, Y.X., Försti, A. (Asta), Chen, B. (Bowang), Landi, S. (Stefano), Franke, A. (Andre), Fischer, A. (Annegret), Ellinghaus, D. (David), Flores, C. (Carlos), Noth, I. (Imre), Ma, S.-F. (Shwu-Fan), Foo, J.-N. (Jia-Nee), Liu, J. (Jianjun), Kim, J.-W. (Jong-Won), Cox, D.G. (David), Delattre, O. (Olivier), Mirabeau, O. (Olivier), Skibola, C.F. (Christine F.), Tang, C.S. (Clara S.), Garcia-Barcelo, M., Chang, K.-P. (Kai-Ping), Su, W.-H. (Wen-Hui), Chang, Y.-S. (Yu-Sun), Martin, N.G. (Nicholas G.), Gordon, S.D. (Scott D.), Wade, T.D. (Tracey D.), Lee, C. (Chaeyoung), Kubo, M. (Michiaki), Cha, P.-C. (Pei-Chieng), Nakamura, Y. (Yusuke), Levy, D. (Daniel), Kimura, M. (Masayuki), Hwang, S.-J. (Shih-Jen), Hunt, S.C. (Steven), Spector, T.D. (Timothy), Soranzo, N. (Nicole), Manichaikul, A.W. (Ani W.), Barr, R.G. (Graham), Kahali, B. (Bratati), Speliotes, E.K. (Elizabeth), Yerges-Armstrong, L.M. (Laura), Cheng, C-Y. (Ching-Yu), Jonas, J.B. (Jost B.), Wong, T.Y. (Tien Yin), Fogh, I. (Isabella), Lin, K. (Kuang), Powell, J. (John), Rice, K. (Kenneth), Relton, C.L. (Caroline), Martin, R.M. (Richard M.), and Smith, A.V. (Davey)

Abstract

IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer ca

Published
2017
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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. Reduced Bone Density and Vertebral Fractures in Smokers. Men and COPD Patients at Increased Risk

Author

Jaramillo, J.D., Wilson, C., Stinson, D.S., Lynch, D.A., Bowler, R.P., Lutz, S., Bon, J.M., Arnold, B., McDonald, M.L., Washko, G.R., Wan, E.S., DeMeo, D.L., Foreman, M.G., Soler, X., Lindsay, S.E., Lane, N.E., Genant, H.K., Silverman, E.K., Hokanson, J.E., Make, B.J., Crapo, J.D., Regan, E.A., Rikxoort, E.M. van, and Ginneken, B. van

Subjects
Adult, Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Copd patients, low bone density, Osteoporosis, Pulmonary Disease, Chronic Obstructive, Risk Factors, Bone Density, Internal medicine, medicine, COPD, Humans, vertebral fractures, Quantitative computed tomography, Original Research, Bone mineral, COPDGene Investigators, medicine.diagnostic_test, Reduced bone density, business.industry, Incidence, Smoking, Middle Aged, medicine.disease, United States, respiratory tract diseases, quantitative computed tomography, Increased risk, Physical therapy, Spinal Fractures, Female, Tomography, X-Ray Computed, business, Body mass index, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract

Contains fulltext : 152655.pdf (Publisher’s version ) (Open Access) RATIONALE: Former smoking history and chronic obstructive pulmonary disease (COPD) are potential risk factors for osteoporosis and fractures. Under existing guidelines for osteoporosis screening, women are included but men are not, and only current smoking is considered. OBJECTIVES: To demonstrate the impact of COPD and smoking history on the risk of osteoporosis and vertebral fracture in men and women. METHODS: Characteristics of participants with low volumetric bone mineral density (vBMD) were identified and related to COPD and other risk factors. We tested associations of sex and COPD with both vBMD and fractures adjusting for age, race, body mass index (BMI), smoking, and glucocorticoid use. MEASUREMENTS AND MAIN RESULTS: vBMD by calibrated quantitative computed tomography (QCT), visually scored vertebral fractures, and severity of lung disease were determined from chest CT scans of 3,321 current and ex-smokers in the COPDGene study. Low vBMD as a surrogate for osteoporosis was calculated from young adult normal values. Male smokers had a small but significantly greater risk of low vBMD (2.5 SD below young adult mean by calibrated QCT) and more fractures than female smokers. Low vBMD was present in 58% of all subjects, was more frequent in those with worse COPD, and rose to 84% among subjects with very severe COPD. Vertebral fractures were present in 37% of all subjects and were associated with lower vBMD at each Global Initiative for Chronic Obstructive Lung Disease stage of severity. Vertebral fractures were most common in the midthoracic region. COPD and especially emphysema were associated with both low vBMD and vertebral fractures after adjustment for steroid use, age, pack-years of smoking, current smoking, and exacerbations. Airway disease was associated with higher bone density after adjustment for other variables. Calibrated QCT identified more subjects with abnormal values than the standard dual-energy X-ray absorptiometry in a subset of subjects and correlated well with prevalent fractures. CONCLUSIONS: Male smokers, with or without COPD, have a significant risk of low vBMD and vertebral fractures. COPD was associated with low vBMD after adjusting for race, sex, BMI, smoking, steroid use, exacerbations, and age. Screening for low vBMD by using QCT in men and women who are smokers will increase opportunities to identify and treat osteoporosis in this at-risk population.

Published
2015
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42. Chest CT Measures of Muscle and Adipose Tissue in COPD : Gender-based Differences in Content and in Relationships with Blood Biomarkers

Author

Diaz, A.A., Zhou, L., Young, T.P., McDonald, M.L., Harmouche, R., Ross, J.C., Estepar, R.S.J., Wouters, E.F.M., Coxson, H.O., MacNee, W., Rennard, S., Maltais, F., Kinney, G.L., Hokanson, J.E., Washko, G.R., ECLIPSE Investigators, the, Pulmonologie, RS: CAPHRI School for Public Health and Primary Care, and RS: CAPHRI - Asthma and COPD

Subjects
CROSS-SECTIONAL AREA, NATIONAL-HEALTH, LUNG-DISEASE, IL-6, PREDICTOR, MORTALITY, biomarkers, NUTRITION EXAMINATION, OBSTRUCTIVE PULMONARY-DISEASE, BODY-MASS INDEX, INFLAMMATION, pectoralis muscle, REACTIVE PROTEIN, COPD, fibrinogen, CRP, adipose subcutaneous tissue, CT
Abstract

Rationale and Objectives: Computed tomography (CT) of the chest can be used to assess pectoralis muscle area (PMA) and subcutaneous adipose tissue (SAT) area. Adipose tissue content is associated with inflammatory mediators in chronic obstructive pulmonary disease (COPD) subjects. Based on gender differences in body composition, we aimed to assess the hypothesis that in subjects with COPD, the relationships between PMA, SAT, and blood biomarkers of inflammation differ by gender. Materials and Methods: We compared chest CT measures of PMA and SAT on a single slice at aortic arch and supraesternal notch levels from 73 subjects (28 women) with COPD between genders. The relationships of PMA and SAT area to biomarkers were assessed using within-gender regression models. Results: Women had a lesser PMA and a greater SAT area than men (difference-range for PMA, 13.3-22.8 cm(2); for SAT, 11.8-12.4 cm(2); P

Published
2014

43. Common Genetic Variants Associated with Resting Oxygenation in Chronic Obstructive Pulmonary Disease

Author

McDonald, M.L.N., Cho, M.H., Sorheim, I.C., Lutz, S.M., Castaldi, P.J., Lomas, D.A., Coxson, H.O., Edwards, L.D., MacNee, W., Vestbo, J., Yates, J.C., Agusti, A., Calverley, P.M.A., Celli, B., Crim, C., Rennard, S.I., Wouters, E.F.M., Bakke, P., Tal-Singer, R., Miller, B.E., Gulsvik, A., Casaburi, R., Wells, J.M., Regan, E.A., Make, B.J., Hokanson, J.E., Lange, C., Crapo, J.D., Beaty, T.H., Silverman, E.K., Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints, the, COPDGene Investigators, the, Hersh, C.P., Pulmonologie, RS: CAPHRI School for Public Health and Primary Care, RS: NUTRIM - R3 - Chronic inflammatory disease and wasting, and RS: CAPHRI - Asthma and COPD

Subjects
Male, Candidate gene, Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints and COPDGene Investigators, Respiratory System, Clinical Biochemistry, Genome-wide association study, Cardiorespiratory Medicine and Haematology, Gastroenterology, Hypoxemia, Pulmonary Disease, Chronic Obstructive, Anoxia, 80 and over, 2.1 Biological and endogenous factors, Oximetry, Aetiology, Hypoxia, Lung, Original Research, Genetics, African Americans, Aged, 80 and over, COPD, education.field_of_study, Single Nucleotide, Middle Aged, Prognosis, pulse oximetry, Respiratory, Female, medicine.symptom, Human, Pulmonary and Respiratory Medicine, Chronic Obstructive, medicine.medical_specialty, Chronic Obstructive Pulmonary Disease, Rest, Population, European Continental Ancestry Group, Biology, Polymorphism, Single Nucleotide, Chromosomes, White People, Pulmonary Disease, Chromosome 15, Clinical Research, Internal medicine, Genetic variation, medicine, Humans, Genetic Predisposition to Disease, Polymorphism, education, Molecular Biology, Aged, Chromosomes, Human, Pair 15, hypoxemia, Whites, Prevention, Human Genome, Pair 15, Genetic Variation, Cell Biology, Hypoxia (medical), medicine.disease, oxygen saturation, Black or African American, Oxygen, Genome-Wide Association Study
Abstract

Hypoxemia is a major complication of chronic obstructive pulmonary disease (COPD) that correlates with disease prognosis. Identifying genetic variants associated with oxygenation may provide clues for deciphering the heterogeneity in prognosis among patients with COPD. However, previous genetic studies have been restricted to investigating COPD candidate genes for association with hypoxemia. To report results from the first genome-wide association study (GWAS) of resting oxygen saturation (as measured by pulse oximetry [Spo2]) in subjects with COPD, we performed a GWAS of Spo2 in two large, well characterized COPD populations: COPDGene, including both the non-Hispanic white (NHW) and African American (AA) groups, and Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). We identified several suggestive loci (P < 1 × 10(-5)) associated with Spo2 in COPDGene in the NHW (n = 2810) and ECLIPSE (n = 1758) groups, and two loci on chromosomes 14 and 15 in the AA group (n = 820) from COPDGene achieving a level of genome-wide significance (P < 5 × 10(-8)). The chromosome 14 single-nucleotide polymorphism, rs6576132, located in an intergenic region, was nominally replicated (P < 0.05) in the NHW group from COPDGene. The chromosome 15 single-nucleotide polymorphisms were rare in subjects of European ancestry, so the results could not be replicated. The chromosome 15 region contains several genes, including TICRR and KIF7, and is proximal to RHCG (Rh family C glyocoprotein gene). We have identified two loci associated with resting oxygen saturation in AA subjects with COPD, and several suggestive regions in subjects of European descent with COPD. Our study highlights the importance of investigating the genetics of complex traits in different racial groups.

Published
2014
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44. CHRNA5 risk variant predicts delayed smoking cessation and earlier lung cancer diagnosis--a meta-analysis

Author

Chen, L.S., Hung, R.J., Baker, T., Horton, A., Culverhouse, R., Saccone, N., Cheng, I., Deng, B., Han, Y., Hansen, H.M., Horsman, J., Kim, C., Lutz, S., Rosenberger, A., Aben, K.K.H., Andrew, A.S., Breslau, N., Chang, S.C., Dieffenbach, A.K., Dienemann, H., Frederiksen, B., Han, J., Hatsukami, D.K., Johnson, E.O., Pande, M., Wrensch, M.R., McLaughlin, J., Skaug, V., Heijden, H.F.M. van der, Wampfler, J., Wenzlaff, A., Woll, P., Zienolddiny, S., Bickeboller, H., Brenner, H., Duell, E.J., Haugen, A., Heinrich, J., Hokanson, J.E., Hunter, D.J., Kiemeney, B., Lazarus, P., Marchand, L. Le, Liu, G., Mayordomo, J., Risch, A., Schwartz, A.G., Teare, D., Wu, X., Wiencke, J.K., Yang, P., Zhang, Z.F., Spitz, M.R., Kraft, P., Amos, C.I., Bierut, L.J., Chen, L.S., Hung, R.J., Baker, T., Horton, A., Culverhouse, R., Saccone, N., Cheng, I., Deng, B., Han, Y., Hansen, H.M., Horsman, J., Kim, C., Lutz, S., Rosenberger, A., Aben, K.K.H., Andrew, A.S., Breslau, N., Chang, S.C., Dieffenbach, A.K., Dienemann, H., Frederiksen, B., Han, J., Hatsukami, D.K., Johnson, E.O., Pande, M., Wrensch, M.R., McLaughlin, J., Skaug, V., Heijden, H.F.M. van der, Wampfler, J., Wenzlaff, A., Woll, P., Zienolddiny, S., Bickeboller, H., Brenner, H., Duell, E.J., Haugen, A., Heinrich, J., Hokanson, J.E., Hunter, D.J., Kiemeney, B., Lazarus, P., Marchand, L. Le, Liu, G., Mayordomo, J., Risch, A., Schwartz, A.G., Teare, D., Wu, X., Wiencke, J.K., Yang, P., Zhang, Z.F., Spitz, M.R., Kraft, P., Amos, C.I., and Bierut, L.J.

Abstract

Item does not contain fulltext, BACKGROUND: Recent meta-analyses show strong evidence of associations among genetic variants in CHRNA5 on chromosome 15q25, smoking quantity, and lung cancer. This meta-analysis tests whether the CHRNA5 variant rs16969968 predicts age of smoking cessation and age of lung cancer diagnosis. METHODS: Meta-analyses examined associations between rs16969968, age of quitting smoking, and age of lung cancer diagnosis in 24 studies of European ancestry (n = 29 072). In each dataset, we used Cox regression models to evaluate the association between rs16969968 and the two primary phenotypes (age of smoking cessation among ever smokers and age of lung cancer diagnosis among lung cancer case patients) and the secondary phenotype of smoking duration. Heterogeneity across studies was assessed with the Cochran Q test. All statistical tests were two-sided. RESULTS: The rs16969968 allele (A) was associated with a lower likelihood of smoking cessation (hazard ratio [HR] = 0.95, 95% confidence interval [CI] = 0.91 to 0.98, P = .0042), and the AA genotype was associated with a four-year delay in median age of quitting compared with the GG genotype. Among smokers with lung cancer diagnoses, the rs16969968 genotype (AA) was associated with a four-year earlier median age of diagnosis compared with the low-risk genotype (GG) (HR = 1.08, 95% CI = 1.04 to 1.12, P = 1.1*10(-5)). CONCLUSION: These data support the clinical significance of the CHRNA5 variant rs16969968. It predicts delayed smoking cessation and an earlier age of lung cancer diagnosis in this meta-analysis. Given the existing evidence that this CHRNA5 variant predicts favorable response to cessation pharmacotherapy, these findings underscore the potential clinical and public health importance of rs16969968 in CHRNA5 in relation to smoking cessation success and lung cancer risk.

Published
2015

50. Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use

Author

Polderman, T.J.C., Stefansson, K., Zuccolo, L., Wall, T.L., Stan����kov��, A., Zhan, X., Hunter, D.J., Davila-Velderrain, J., Palviainen, T., Brazel, D.M., 23andMe Research Team, Haller, T., Chen, F., Jiang, Y., Johnson, E.O., Rose, R.J., Martin, N.G., Wedow, R., Rice, J.P., Boehnke, M., Jorgenson, E., Posthuma, D., Haessler, J., Kellis, M., Young, K.A., Jansen, P.R., Bjornsdottir, G., Kardia, S.L.R., Metspalu, A., Chen, C., Eaton, C.B., Madden, P.A.F., Gillespie, N.A., McGue, M., Choquet, H., McMahon, G., Jang, S.-K., Faul, J.D., Nielsen, J.B., Fritsche, L.G., Yin, J., Cucca, F., Medland, S.E., Vrieze, S., Thorgeirsson, T.E., Loukola, A., Reginsson, G.W., Tian, C., Orr��, V., HUNT All-In Psychiatry, Iacono, W.G., Gordon, S.D., Kraft, P., Fiorillo, E., Reiner, A.P., Willer, C.J., Boomsma, D.I., Munaf��, M.R., Tyrfingsson, T., Kaprio, J., Laakso, M., Zajac, G.J.M., Willemsen, G., Hickie, I.B., Runarsdottir, V., Li, Y., Hottenga, J.-J., McQueen, M.B., Ehringer, M.A., Zhou, W., Smith, J.A., Taylor, A.E., Tindle, H.A., Kooperberg, C., Boardman, J.D., Lee, J.J., McGuire, D., Zhao, W., Mulas, A., Cornelis, M.C., Lind, P.A., Hveem, K., Weisner, C., Datta, G., Gudbjartsson, D.F., Lutz, S.M., M��gi, R., Hewitt, J.K., Turman, C., Thai, K.K., Stallings, M.C., Kamatani, Y., Hopfer, C.J., David, S.P., Young, H., Rimm, E., Bierut, L.J., Ling, Y., Foerster, J.R., Harris, K.M., Davies, G.E., Krauter, K.S., Matoba, N., Abecasis, G., Esko, T., Keller, M.C., Whitfield, J.B., Liu, D.J., Huang, H., Stitzel, J.A., Liu, M., Peters, U., Saccone, N.L., Docherty, A.R., Pandit, A., Stefansson, H., Hokanson, J.E., Heath, A.C., Okada, Y., Weir, D.R., and Mohlke, K.L.

Subjects
3. Good health
Abstract

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders. They are heritable and etiologically related behaviors that have been resistant to gene discovery efforts. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures.

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