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1. Susceptibility to Chronic Mucus Hypersecretion, a Genome Wide Association Study

Author

Dijkstra, Akkelies E., Smolonska, J, Van Den Berge, M, Wijmenga, C, Zanen, P, Luinge, MA, Platteel, M, Lammers, JW, Dahlback, M, Tosh, K, Hiemstra, PS, Sterk, PJ, Spira, A, Vestbo, J, Nordestgaard, BG, Benn, M, Nielsen, SF, Dahl, M, Verschuren, WM, Picavet, HSJ, Smit, HA, Owsijewitsch, M, Kauczor, HU, De Koning, HJ, Nizankowska-Mogilnicka, E, Mejza, F, Nastalek, P, Van Diemen, CC, Cho, MH, Silverman, EK, Crapo, JD, Beaty, TH, Lomas, DA, Bakke, Per, Gulsvik, Amund, Bosse, Y, Obeidat, MA, Loth, DW, Lahousse, L, Rivadeneira, F, Uitterlinden, AG, Hofman, A, Stricker, BH, Brusselle, GG, Van Duijn, CM, Brouwer, U, Koppelman, GH, Vonk, JM, Nawijn, MC, Groen, HJM, Timens, W, Boezen, HM, Postma, DS, Alizadeh, BZ, De Boer, RA, Bruinenberg, M, Franke, L, Van Der Harst, P, Hillege, HL, Van Der Klauw, MM, Navis, G, Ormel, J, Rosmalen, J, Slaets, JP, Snieder, H, Stolk, RP, Wolffenbuttel, B, Amsterdam institute for Infection and Immunity, Pulmonology, Clinical Chemistry, Public Health, Otorhinolaryngology and Head and Neck Surgery, Epidemiology, Internal Medicine, Groningen Research Institute for Asthma and COPD (GRIAC), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Damage and Repair in Cancer Development and Cancer Treatment (DARE), and Guided Treatment in Optimal Selected Cancer Patients (GUTS)

Subjects
CHROMATIN, Male, Chronic bronchitis, Pulmonology, Epidemiology, OBSTRUCTIVE PULMONARY-DISEASE CHRONIC-BRONCHITIS GENETIC EPIDEMIOLOGY GENERAL-POPULATION BINDING-PROTEIN RISK-FACTORS COPD CHROMATIN SATB1 EXPRESSION, lcsh:Medicine, Genome-wide association study, Lung/metabolism, Mucus/metabolism, Drug Addiction, Matrix Attachment Region Binding Proteins/genetics, Recreational Drug Addiction, Cohort Studies, Pulmonary Disease, Chronic Obstructive, Medicine and Health Sciences, Psychology, Clinical Epidemiology, lcsh:Science, Lung, Cells, Cultured, GENETIC EPIDEMIOLOGY, GENERAL-POPULATION, Aged, 80 and over, education.field_of_study, Multidisciplinary, Medical sciences: 700::Basic medical, dental and veterinary sciences: 710::Medical genetics: 714 [VDP], Genomics, respiratory system, Middle Aged, 3. Good health, Functional Genomics, BINDING-PROTEIN, medicine.anatomical_structure, CHRONIC-BRONCHITIS, Genetic Epidemiology, Medical sciences: 700::Clinical medical sciences: 750::Lung diseases: 777 [VDP], Epidemiological Methods and Statistics, Female, medicine.symptom, Transcriptome Analysis, Medisinske fag: 700::Klinisk medisinske fag: 750::Lungesykdommer: 777 [VDP], Research Article, EXPRESSION, Adult, Chronic Obstructive Pulmonary Disease, Population, Addiction, Single-nucleotide polymorphism, Biology, Environmental and Occupational Lung Diseases, OBSTRUCTIVE PULMONARY-DISEASE, Polymorphism, Single Nucleotide, Environmental Epidemiology, SATB1, SDG 3 - Good Health and Well-being, medicine, Genome-Wide Association Studies, Genetics, SNP, COPD, Humans, education, Lifecourse Epidemiology, Aged, lcsh:R, Biology and Life Sciences, Computational Biology, Correction, Matrix Attachment Region Binding Proteins, Genome Analysis, Pulmonary Disease, Chronic Obstructive/genetics, Medisinske fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714 [VDP], Mucus, Genetic epidemiology, Immunology, Respiratory Infections, Chronic Disease, RISK-FACTORS, Sputum, lcsh:Q, Genome Expression Analysis, Genome-Wide Association Study
Abstract

Background: Chronic mucus hypersecretion (CMH) is associated with an increased frequency of respiratory infections, excess lung function decline, and increased hospitalisation and mortality rates in the general population. It is associated with smoking, but it is unknown why only a minority of smokers develops CMH. A plausible explanation for this phenomenon is a predisposing genetic constitution. Therefore, we performed a genome wide association (GWA) study of CMH in Caucasian populations. Methods: GWA analysis was performed in the NELSON-study using the Illumina 610 array, followed by replication and metaanalysis in 11 additional cohorts. In total 2,704 subjects with, and 7,624 subjects without CMH were included, all current or former heavy smokers (>= 20 pack-years). Additional studies were performed to test the functional relevance of the most significant single nucleotide polymorphism (SNP). Results: A strong association with CMH, consistent across all cohorts, was observed with rs6577641 (p = 4.25610(-6), OR = 1.17), located in intron 9 of the special AT-rich sequence-binding protein 1 locus (SATB1) on chromosome 3. The risk allele (G) was associated with higher mRNA expression of SATB1 (4.3610 29) in lung tissue. Presence of CMH was associated with increased SATB1 mRNA expression in bronchial biopsies from COPD patients. SATB1 expression was induced during differentiation of primary human bronchial epithelial cells in culture. Conclusions: Our findings, that SNP rs6577641 is associated with CMH in multiple cohorts and is a cis-eQTL for SATB1, together with our additional observation that SATB1 expression increases during epithelial differentiation provide suggestive evidence that SATB1 is a gene that affects CMH. Background: Chronic mucus hypersecretion (CMH) is associated with an increased frequency of respiratory infections, excess lung function decline, and increased hospitalisation and mortality rates in the general population. It is associated with smoking, but it is unknown why only a minority of smokers develops CMH. A plausible explanation for this phenomenon is a predisposing genetic constitution. Therefore, we performed a genome wide association (GWA) study of CMH in Caucasian populations. Methods: GWA analysis was performed in the NELSON-study using the Illumina 610 array, followed by replication and meta-analysis in 11 additional cohorts. In total 2,704 subjects with, and 7,624 subjects without CMH were included, all current or former heavy smokers (≥20 pack-years). Additional studies were performed to test the functional relevance of the most significant single nucleotide polymorphism (SNP). Results: A strong association with CMH, consistent across all cohorts, was observed with rs6577641 (p = 4.25x10 -6, OR = 1.17), located in intron 9 of the special AT-rich sequence-binding protein 1 locus (SATB1) on chromosome 3. The risk allele (G) was associated with higher mRNA expression of SATB1 (4.3x10 -9) in lung tissue. Presence of CMH was associated with increased SATB1 mRNA expression in bronchial biopsies from COPD patients. SATB1 expression was induced during differentiation of primary human bronchial epithelial cells in culture. Conclusions: Our findings, that SNP rs6577641 is associated with CMH in multiple cohorts and is a cis-eQTL for SATB1, together with our additional observation that SATB1 expression increases during epithelial differentiation provide suggestive evidence that SATB1 is a gene that affects CMH.

Published
2013
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2. Novel Genes for Airway Wall Thickness Identified with Combined Genome Wide Association and Expression Analyses

Author

Dijkstra, A.E., Postma, D.S., Ginneken, B. van, Wielpuetz, M.O., Schmidt, M., Becker, N., Owsijewitsch, M., Kauczor, H.-U., Koning, H.J. de, Lammers, J.W., Oudkerk, M., Brandsma, C.-A., Bosse, Y., Nickle, D.C., Sin, D.D., Hiemstra, P.S., Wijmenga, C., Smolonska, J., Zanen, P., Vonk, J.M., Berge, M. ten, Boezen, H.M., Groen, H.J.M., Dijkstra, A.E., Postma, D.S., Ginneken, B. van, Wielpuetz, M.O., Schmidt, M., Becker, N., Owsijewitsch, M., Kauczor, H.-U., Koning, H.J. de, Lammers, J.W., Oudkerk, M., Brandsma, C.-A., Bosse, Y., Nickle, D.C., Sin, D.D., Hiemstra, P.S., Wijmenga, C., Smolonska, J., Zanen, P., Vonk, J.M., Berge, M. ten, Boezen, H.M., and Groen, H.J.M.

Abstract

Contains fulltext : 153524.pdf (Publisher’s version ) (Open Access), Rationale Airway wall thickness (AWT) is affected by both environmental and genetic factors and is strongly associated with airflow limitation in smaller airways. Objectives The aim of our study was to investigate its genetic component. Methods AWT was measured on low-dose CT-scans in male heavy smokers participating in a lung cancer screening study (n = 2,640). Genome wide association studies on AWT were performed under an additive model using linear regression (adjusted for pack-years, lung volume), followed by meta-analysis. An independent cohort was used for validation of the most strongly associated single nucleotide polymorphisms (SNPs). The functional relevance of significant SNPs was evaluated. Measurements and main results Three significant loci on chromosomes 2q (rs734556, p = 6.2x10-7) and 10q (rs10794108, p = 8.6x10-8; rs7078439, p = 2.3x10-7) were associated with AWT and confirmed in the meta-analysis in cohorts with comparable lung function: p-values 4.6x10-8, 7.4x10-8 and 7.5x10-8, respectively. SNP rs734556 was associated with decreased lung tissue expression of SERPINE2, a susceptibility gene for emphysema. Two nominally significant SNPs showed effects with similar direction: rs10251504 in MAGI2 (p = 5.8x10-7) and rs4796712 in NT5C3B (p = 3.1x10-6). Higher MAGI2 expression in bronchial biopsies of COPD patients was significantly associated with lower inflammatory cell numbers, lower NT5C3B expression with worse lung function. The NT5C3B risk allele was associated with higher lung tissue expression (p = 1.09x10-41). Conclusions Genetic variants contribute to AWT. Amongst others, the identified genes are involved in emphysema, airway obstruction and bronchial inflammation.

Published
2015

3. Susceptibility to chronic mucus hypersecretion, a genome wide association study

Author

Dijkstra, A.E. (Akkelies), Smolonska, J. (Joanna), Berge, M. (Maarten) van den, Wijmenga, C. (Ciska), Zanen, P. (Pieter), Luinge, M.A. (Marjan), Platteel, I. (Inge), Lammers, J.-W.J. (Jan-Willem), Dahlback, M. (Magnus), Tosh, K. (Kerrie), Hiemstra, P.S. (Pieter), Sterk, P.J. (Peter), Spira, M.E. (Micha), Vestbo, J. (Jorgen), Nordestgaard, B.G. (Børge), Benn, M. (Marianne), Nielsen, S.F. (Sune), Dahl, M. (Morten), Verschuren, W.M.M. (W. M. Monique), Picavet, H.S.J. (Susan), Smit, H.A. (Henriëtte), Owsijewitsch, M. (Michael), Kauczor, H.U. (Hans), Koning, H.J. (Harry) de, Nizankowska-Mogilnicka, E. (Eva), Mejza, F. (Filip), Nastalek, P. (Pawel), Diemen, C.C. (Cleo) van, Cho, M.H. (Michael), Silverman, E.K. (Edwin), Crapo, R.O. (Robert), Beaty, T.H. (Terri), Lomas, D.J. (David John), Bakke, A.B. (Arnold B.), Gulsvik, A. (Amund), Bossé, Y. (Yohan), Obeidat, M. (Ma'en), Loth, D.W. (Daan), Lahousse, L. (Lies), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Hofman, A. (Albert), Stricker, B.H.Ch. (Bruno), Brusselle, G.G. (Guy), Duijn, C.M. (Cornelia) van, Brouwer, U. (Uilke), Koppelman, G.H. (Gerard), Vonk, J.M. (Judith), Nawijn, M.C. (Martijn), Groen, H.J.M. (Henk), Timens, W. (Wim), Boezen, H.M. (Marike), Postma, D.S. (Dirkje), Alizadeh, B.Z. (Behrooz), Boer, R.A. (Rudolf) de, Bruinenberg, M. (M.), Franke, L. (Lude), Harst, P. (Pim) van der, Hillege, H.L. (Hans), Klauw, M.M. (Melanie) van der, Navis, G. (Gerjan), Ormel, J. (Johan), Rosmalen, J.G.M. (Judith), Slaets, J.P.J. (Joris), Snieder, H. (Harold), Stolk, R.P. (Ronald), Wolffenbuttel, B. (Bhr), Dijkstra, A.E. (Akkelies), Smolonska, J. (Joanna), Berge, M. (Maarten) van den, Wijmenga, C. (Ciska), Zanen, P. (Pieter), Luinge, M.A. (Marjan), Platteel, I. (Inge), Lammers, J.-W.J. (Jan-Willem), Dahlback, M. (Magnus), Tosh, K. (Kerrie), Hiemstra, P.S. (Pieter), Sterk, P.J. (Peter), Spira, M.E. (Micha), Vestbo, J. (Jorgen), Nordestgaard, B.G. (Børge), Benn, M. (Marianne), Nielsen, S.F. (Sune), Dahl, M. (Morten), Verschuren, W.M.M. (W. M. Monique), Picavet, H.S.J. (Susan), Smit, H.A. (Henriëtte), Owsijewitsch, M. (Michael), Kauczor, H.U. (Hans), Koning, H.J. (Harry) de, Nizankowska-Mogilnicka, E. (Eva), Mejza, F. (Filip), Nastalek, P. (Pawel), Diemen, C.C. (Cleo) van, Cho, M.H. (Michael), Silverman, E.K. (Edwin), Crapo, R.O. (Robert), Beaty, T.H. (Terri), Lomas, D.J. (David John), Bakke, A.B. (Arnold B.), Gulsvik, A. (Amund), Bossé, Y. (Yohan), Obeidat, M. (Ma'en), Loth, D.W. (Daan), Lahousse, L. (Lies), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Hofman, A. (Albert), Stricker, B.H.Ch. (Bruno), Brusselle, G.G. (Guy), Duijn, C.M. (Cornelia) van, Brouwer, U. (Uilke), Koppelman, G.H. (Gerard), Vonk, J.M. (Judith), Nawijn, M.C. (Martijn), Groen, H.J.M. (Henk), Timens, W. (Wim), Boezen, H.M. (Marike), Postma, D.S. (Dirkje), Alizadeh, B.Z. (Behrooz), Boer, R.A. (Rudolf) de, Bruinenberg, M. (M.), Franke, L. (Lude), Harst, P. (Pim) van der, Hillege, H.L. (Hans), Klauw, M.M. (Melanie) van der, Navis, G. (Gerjan), Ormel, J. (Johan), Rosmalen, J.G.M. (Judith), Slaets, J.P.J. (Joris), Snieder, H. (Harold), Stolk, R.P. (Ronald), and Wolffenbuttel, B. (Bhr)

Abstract

Background: Chronic mucus hypersecretion (CMH) is associated with an increased frequency of respiratory infections, excess lung function decline, and increased hospitalisation and mortality rates in the general population. It is associated with smoking, but it is unknown why only a minority of smokers develops CMH. A plausible explanation for this phenomenon is a predisposing genetic constitution. Therefore, we performed a genome wide association (GWA) study of CMH in Caucasian populations. Methods: GWA analysis was performed in the NELSON-study using the Illumina 610 array, followed by replication and meta-analysis in 11 additional cohorts. In total 2,704 subjects with, and 7,624 subjects without CMH were included, all current or former heavy smokers (≥20 pack-years). Additional studies were performed to test the functional relevance of the most significant single nucleotide polymorphism (SNP). Results: A strong association with CMH, consistent across all cohorts, was observed with rs6577641 (p = 4.25x10-6, OR = 1.17), located in intron 9 of the special AT-rich sequence-binding protein 1 locus (SATB1) on chromosome 3. The risk allele (G) was associated with higher mRNA expression of SATB1 (4.3x10 -9) in lung tissue. Presence of CMH was associated with increased SATB1 mRNA expression in bronchial biopsies from COPD patients. SATB1 expression was induced during differentiation of primary human bronchial epithelial cells in culture. Conclusions: Our findings, that SNP rs6577641 is associated with CMH in multiple cohorts and is a cis-eQTL for SATB1, together with our additional observation that SATB1 expression increases during epithelial differentiation provide suggestive evidence that SATB1 is a gene that affects CMH.

Published
2014
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4. Susceptibility to Chronic Mucus Hypersecretion, a Genome Wide Association Study

Author

Dijkstra, AE, Smolonska, J, van den Berge, M (Maarten), Wijmenga, C, Zanen, P, Luinge, MA, Platteel, M, Lammers, JW, Dahlback, M, Tosh, K, Hiemstra, PS, Sterk, PJ, Spira, A, Vestbo, J, Nordestgaard, BG, Benn, M, Nielsen, SF, Dahl, M, Verschuren, WM, Picavet, HSJ, Smit, HA, Owsijewitsch, M, Kauczor, HU, de Koning, Harry, Nizankowska-Mogilnicka, E, Mejza, F, Nastalek, P, van Diemen, CC, Cho, MH, Silverman, EK, Crapo, JD, Beaty, TH, Lomas, DA, Bakke, P, Gulsvik, A, Bosse, Y, Obeidat, MA, Loth, Daan, Lahousse, Lies, Rivadeneira, Fernando, Uitterlinden, André, Hofman, Bert, Stricker, Bruno, Brusselle, Guy, Duijn, Cornelia, Brouwer, U, Koppelman, GH, Vonk, JM, Nawijn, MC, Groen, HJM, Timens, W, Boezen, HM, Postma, DS, Dijkstra, AE, Smolonska, J, van den Berge, M (Maarten), Wijmenga, C, Zanen, P, Luinge, MA, Platteel, M, Lammers, JW, Dahlback, M, Tosh, K, Hiemstra, PS, Sterk, PJ, Spira, A, Vestbo, J, Nordestgaard, BG, Benn, M, Nielsen, SF, Dahl, M, Verschuren, WM, Picavet, HSJ, Smit, HA, Owsijewitsch, M, Kauczor, HU, de Koning, Harry, Nizankowska-Mogilnicka, E, Mejza, F, Nastalek, P, van Diemen, CC, Cho, MH, Silverman, EK, Crapo, JD, Beaty, TH, Lomas, DA, Bakke, P, Gulsvik, A, Bosse, Y, Obeidat, MA, Loth, Daan, Lahousse, Lies, Rivadeneira, Fernando, Uitterlinden, André, Hofman, Bert, Stricker, Bruno, Brusselle, Guy, Duijn, Cornelia, Brouwer, U, Koppelman, GH, Vonk, JM, Nawijn, MC, Groen, HJM, Timens, W, Boezen, HM, and Postma, DS

Abstract

Background: Chronic mucus hypersecretion (CMH) is associated with an increased frequency of respiratory infections, excess lung function decline, and increased hospitalisation and mortality rates in the general population. It is associated with smoking, but it is unknown why only a minority of smokers develops CMH. A plausible explanation for this phenomenon is a predisposing genetic constitution. Therefore, we performed a genome wide association (GWA) study of CMH in Caucasian populations. Methods: GWA analysis was performed in the NELSON-study using the Illumina 610 array, followed by replication and metaanalysis in 11 additional cohorts. In total 2,704 subjects with, and 7,624 subjects without CMH were included, all current or former heavy smokers (>= 20 pack-years). Additional studies were performed to test the functional relevance of the most significant single nucleotide polymorphism (SNP). Results: A strong association with CMH, consistent across all cohorts, was observed with rs6577641 (p = 4.25610(-6), OR = 1.17), located in intron 9 of the special AT-rich sequence-binding protein 1 locus (SATB1) on chromosome 3. The risk allele (G) was associated with higher mRNA expression of SATB1 (4.3610 29) in lung tissue. Presence of CMH was associated with increased SATB1 mRNA expression in bronchial biopsies from COPD patients. SATB1 expression was induced during differentiation of primary human bronchial epithelial cells in culture. Conclusions: Our findings, that SNP rs6577641 is associated with CMH in multiple cohorts and is a cis-eQTL for SATB1, together with our additional observation that SATB1 expression increases during epithelial differentiation provide suggestive evidence that SATB1 is a gene that affects CMH.

Published
2014

5. GOLD stage predicts thoracic aortic calcifications in patients with COPD.

Author

Jobst BJ, Owsijewitsch M, Kauczor HU, Biederer J, Ley S, Becker N, Kopp-Schneider A, Delorme S, Heussel CP, Puderbach M, Wielpütz MO, and Ley-Zaporozhan J

Abstract

Although some of the associations between chronic obstructive pulmonary disease (COPD) and atherosclerosis are based on shared risk factors such as smoking, recent epidemiological evidence suggests that COPD is a risk factor for vascular disease due to systemic inflammation. The present study assessed the hypothesis that disease severity (as expressed by the GOLD stage) independently predicts the extent of vascular calcifications. A total of 160 smokers diagnosed with COPD (GOLD I-IV, 40 subjects of each GOLD stage) and 40 smokers at risk (GOLD 0; median age of 60 years old; Q1:56;Q3:65; 135 males and 65 females) underwent non-contrast, non-electrocardiography synchronized chest computerised tomography. The volume of thoracic aortic calcifications was quantified semi-automatically within a region from T1 through T12. Multiparametric associations with GOLD stage, smoking history, sex, age, body mass index and emphysema index were evaluated using generalized linear regression analysis. Thoracic aortic calcifications were highly prevalent in this cohort (187/200 subjects, 709 (Q1:109;Q3:2163) mm 3 ). Analysis of variance on ranks demonstrated a significant difference in calcium between different GOLD-stages as well as patients at risk of COPD (F=36.8, P<0.001). In the multivariable analysis, GOLD-stages were indicated to be predictive of thoracic aortic calcifications (P≤0.0033) besides age (P<0.0001), while age appeared to be the strongest predictor. Other variables were not statistically linked to thoracic aortic calcifications in the multivariable model. COPD severity, as expressed by the GOLD-stage, is a significant predictor of thoracic aortic calcifications, independent of covariates such as age or tobacco consumption.

Published
2019
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6. Correction: Susceptibility to chronic mucus hypersecretion, a genome wide association study.

Author

Dijkstra AE, Smolonska J, van den Berge M, Wijmenga C, Zanen P, Luinge MA, Platteel M, Lammers JW, Dahlback M, Tosh K, Hiemstra PS, Sterk PJ, Spira A, Vestbo J, Nordestgaard BG, Benn M, Nielsen SF, Dahl M, Verschuren WM, Picavet HS, Smit HA, Owsijewitsch M, Kauczor HU, de Koning HJ, Nizankowska-Mogilnicka E, Mejza F, Nastalek P, van Diemen CC, Cho MH, Silverman EK, Crapo JD, Beaty TH, Lomas DA, Bakke P, Gulsvik A, Bossé Y, Obeidat M, Loth DW, Lahousse L, Rivadeneira F, Uitterlinden AG, Hofman A, Stricker BH, Brusselle GG, van Duijn CM, Brouwer U, Koppelman GH, Vonk JM, Nawijn MC, Groen HJ, Timens W, Boezen HM, and Postma DS

Published
2015
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7. Novel genes for airway wall thickness identified with combined genome-wide association and expression analyses.

Author

Dijkstra AE, Postma DS, van Ginneken B, Wielpütz MO, Schmidt M, Becker N, Owsijewitsch M, Kauczor HU, de Koning HJ, Lammers JW, Oudkerk M, Brandsma CA, Bossé Y, Nickle DC, Sin DD, Hiemstra PS, Wijmenga C, Smolonska J, Zanen P, Vonk JM, van den Berge M, Boezen HM, and Groen HJ

Subjects
5'-Nucleotidase genetics, Adaptor Proteins, Signal Transducing, Aged, Carrier Proteins genetics, Chromosomes, Human, Pair 10 genetics, Chromosomes, Human, Pair 2 genetics, Female, Gene Expression, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Glycoproteins genetics, Guanylate Kinases, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Pulmonary Emphysema genetics, Serpin E2 genetics, Tomography, X-Ray Computed, Airway Remodeling genetics, Pulmonary Disease, Chronic Obstructive genetics
Abstract

Rationale: Airway wall thickness (AWT) is affected by both environmental and genetic factors and is strongly associated with airflow limitation in smaller airways., Objectives: To investigate the genetic component of AWT., Methods: AWT was measured on low-dose computed tomography scans in male heavy smokers participating in a lung cancer screening study (n = 2,640). Genome-wide association studies on AWT were performed under an additive model using linear regression (adjusted for pack-years, lung volume), followed by metaanalysis. An independent cohort was used for validation of the most strongly associated single-nucleotide polymorphisms (SNPs). The functional relevance of significant SNPs was evaluated., Measurements and Main Results: Three significant loci on chromosomes 2q (rs734556; P =  6.2 × 10(-7)) and 10q (rs10794108, P = 8.6 × 10(-8); rs7078439, P = 2.3 × 10(-7)) were associated with AWT and confirmed in the metaanalysis in cohorts with comparable lung function: P values = 4.6 × 10(-8), 7.4 × 10(-8), and 7.5 × 10(-8), respectively. SNP rs734556 was associated with decreased lung tissue expression of SERPINE2, a susceptibility gene for emphysema. Two nominally significant SNPs showed effects with similar direction: rs10251504 in MAGI2 (P = 5.8 × 10(-7)) and rs4796712 in NT5C3B (P = 3.1 × 10(-6)). Higher MAGI2 expression in bronchial biopsies of patients with chronic obstructive pulmonary disease was significantly associated with fewer inflammatory cells. The presence of the NT5C3B risk allele was associated with higher lung tissue expression (P = 1.09 × 10(-41))., Conclusions: Genetic variants contribute to AWT. Among others, the identified genes are also involved in emphysema, airway obstruction, and bronchial inflammation.

Published
2015
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8. [18F]FDG and [18F]FLT PET-CT and MR imaging of human neuroblastomas in a SCID mouse xenograft model.

Author

Valentiner U, Haane C, Peldschus K, Gustke H, Brenner W, Wilke F, Pommert A, Owsijewitsch M, Schumacher U, and Klutmann S

Subjects
Animals, Cell Line, Tumor, Female, Humans, Magnetic Resonance Imaging methods, Male, Mice, Mice, SCID, Neoplasm Transplantation, Positron-Emission Tomography methods, Transplantation, Heterologous, Dideoxynucleosides, Fluorodeoxyglucose F18, Neuroblastoma diagnostic imaging, Neuroblastoma pathology, Radiopharmaceuticals
Abstract

Background: Finding new therapeutic agents is of great clinical interest in neuroblastoma research because prognosis of children with disseminated stages of disease is still poor. As xenograft mouse models are frequently used for studying anticancer drugs in vivo, small animal imaging is an important method of monitoring in anticancer research., Materials and Methods: SCID mice inoculated with human neuroblastoma SK-N-SH cells were examined with positron-emission tomography-computed tomography (PET-CT) using [18F]fluorodeoxyglucose (FDG) or [18F]fluoro-L-thymidine (FLT) and with magnetic resonance imaging (MRI)., Results: All neuroblastomas were detected by MRI. In PET-CT imaging, no tumour was visualized with [18F]FDG, but 13 out of 14 (93%) were found with [18F]FLT. Uptake of [18F]FLT was significantly associated with tumour weight. Necrotic areas could not be identified either by MR imaging or on PET-CT scans., Conclusion: Both MR and PET-CT imaging with [18F]FLT are highly qualified for the detection of neuroblastomas grown in SCID mice. However, [18F]FDG, which is the standard tracer in clinical PET-CT imaging, is not suited for PET-CT imaging in the neuroblastoma model.

Published
2008

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