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1. Genome-wide association study of body mass index in 23 000 individuals with and without asthma

Author

Melén, E., Granell, R., Kogevinas, M., Strachan, D., Gonzalez, J. R., Wjst, M., Jarvis, D., Ege, M., Braun-Fahrländer, C., Genuneit, J., Horak, E., Bouzigon, E., Demenais, F., Kauffmann, F., Siroux, V., Michel, S., von Berg, A., Heinzmann, A., Kabesch, M., Probst-Hensch, N. M., Curjuric, I., Imboden, M., Rochat, T., Henderson, J., Sterne, J. A. C., McArdle, W. L., Hui, J., James, A. L., Musk, A. William, Palmer, L. J., Becker, A., Kozyrskyj, A. L., Chan-Young, M., Park, J. E., Leung, A., Daley, D., Freidin, M. B., Deev, I. A., Ogorodova, L. M., Puzyrev, V. P., Celedón, J. C., Brehm, J. M., Cloutier, M. M., Canino, G., Acosta-Pérez, E., Soto-Quiros, M., Avila, L., Bergström, A., Magnusson, J., Söderhäll, C., Kull, I., Scholtens, S., Boezen, H. Marike, Koppelman, G. H., Wijga, A. H., Marenholz, I., Esparza-Gordillo, J., Lau, S., Lee, Y. A., Standl, M., Tiesler, C. M. T., Flexeder, C., Heinrich, J., Myers, R. A., Ober, C., Nicolae, D. L., Farrall, M., Kumar, A., Moffatt, M. F., Cookson, W. O. C. M., and Lasky-Su, J.

Published
2013
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4. Author Correction: Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Author

Waage, J, Standl, M, Curtin, JA, Jessen, LE, Thorsen, J, Tian, C, Schoettler, N, 23andMe Research Team, AAGC collaborators, Flores, C, Abdellaoui, A, Ahluwalia, TS, Alves, AC, Amaral, AFS, Antó, JM, Arnold, A, Barreto-Luis, A, Baurecht, H, van Beijsterveldt, CEM, Bleecker, ER, Bonàs-Guarch, S, Boomsma, DI, Brix, S, Bunyavanich, S, Burchard, EG, Chen, Z, Curjuric, I, Custovic, A, den Dekker, HT, Dharmage, SC, Dmitrieva, J, Duijts, L, Ege, MJ, Gauderman, WJ, Georges, M, Gieger, C, Gilliland, F, Granell, R, Gui, H, Hansen, T, Heinrich, J, Henderson, J, Hernandez-Pacheco, N, Holt, P, Imboden, M, Jaddoe, VWV, Jarvelin, M-R, Jarvis, DL, Jensen, KK, Jónsdóttir, I, Kabesch, M, Kaprio, J, Kumar, A, Lee, Y-A, Levin, AM, Li, X, Lorenzo-Diaz, F, Melén, E, Mercader, JM, Meyers, DA, Myers, R, Nicolae, DL, Nohr, EA, Palviainen, T, Paternoster, L, Pennell, CE, Pershagen, G, Pino-Yanes, M, Probst-Hensch, NM, Rüschendorf, F, Simpson, A, Stefansson, K, Sunyer, J, Sveinbjornsson, G, Thiering, E, Thompson, PJ, Torrent, M, Torrents, D, Tung, JY, Wang, CA, Weidinger, S, Weiss, S, Willemsen, G, Williams, LK, Ober, C, Hinds, DA, Ferreira, MA, Bisgaard, H, Strachan, DP, and Bønnelykke, K

Subjects
ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, ComputingMethodologies_IMAGEPROCESSINGANDCOMPUTERVISION, ComputingMethodologies_COMPUTERGRAPHICS
Abstract

In the version of this article initially published, in Fig. 3, the y-axis numbering did not match the log scale indicated in the axis label. The error has been corrected in the HTML and PDF version of the article.

Published
2018

5. Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Author

Waage, J, Standl, M, Curtin, JA, Jessen, L, Thorsen, J, Tian, C, Schoettler, N, The 23andMe Research Team, AAGC Collaborators, Flores, C, Abdellaoui, A, Ahluwalia, TS, Alves, A, Amaral, AFS, Antó, JM, Arnold, A, Barreto-Luis, A, Baurecht, H, van Beijsterveldt, CEM, Bleecker, ER, Bonàs-Guarch, S, Boomsma, D, Brix, S, Bunyavanich, S, Burchard, E, Chen, Z, Curjuric, I, Custovic, A, den Dekker, HT, Dharmage, SC, Dmitrieva, J, Duijts, L, Ege, MJ, Gauderman, WJ, Georges, M, Gieger, C, Gilliland, F, Granell, R, Gui, H, Hansen, T, Heinrich, J, Henderson, J, Hernandez-Pacheco, N, Holt, P, Imboden, M, Jaddoe, VWV, Jarvelin, M-R, Jarvis, DL, Jensen, KK, Jónsdóttir, I, Kabesch, M, Kaprio, J, Kumar, A, Lee, Y-A, Levin, AM, Li, X, Lorenzo-Diaz, F, Melén, E, Mercader, JM, Meyers, DA, Myers, R, Nicolae, DL, Nohr, EA, Palviainen, T, Paternoster, L, Pennell, C, Pershagen, G, Pino-Yanes, M, Probst-Hensch, NM, Rüschendorf, F, Simpson, A, Stefansson, K, Sunyer, J, Sveinbjornsson, G, Thiering, E, Thompson, PJ, Torrent, M, Torrents, D, Tung, JY, Wang, CA, Weidinger, S, Weiss, S, Willemsen, G, Williams, LK, Ober, C, Hinds, DA, Ferreira, MA, Bisgaard, H, Strachan, DP, and Bønnelykke, K

Abstract

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis.

Published
2018

6. Erratum to: Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Author

Waage, J. (Johannes), Standl, M. (Marie), Curtin, J.A. (John), Jessen, L.E. (Leon E.), Thorsen, J. (Jonathan), Tian, C. (Chao), Schoettler, N. (Nathan), Flores, C. (Carlos), Abdellaoui, A. (Abdel), Ahluwalia, T.S. (Tarunveer Singh), Alves, A.C. (Alexessander Couto), Amaral, A.F.S. (André), Anto, J.M. (Josep), Barreto-Luis, A. (Amalia), Baurecht, H. (Hansjörg), Beijsterveldt, C.E.M. (Toos) van, Bleecker, E.R. (E.), Bonàs-Guarch, S. (Silvia), Boomsma, D.I. (Dorret), Brix, S. (Susanne), Bunyavanich, S. (Supinda), Burchard, E.G. (Esteban), Chen, Z. (Zhanghua), Curjuric, I. (Ivan), Custovic, A. (Adnan), Dekker, H.T. (Herman) den, Dharmage, S.C. (Shyamali C.), Dmitrieva, J. (Julia), Duijts, L. (Liesbeth), Ege, M. (Markus), Gauderman, W.J. (W James), Georges, M. (Michel), Gieger, C. (Christian), Gilliland, D.G. (Gary), Granell, R. (Raquel), Gui, H. (Hongsheng), Hansen, T. (Torben), Heinrich, J. (Joachim), Henderson, J. (John), Hernandez-Pacheco, N. (Natalia), Holt, P.G. (Patrick), Imboden, M. (Medea), Jaddoe, V.W.V. (Vincent), Jarvelin, M.-R. (Marjo-Riitta), Jarvis, D.L. (Deborah), Jensen, K.K. (Kamilla K.), Jonsdottir, I. (Ingileif), Kabesch, M. (Michael), Kaprio, J. (Jaakko), Kumar, A. (Ashish), Lee, Y.-A. (Young-Ae), Levin, A.M. (Albert M.), Li, X. (Xingnan), Lorenzo-Diaz, F. (Fabian), Melén, E. (Erik), Mercader, J.M. (Josep M.), Meyers, D.A. (Deborah A.), Myers, R.A. (Rachel A.), Nicolae, D. (Dan), Nohr, C. (Christian), Palviainen, T. (Teemu), Paternoster, L. (Lavinia), Pennell, C.E. (Craig E.), Pershagen, G. (Göran), Pino-Yanes, M. (Maria), Probst-Hensch, N.M. (Nicole M.), Rüschendorf, F. (Franz), Simpson, A. (Angela), Zwart, J-A. (John-Anker), Sunyer, J. (Jordi), Sveinbjornsson, G. (Gardar), Thiering, E. (Elisabeth), Thompson, P.J. (Philip J.), Torrent, M. (Maties), Torrents, D. (David), Tung, J.Y. (Joyce Y.), Wang, C.A. (Carol A.), Weidinger, S. (Stephan), Weiss, S.T. (Scott T.), Willemsen, G.A.H.M. (Gonneke), Williams, L.K. (L. Keoki), Ober, C. (Carole), Hinds, D.A. (David A.), Ferreira, M.A. (Manuel), Bisgaard, H. (Hans), Arnold, A.M. (Alice), Strachan, D.P. (David), Bønnelykke, K. (Klaus), Waage, J. (Johannes), Standl, M. (Marie), Curtin, J.A. (John), Jessen, L.E. (Leon E.), Thorsen, J. (Jonathan), Tian, C. (Chao), Schoettler, N. (Nathan), Flores, C. (Carlos), Abdellaoui, A. (Abdel), Ahluwalia, T.S. (Tarunveer Singh), Alves, A.C. (Alexessander Couto), Amaral, A.F.S. (André), Anto, J.M. (Josep), Barreto-Luis, A. (Amalia), Baurecht, H. (Hansjörg), Beijsterveldt, C.E.M. (Toos) van, Bleecker, E.R. (E.), Bonàs-Guarch, S. (Silvia), Boomsma, D.I. (Dorret), Brix, S. (Susanne), Bunyavanich, S. (Supinda), Burchard, E.G. (Esteban), Chen, Z. (Zhanghua), Curjuric, I. (Ivan), Custovic, A. (Adnan), Dekker, H.T. (Herman) den, Dharmage, S.C. (Shyamali C.), Dmitrieva, J. (Julia), Duijts, L. (Liesbeth), Ege, M. (Markus), Gauderman, W.J. (W James), Georges, M. (Michel), Gieger, C. (Christian), Gilliland, D.G. (Gary), Granell, R. (Raquel), Gui, H. (Hongsheng), Hansen, T. (Torben), Heinrich, J. (Joachim), Henderson, J. (John), Hernandez-Pacheco, N. (Natalia), Holt, P.G. (Patrick), Imboden, M. (Medea), Jaddoe, V.W.V. (Vincent), Jarvelin, M.-R. (Marjo-Riitta), Jarvis, D.L. (Deborah), Jensen, K.K. (Kamilla K.), Jonsdottir, I. (Ingileif), Kabesch, M. (Michael), Kaprio, J. (Jaakko), Kumar, A. (Ashish), Lee, Y.-A. (Young-Ae), Levin, A.M. (Albert M.), Li, X. (Xingnan), Lorenzo-Diaz, F. (Fabian), Melén, E. (Erik), Mercader, J.M. (Josep M.), Meyers, D.A. (Deborah A.), Myers, R.A. (Rachel A.), Nicolae, D. (Dan), Nohr, C. (Christian), Palviainen, T. (Teemu), Paternoster, L. (Lavinia), Pennell, C.E. (Craig E.), Pershagen, G. (Göran), Pino-Yanes, M. (Maria), Probst-Hensch, N.M. (Nicole M.), Rüschendorf, F. (Franz), Simpson, A. (Angela), Zwart, J-A. (John-Anker), Sunyer, J. (Jordi), Sveinbjornsson, G. (Gardar), Thiering, E. (Elisabeth), Thompson, P.J. (Philip J.), Torrent, M. (Maties), Torrents, D. (David), Tung, J.Y. (Joyce Y.), Wang, C.A. (Carol A.), Weidinger, S. (Stephan), Weiss, S.T. (Scott T.), Willemsen, G.A.H.M. (Gonneke), Williams, L.K. (L. Keoki), Ober, C. (Carole), Hinds, D.A. (David A.), Ferreira, M.A. (Manuel), Bisgaard, H. (Hans), Arnold, A.M. (Alice), Strachan, D.P. (David), and Bønnelykke, K. (Klaus)

Abstract

In the version of this article initially published, in Fig. 3, the _y_-axis numbering did not match the log scale indicated in the axis label. The error has been corrected in the HTML and PDF version of the article.

Published
2018
Full Text
View/download PDF

7. Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Author

Waage, J. (Johannes), Standl, M. (Marie), Curtin, J. A. (John A.), Jessen, L. E. (Leon E.), Thorsen, J. (Jonathan), Tian, C. (Chao), Schoettler, N. (Nathan), Flores, C. (Carlos), Abdellaoui, A. (Abdel), Ahluwalia, T. S. (Tarunveer S.), Alves, A. C. (Alexessander C.), Amaral, A. F. (Andre F. S.), Anto, J. M. (Josep M.), Arnold, A. (Andreas), Barreto-Luis, A. (Amalia), Baurecht, H. (Hansjoerg), van Beijsterveldt, C. E. (Catharina E. M.), Bleecker, E. R. (Eugene R.), Bonas-Guarch, S. (Silvia), Boomsman, D. I. (Dorret I.), Brix, S. (Susanne), Bunyavanich, S. (Supinda), Burchard, E. G. (Esteban G.), Chen, Z. (Zhanghua), Curjuric, I. (Ivan), Custovic, A. (Adnan), den Dekker, H. T. (Herman T.), Dharmage, S. C. (Shyamali C.), Dmitrieva, J. (Julia), Duijts, L. (Liesbeth), Ege, M. J. (Markus J.), Gauderman, W. J. (W. James), Georges, M. (Michel), Gieger, C. (Christian), Gilliland, F. (Frank), Granell, R. (Raquel), Gui, H. (Hongsheng), Hansen, T. (Torben), Heinrich, J. (Joachim), Henderson, J. (John), Hernandez-Pacheco, N. (Natalia), Holt, P. (Patrick), Imboden, M. (Medea), Jaddoe, V. W. (Vincent W. V.), Järvelin, M.-R. (Marjo-Riitta), Jarvis, D. L. (Deborah L.), Jensen, K. K. (Kamilla K.), Jonsdottir, I. (Ingileif), Kabesch, M. (Michael), Kaprio, J. (Jaakko), Kumar, A. (Ashish), Lee, Y.-A. (Young-Ae), Levin, A. M. (Albert M.), Li, X. (Xingnan), Lorenzo-Diaz, F. (Fabian), Melen, E. (Erik), Mercader, J. M. (Josep M.), Meyers, D. A. (Deborah A.), Myers, R. (Rachel), Nicolae, D. L. (Dan L.), Nohr, E. A. (Ellen A.), Palviainen, T. (Teemu), Paternoster, L. (Lavinia), Pennell, C. E. (Craig E.), Pershagen, G. (Goran), Pino-Yanes, M. (Maria), Probst-Hensch, N. M. (Nicole M.), Ruschendorf, F. (Franz), Simpson, A. (Angela), Stefansson, K. (Kari), Sunyer, J. (Jordi), Sveinbjornsson, G. (Gardar), Thiering, E. (Elisabeth), Thompson, P. J. (Philip J.), Torrent, M. (Maties), Torrents, D. (David), Tung, J. Y. (Joyce Y.), Wang, C. A. (Carol A.), Weidinger, S. (Stephan), Weiss, S. (Scott), Willemsen, G. (Gonneke), Williams, L. K. (L. Keoki), Ober, C. (Carole), Hinds, D. A. (David A.), Ferreira, M. A. (Manuel A.), Bisgaard, H. (Hans), Strachan, D. P. (David P.), Bonnelykke, K. (Klaus), Waage, J. (Johannes), Standl, M. (Marie), Curtin, J. A. (John A.), Jessen, L. E. (Leon E.), Thorsen, J. (Jonathan), Tian, C. (Chao), Schoettler, N. (Nathan), Flores, C. (Carlos), Abdellaoui, A. (Abdel), Ahluwalia, T. S. (Tarunveer S.), Alves, A. C. (Alexessander C.), Amaral, A. F. (Andre F. S.), Anto, J. M. (Josep M.), Arnold, A. (Andreas), Barreto-Luis, A. (Amalia), Baurecht, H. (Hansjoerg), van Beijsterveldt, C. E. (Catharina E. M.), Bleecker, E. R. (Eugene R.), Bonas-Guarch, S. (Silvia), Boomsman, D. I. (Dorret I.), Brix, S. (Susanne), Bunyavanich, S. (Supinda), Burchard, E. G. (Esteban G.), Chen, Z. (Zhanghua), Curjuric, I. (Ivan), Custovic, A. (Adnan), den Dekker, H. T. (Herman T.), Dharmage, S. C. (Shyamali C.), Dmitrieva, J. (Julia), Duijts, L. (Liesbeth), Ege, M. J. (Markus J.), Gauderman, W. J. (W. James), Georges, M. (Michel), Gieger, C. (Christian), Gilliland, F. (Frank), Granell, R. (Raquel), Gui, H. (Hongsheng), Hansen, T. (Torben), Heinrich, J. (Joachim), Henderson, J. (John), Hernandez-Pacheco, N. (Natalia), Holt, P. (Patrick), Imboden, M. (Medea), Jaddoe, V. W. (Vincent W. V.), Järvelin, M.-R. (Marjo-Riitta), Jarvis, D. L. (Deborah L.), Jensen, K. K. (Kamilla K.), Jonsdottir, I. (Ingileif), Kabesch, M. (Michael), Kaprio, J. (Jaakko), Kumar, A. (Ashish), Lee, Y.-A. (Young-Ae), Levin, A. M. (Albert M.), Li, X. (Xingnan), Lorenzo-Diaz, F. (Fabian), Melen, E. (Erik), Mercader, J. M. (Josep M.), Meyers, D. A. (Deborah A.), Myers, R. (Rachel), Nicolae, D. L. (Dan L.), Nohr, E. A. (Ellen A.), Palviainen, T. (Teemu), Paternoster, L. (Lavinia), Pennell, C. E. (Craig E.), Pershagen, G. (Goran), Pino-Yanes, M. (Maria), Probst-Hensch, N. M. (Nicole M.), Ruschendorf, F. (Franz), Simpson, A. (Angela), Stefansson, K. (Kari), Sunyer, J. (Jordi), Sveinbjornsson, G. (Gardar), Thiering, E. (Elisabeth), Thompson, P. J. (Philip J.), Torrent, M. (Maties), Torrents, D. (David), Tung, J. Y. (Joyce Y.), Wang, C. A. (Carol A.), Weidinger, S. (Stephan), Weiss, S. (Scott), Willemsen, G. (Gonneke), Williams, L. K. (L. Keoki), Ober, C. (Carole), Hinds, D. A. (David A.), Ferreira, M. A. (Manuel A.), Bisgaard, H. (Hans), Strachan, D. P. (David P.), and Bonnelykke, K. (Klaus)

Abstract

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis. An Author Correction to this article was published on 16 August 2018. https://www.nature.com/articles/s41588-018-0197-6

Published
2018

8. Novel childhood asthma genes interact with in utero and early-life tobacco smoke exposure

Author

Scholtens, S, Postma, DS, Moffatt, MF, Panasevich, S, Granell, R, Henderson, AJ, Melén, E, Nyberg, F, Pershagen, G, Jarvis, D, Ramasamy, A, Wjst, M, Svanes, C, Bouzigon, E, Demenais, F, Kauffmann, F, Siroux, V, Von Mutius, E, Ege, MJ, Braun-Fahrländer, C, Genuneit, J, Brunekreef, B, Smit, HA, Wijga, AH, Kerkhof, M, Curjuric, I, Imboden, M, Thun, GA, Probst-Hensch, N, Freidin, MB, Bragina, EI, Deev, IA, Puzyrev, VP, Daley, D, Park, J, Becker, A, Chan-Yeung, M, Kozyrskyj, AL, Pare, P, Marenholz, I, Lau, S, Keil, T, Lee, YA, Kabesch, M, Wijmenga, C, Franke, L, Nolte, IM, Vonk, J, Kumar, A, Farrall, M, Cookson, WOCM, Strachan, DP, Koppelman, GH, Boezen, HM, Life Course Epidemiology (LCE), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Research Institute for Asthma and COPD (GRIAC), and Stem Cell Aging Leukemia and Lymphoma (SALL)

Subjects
Candidate gene, Passive smoking, Immunology, Single-nucleotide polymorphism, VARIANTS, medicine.disease_cause, Polymorphism, Single Nucleotide, PARKIN, Tobacco smoke, 03 medical and health sciences, 0302 clinical medicine, Missing heritability problem, Genetic predisposition, medicine, Humans, Immunology and Allergy, Letter to the Editor, 030304 developmental biology, Asthma, Genetics, 0303 health sciences, business.industry, Microfilament Proteins, medicine.disease, 3. Good health, 030228 respiratory system, Maternal Exposure, Cardiovascular and Metabolic Diseases, Motile cilium, Female, Gene-Environment Interaction, Tobacco Smoke Pollution, business
Abstract

To the Editor: Complex diseases, including asthma, have genetic and environmental origins. Genome-wide association studies have identified multiple genes for the development of asthma, yet they only explain a limited proportion of asthma heritability. Interactions between genetic predisposition and exposure to passive smoking might explain in part the hidden heritability of childhood asthma. However, to date, this approach has not been reported for the discovery of interactions between genes and tobacco smoke exposure. We performed a genome-wide interaction study (GWIS) on childhood asthma to identify genes that interact with 2 well-known environmental risk factors for childhood-onset asthma: in utero and childhood tobacco smoke exposure. We meta-analyzed interaction results from 9 studies participating in the GABRIEL consortium1 including more than 6,000 subjects of European descent. We replicated our findings in 4 independent studies including more than 13,000 subjects. Childhood-onset asthma was defined as asthma diagnosed by a doctor before the age of 16 years, which is consistent with the definition in the GABRIEL consortium.1 In utero tobacco smoke exposure was defined as “exposure to maternal tobacco smoking at any time during pregnancy.” Childhood tobacco smoke exposure was defined as “exposure to passive tobacco smoking at any time from birth until 16 years of age.” Details on the number of subjects, the design of the individual studies, and outcome and exposure definitions are provided in Tables E1 to E4 in this article's Online Repository at www.jacionline.org. The effects of in utero tobacco smoke exposure and childhood tobacco smoke exposure were analyzed separately. All individual studies were analyzed by using a logistic regression model containing the genetic effect, the effect of tobacco smoke exposure, and an interaction term indicating the interaction between the genetic effect and tobacco smoke exposure. Further methodological considerations on GWISs and details on the statistical analyses are described in this article's Online Repository at www.jacionline.org. For in utero tobacco smoke exposure, the discovery genome-wide meta-analysis consisted of 2,654 cases and 3,073 control subjects derived from 7 studies (see Table E1). Overall, in utero tobacco smoke exposure increased the risk of childhood-onset asthma (see Fig E1 in this article's Online Repository at www.jacionline.org). A total of 536,705 single nucleotide polymorphisms (SNPs) were included in the interaction meta-analysis. Fig E2 in this article's Online Repository at www.jacionline.org shows the Manhattan plot. We identified 27 SNPs in the discovery sample with a P value of less than 10−4 based on the fixed effect model (Table I and see Table E5 in this article's Online Repository at www.jacionline.org). Findings did not reach genome-wide significance but were consistent over all studies included, and no significant heterogeneity across studies was present (P value Q-statistic < .05). Four of these SNPs on chromosome 10 were in high linkage disequilibrium with each other in the discovery meta-analysis (r2 = 0.82-0.96). The most prominent marker was located on chromosome 18 near EPB41L3 (Forest plot, see Fig E3 in this article's Online Repository at www.jacionline.org). Table E6 in this article's Online Repository at www.jacionline.org shows the associations in exposed and nonexposed subjects. EPB41L3 belongs to the protein 4.1 family of membrane-associated proteins, is involved in cell-cell junctions,2 and might play a role in apoptosis.3 The literature shows that in utero tobacco smoke exposure affects the expression of genes involved in biological processes, such as cell proliferation and apoptosis, and influences lung development of the child in general.4 Our data suggest that this effect of in utero smoke exposure might potentially occur through mechanisms involving EPB41L3 (see the additional text in this article's Online Repository). Table I Results of the GWIS of in utero tobacco smoke exposure and childhood-onset asthma For childhood tobacco smoke exposure, the discovery genome-wide meta-analysis consisted of 3,048 cases and 3,509 control subjects derived from 9 studies (see Table E1). Overall, childhood tobacco smoke exposure increased the risk of childhood-onset asthma (see Fig E1). A total of 538,233 SNPs were included in the interaction meta-analysis. Fig E4 in this article's Online Repository at www.jacionline.org shows the Manhattan plot. We identified 35 SNPs in the discovery sample with a P value of less than 10−4 based on the fixed effect model. Four of these SNPs were excluded because they showed heterogeneity, and the P value of the random effect was greater than 10−4. Findings did not reach genome-wide significance. Table II and Table E7 (see this article's Online Repository at www.jacionline.org) the results for the top SNPs. Seven SNPs on chromosome 5 (except rs2312164) were in high linkage disequilibrium with each other in the discovery studies (r2 = 0.83-1.00). Table II Results of the GWIS on childhood tobacco smoke exposure and childhood-onset asthma The most prominent marker was located on chromosome 6 in PACRG (parkin coregulated gene; Forest plot, see Fig E5 in this article's Online Repository at www.jacionline.org). Table E8 in this article's Online Repository at www.jacionline.org shows the associations in exposed and nonexposed subjects. PACRG is located next to and has an overlapping promoter region with parkin 2 (PARK2).5 The gene has been associated with leprosy and parkinsonian diseases and has an important role in motile cilia function and cilia morphogenesis.2,6 PACRG is relatively highly expressed in the trachea and nasal mucosa. Ciliary dysfunction might impair mucus clearance from the airways and has been shown to affect asthma severity. Our data suggest that changes in ciliary function particularly affect the development of asthma in children exposed to passive tobacco smoke. The genes that have been reported previously to interact with tobacco smoke exposure with respect to asthma development (ie, TNF,7 GSTP1,7 and ADAM338) were not among our most significant hits. This can be explained by the fact that the genetic variants in these candidate gene studies have a strong main effect on asthma development. Bouzigon et al9 showed a more pronounced effect of the 17q21 region on the development of early-onset asthma in children with early-life tobacco smoke exposure than in those without. The genetic effect of these markers in our GWIS showed a similar direction, but the interaction was not significant. This study on childhood asthma is the first hypothesis-free GWIS specifically aiming to identify SNPs that interact with tobacco smoke exposure in disease development. We found suggestive evidence for an interaction between rs8094633 on chromosome 18 near EPB41L3 and in utero tobacco smoke exposure and an interaction between rs1575472 on chromosome 6 in PACRG and childhood tobacco smoke exposure. The SNPs found have not been identified previously in general genome-wide association studies on childhood asthma. Interestingly, the SNPs interacting with in utero and childhood tobacco smoke exposure were different and were not involved in the same pathway (see Fig E6 in this article's Online Repository at www.jacionline.org). Interactions between these SNPs and tobacco smoke exposure in utero and in childhood might explain part of the missing heritability of asthma. Future research needs to confirm these findings and further unravel the biological pathways.

Published
2016

9. Occupational Exposure to Dusts, Gases, and Fumes and Incidence of Chronic Obstructive Pulmonary Disease in the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults

Author

Mehta, A.J., Miedinger, D., Keidel, D., Bettschart, R., Bircher, A., Bridevaux, P.O., Curjuric, I, Kromhout, H., Rochat, T., Rothe, T., Russi, E.W., Schikowski, T., Schindler, C., Schwartz, J., Turk, A., Vermeulen, R., Probst-Hensch, N., Künzli, N., Risk Assessment of Toxic and Immunomodulatory Agents, Dep IRAS, University of Zurich, Mehta, Amar J, Risk Assessment of Toxic and Immunomodulatory Agents, and Dep IRAS

Subjects
Male, Vital capacity, Chronic bronchitis, mineral, air pollution, heart disease, Critical Care and Intensive Care Medicine, Severity of Illness Index, Cohort Studies, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, 540 Chemistry, gender, occupation, Poisson Distribution, Prospective Studies, 030212 general & internal medicine, risk, 10038 Institute of Clinical Chemistry, mineral dust, education.field_of_study, COPD, medicine.diagnostic_test, adult, Incidence, Dust, Swiss, Middle Aged, respiratory system, cohort analysis, Prognosis, forced expiratory volume, Obstructive lung disease, 3. Good health, Causality, Occupational Diseases, fume, Epidemiological Monitoring, chronic bronchitis, Female, dust, Gases, bronchodilating agent, 2706 Critical Care and Intensive Care Medicine, Switzerland, Environmental Monitoring, Adult, Pulmonary and Respiratory Medicine, Spirometry, medicine.medical_specialty, Adolescent, Population, 610 Medicine & health, European, smoking, lung, Young Adult, 03 medical and health sciences, FEV1/FVC ratio, Age Distribution, work, forced vital capacity, gas, Occupational Exposure, Internal medicine, medicine, follow up, Humans, human, Sex Distribution, education, Asthma, business.industry, occupational exposure, prediction, asthma, medicine.disease, respiratory tract diseases, society, 030228 respiratory system, exposure, 2740 Pulmonary and Respiratory Medicine, Physical therapy, business, chronic obstructive lung disease
Abstract

Rationale: There is limited evidence from population-based studies demonstrating incidence of spirometric-defined chronic obstructive pulmonary disease (COPD) in association with occupational exposures. Objectives: We evaluated the association between occupational exposures and incidence of COPD in the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA). Measurements and Main Results: Prebronchodilator ratio of forced expiratory volume in 1 second over forced vital capacity (FEV1/FVC) was measured in 4,267 nonasthmatic SAPALDIA participants ages 18–62 at baseline in 1991 and at follow-up in 2001–2003. COPD was defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criterion (FEV1/FVC < 0.70) and Quanjer reference equation (FEV1/FVC < lower limit of normal [LLN]), and categorized by severity (≥80% and

Published
2012

10. Adult onset asthma and interaction between genes and active tobacco smoking: The GABRIEL consortium

Author

Vonk, J. M., primary, Scholtens, S., additional, Postma, D. S., additional, Moffatt, M. F., additional, Jarvis, D., additional, Ramasamy, A., additional, Wjst, M., additional, Omenaas, E. R., additional, Bouzigon, E., additional, Demenais, F., additional, Nadif, R., additional, Siroux, V., additional, Polonikov, A. V., additional, Solodilova, M., additional, Ivanov, V. P., additional, Curjuric, I., additional, Imboden, M., additional, Kumar, A., additional, Probst-Hensch, N., additional, Ogorodova, L. M., additional, Puzyrev, V. P., additional, Bragina, E. Yu, additional, Freidin, M. B., additional, Nolte, I. M., additional, Farrall, A. M., additional, Cookson, W. O. C. M., additional, Strachan, D. P., additional, Koppelman, G. H., additional, and Boezen, H. M., additional

Published
2017
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11. Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis

Author

Paternoster, L, Standl, M, Waage, J, Baurecht, H, Hotze, M, Strachan, DP, Curtin, JA, Bonnelykke, K, Tian, C, Takahashi, A, Esparza-Gordillo, J, Alves, AC, Thyssen, JP, den Dekker, HT, Ferreira, MA, Altmaier, E, Sleiman, PMA, Xiao, FL, Gonzalez, JR, Marenholz, I, Kalb, B, Pino-Yanes, M, Xu, C-J, Carstensen, L, Groen-Blokhuis, MM, Venturini, C, Pennell, CE, Barton, SJ, Levin, AM, Curjuric, I, Bustamante, M, Kreiner-Moller, E, Lockett, GA, Bacelis, J, Bunyavanich, S, Myers, RA, Matanovic, A, Kumar, A, Tung, JY, Hirota, T, Kubo, M, McArdle, WL, Henderson, AJ, Kemp, JP, Zheng, J, Smith, GD, Rueschendorf, F, Bauerfeind, A, Lee-Kirsch, MA, Arnold, A, Homuth, G, Schmidt, CO, Mangold, E, Cichon, S, Keil, T, Rodriguez, E, Peters, A, Franke, A, Lieb, W, Novak, N, Foelster-Holst, R, Horikoshi, M, Pekkanen, J, Sebert, S, Husemoen, LL, Grarup, N, De Jongste, JC, Rivadeneira, F, Hofman, A, Jaddoe, VWV, Pasmans, SGMA, Elbert, NJ, Uitterlinden, AG, Marks, GB, Thompson, PJ, Matheson, MC, Robertson, CF, Ried, JS, Li, J, Zuo, XB, Zheng, XD, Yin, XY, Sun, LD, McAleer, MA, O'Regan, GM, Fahy, CMR, Campbell, LE, Macek, M, Kurek, M, Hu, D, Eng, C, Postma, DS, Feenstra, B, Geller, F, Hottenga, JJ, Middeldorp, CM, Hysi, P, Bataille, V, Spector, T, Tiesler, CMT, Thiering, E, Pahukasahasram, B, Yang, JJ, Imboden, M, Huntsman, S, Vilor-Tejedor, N, Relton, CL, Myhre, R, Nystad, W, Custovic, A, Weiss, ST, Meyers, DA, Soederhaell, C, Melen, E, Ober, C, Raby, BA, Simpson, A, Jacobsson, B, Holloway, JW, Bisgaard, H, Sunyer, J, Probst-Hensch, NM, Williams, LK, Godfrey, KM, Wang, CA, Boomsma, DI, Melbye, M, Koppelman, GH, Jarvis, D, McLean, WHI, Irvine, AD, Zhang, XJ, Hakonarson, H, Gieger-, C, Burchard, EG, Martin, NG, Duijts, L, Linneberg, A, Jarvelin, M-R, Noethen, MM, Lau, S, Huebner, N, Lee, Y-A, Tamari, M, Hinds, DA, Glass, D, Brown, SJ, Heinrich, J, Evans, DM, Weidinger, S, AAGC, AAGC, and Epidemio, EGL

Abstract

Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis.

Published
2015

13. Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis

Author

Paternoster, L, Standl, M, Chen, CM, Ramasamy, A, Bønnelykke, K, Duijts, L, Ferreira, MA, Alves, AC, Thyssen, JP, Albrecht, E, Baurecht, H, Feenstra, B, Sleiman, PM, Hysi, P, Warrington, NM, Curjuric, I, Myhre, R, Curtin, JA, Groen-Blokhuis, MM, Kerkhof, M, Sääf, A, Franke, A, Ellinghaus, D, Fölster-Holst, R, Dermitzakis, E, Montgomery, SB, Prokisch, H, Heim, K, Hartikainen, AL, Pouta, A, Pekkanen, J, Blakemore, AI, Buxton, JL, Kaakinen, M, Duffy, DL, Madden, PA, Heath, AC, Montgomery, GW, Thompson, PJ, Matheson, MC, Le Souëf, P, Australian Asthma Genetics Consortium (AAGC), St Pourcain, B, Smith, GD, Henderson, J, Kemp, JP, Timpson, NJ, Deloukas, P, Ring, SM, Wichmann, HE, Müller-Nurasyid, M, Novak, N, Klopp, N, Rodríguez, E, McArdle, W, Linneberg, A, Menné, T, Nohr, EA, Hofman, A, Uitterlinden, AG, van Duijn, CM, Rivadeneira, F, de Jongste, JC, van der Valk, RJ, Wjst, M, Jogi, R, Geller, F, Boyd, HA, Murray, JC, Kim, C, Mentch, F, March, M, Mangino, M, Spector, TD, Bataille, V, Pennell, CE, Holt, PG, Sly, P, Tiesler, CM, Thiering, E, Illig, T, Imboden, M, Nystad, W, Simpson, A, Hottenga, JJ, Postma, D, Koppelman, GH, Smit, HA, Söderhäll, C, Chawes, B, Kreiner-Møller, E, Bisgaard, H, Melén, E, Boomsma, DI, Custovic, A, Jacobsson, B, Probst-Hensch, NM, Palmer, LJ, Glass, D, Hakonarson, H, Melbye, M, Jarvis, DL, Jaddoe, VW, Gieger, C, Genetics of Overweight Young Adults (GOYA) Consortium, Strachan, DP, Martin, NG, Jarvelin, MR, Heinrich, J, Evans, DM, Weidinger, S, and EArly Genetics & Lifecourse Epidemiology (EAGLE) Consortium

Abstract

Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 × 10−13) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 × 10−9), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 × 10−8). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis.

Published
2012

15. Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function

Author

Tang, W. (Wenbo), Kowgier, M. (Matthew), Loth, D.W. (Daan), Soler Artigas, M. (Maria), Joubert, B.R. (Bonnie), Hodge, E. (Emily), Gharib, S.A. (Sina), Smith, A.V. (Davey), Ruczinski, I. (Ingo), Gudnason, V. (Vilmundur), Mathias, J. (Jasmine), Harris, T.B. (Tamara), Hansel, C.R.W. (Christian), Launer, L.J. (Lenore), Barnes, K.C. (Kathleen), Hansen, J.G. (Joyanna), Albrecht, E. (Eva), Aldrich, M.C. (Melinda), Allerhand, M.M. (Michael), Barr, R.G. (Graham), Brusselle, G.G. (Guy), Couper, D.J. (David), Curjuric, I. (Ivan), Davies, G. (Gail), Deary, I.J. (Ian), Dupuis, J. (Josée), Fall, M. (Magnus), Foy, M. (Millennia), Franceschini, N. (Nora), Gao, W. (Wei), Gläser, S. (Sven), Gu, X. (Xiangjun), Hancock, D.B. (Dana), Heinrich, J. (Joachim), Hofman, A. (Albert), Imboden, M. (Medea), Ingelsson, E. (Erik), James, A. (Alan), Karrasch, S. (Stefan), Koch, B. (Beate), Kritchevsky, S.B. (Stephen), Kumar, A. (Ashish), Lahousse, L. (Lies), Li, G. (Guo), Lind, L. (Lars), Lindgren, C.M. (Cecilia), Liu, Y. (YongMei), Lohman, K. (Kurt), Lumley, T. (Thomas), McArdle, W.L. (Wendy), Meibohm, B. (Bernd), Morris, A.P. (Andrew), Morrison, A.C. (Alanna), Musk, A.W. (Arthur), North, K.E. (Kari), Palmer, C. (Cameron), Probst-Hensch, N.M. (Nicole M.), Psaty, B.M. (Bruce), Rivadeneira Ramirez, F. (Fernando), Rotter, J.I. (Jerome), Schulz, H. (Holger), Smith, L.J. (Lewis), Sood, A. (Akshay), Starr, J.M. (John), Strachan, D.P. (David), Teumer, A. (Alexander), Uitterlinden, A.G. (André), Völzke, H. (Henry), Voorman, J.M. (Jeanine), Wain, L.V. (Louise), Wells, M.T. (Martin), Wilk, J.B. (Jemma), Williams, O.D. (Dale), Heckbert, S.R. (Susan), Stricker, B.H.Ch. (Bruno), London, S.J. (Stephanie), Fornage, M. (Myriam), Tobin, M.D. (Martin), O'Connor, G.T. (George), Hall, I.P. (Ian), Cassano, P.A. (Patricia), Tang, W. (Wenbo), Kowgier, M. (Matthew), Loth, D.W. (Daan), Soler Artigas, M. (Maria), Joubert, B.R. (Bonnie), Hodge, E. (Emily), Gharib, S.A. (Sina), Smith, A.V. (Davey), Ruczinski, I. (Ingo), Gudnason, V. (Vilmundur), Mathias, J. (Jasmine), Harris, T.B. (Tamara), Hansel, C.R.W. (Christian), Launer, L.J. (Lenore), Barnes, K.C. (Kathleen), Hansen, J.G. (Joyanna), Albrecht, E. (Eva), Aldrich, M.C. (Melinda), Allerhand, M.M. (Michael), Barr, R.G. (Graham), Brusselle, G.G. (Guy), Couper, D.J. (David), Curjuric, I. (Ivan), Davies, G. (Gail), Deary, I.J. (Ian), Dupuis, J. (Josée), Fall, M. (Magnus), Foy, M. (Millennia), Franceschini, N. (Nora), Gao, W. (Wei), Gläser, S. (Sven), Gu, X. (Xiangjun), Hancock, D.B. (Dana), Heinrich, J. (Joachim), Hofman, A. (Albert), Imboden, M. (Medea), Ingelsson, E. (Erik), James, A. (Alan), Karrasch, S. (Stefan), Koch, B. (Beate), Kritchevsky, S.B. (Stephen), Kumar, A. (Ashish), Lahousse, L. (Lies), Li, G. (Guo), Lind, L. (Lars), Lindgren, C.M. (Cecilia), Liu, Y. (YongMei), Lohman, K. (Kurt), Lumley, T. (Thomas), McArdle, W.L. (Wendy), Meibohm, B. (Bernd), Morris, A.P. (Andrew), Morrison, A.C. (Alanna), Musk, A.W. (Arthur), North, K.E. (Kari), Palmer, C. (Cameron), Probst-Hensch, N.M. (Nicole M.), Psaty, B.M. (Bruce), Rivadeneira Ramirez, F. (Fernando), Rotter, J.I. (Jerome), Schulz, H. (Holger), Smith, L.J. (Lewis), Sood, A. (Akshay), Starr, J.M. (John), Strachan, D.P. (David), Teumer, A. (Alexander), Uitterlinden, A.G. (André), Völzke, H. (Henry), Voorman, J.M. (Jeanine), Wain, L.V. (Louise), Wells, M.T. (Martin), Wilk, J.B. (Jemma), Williams, O.D. (Dale), Heckbert, S.R. (Susan), Stricker, B.H.Ch. (Bruno), London, S.J. (Stephanie), Fornage, M. (Myriam), Tobin, M.D. (Martin), O'Connor, G.T. (George), Hall, I.P. (Ian), and Cassano, P.A. (Patricia)

Published
2014
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16. Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function

Author

Tang, WB, Kowgier, M, Loth, Daan, Artigas, MS, Joubert, BR, Hodge, E, Gharib, SA, Smith, AV, Ruczinski, I, Gudnason, V, Mathias, RA, Harris, TB, Hansel, NN, Launer, LJ (Lenore), Barnes, KC, Hansen, JG, Albrecht, E, Aldrich, MC, Allerhand, M, Barr, RG, Brusselle, Guy, Couper, DJ, Curjuric, I, Davies, G, Deary, IJ, Dupuis, J, Fall, T, Foy, M, Franceschini, N, Gao, W, Glaser, S, Gu, XJ, Hancock, DB, Heinrich, J (Joachim), Hofman, Bert, Imboden, M, Ingelsson, E, James, A, Karrasch, S, Koch, B, Kritchevsky, SB, Kumar, A, Lahousse, Lies, Li, G, Lind, L, Lindgren, C, Liu, YM, Lohman, K, Lumley, T, McArdle, WL, Meibohm, B, Morris, AP, Morrison, AC, Musk, B, North, KE, Palmer, LJ, Probst-Hensch, NM, Psaty, BM, Rivadeneira, Fernando, Rotter, JI, Schulz, H, Smith, LJ, Sood, A, Starr, JM, Strachan, DP, Teumer, A, Uitterlinden, André, Volzke, H, Voorman, A, Wain, LV, Wells, MT, Wilk, JB, Williams, OD, Heckbert, SR, Stricker, Bruno, London, SJ, Fornage, M, Tobin, MD, O'Connor, GT, Hall, IP, Cassano, PA, Tang, WB, Kowgier, M, Loth, Daan, Artigas, MS, Joubert, BR, Hodge, E, Gharib, SA, Smith, AV, Ruczinski, I, Gudnason, V, Mathias, RA, Harris, TB, Hansel, NN, Launer, LJ (Lenore), Barnes, KC, Hansen, JG, Albrecht, E, Aldrich, MC, Allerhand, M, Barr, RG, Brusselle, Guy, Couper, DJ, Curjuric, I, Davies, G, Deary, IJ, Dupuis, J, Fall, T, Foy, M, Franceschini, N, Gao, W, Glaser, S, Gu, XJ, Hancock, DB, Heinrich, J (Joachim), Hofman, Bert, Imboden, M, Ingelsson, E, James, A, Karrasch, S, Koch, B, Kritchevsky, SB, Kumar, A, Lahousse, Lies, Li, G, Lind, L, Lindgren, C, Liu, YM, Lohman, K, Lumley, T, McArdle, WL, Meibohm, B, Morris, AP, Morrison, AC, Musk, B, North, KE, Palmer, LJ, Probst-Hensch, NM, Psaty, BM, Rivadeneira, Fernando, Rotter, JI, Schulz, H, Smith, LJ, Sood, A, Starr, JM, Strachan, DP, Teumer, A, Uitterlinden, André, Volzke, H, Voorman, A, Wain, LV, Wells, MT, Wilk, JB, Williams, OD, Heckbert, SR, Stricker, Bruno, London, SJ, Fornage, M, Tobin, MD, O'Connor, GT, Hall, IP, and Cassano, PA

Abstract

Background: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. Methods: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. Results: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P = 5.71 x 10(-7)). In addition, meta-analysis using the five cohorts with >= 3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P = 2.18 x 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. Conclusions: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.

Published
2014

17. Genetic heterogeneity of asthma phenotypes identified by a clustering approach

Author

Siroux, V., primary, Gonzalez, J. R., additional, Bouzigon, E., additional, Curjuric, I., additional, Boudier, A., additional, Imboden, M., additional, Anto, J. M., additional, Gut, I., additional, Jarvis, D., additional, Lathrop, M., additional, Omenaas, E. R., additional, Pin, I., additional, Wjst, M., additional, Demenais, F., additional, Probst-Hensch, N., additional, Kogevinas, M., additional, and Kauffmann, F., additional

Published
2013
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18. Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function

Author

Hancock, D.B. (Dana), Artigas, M.S., Gharib, S.A. (Sina), Henry, A. (Amanda), Manichaikul, A. (Ani), Ramasamy, A. (Adaikalavan), Loth, D.W. (Daan), Imboden, M. (Medea), Koch, B. (Beate), McArdle, W.L. (Wendy), Smith, A.V. (Davey), Smolonska, J. (Joanna), Sood, A. (Akshay), Tang, W. (Wenbo), Wilk, J.B. (Jemma), Zhai, G. (Guangju), Zhao, J.H. (Jing Hua), Aschard, H. (Hugues), Burkart, K.M. (Kristin), Curjuric, I. (Ivan), Eijgelsheim, M. (Mark), Elliott, P. (Paul), Gu, X. (Xiangjun), Harris, T.B. (Tamara), Janson, C. (Christer), Homuth, G. (Georg), Hysi, P.G. (Pirro), Liu, J. (Jason), Loehr, L.R. (Laura), Lohman, K. (Kurt), Loos, R.J.F. (Ruth), Manning, A.K. (Alisa), Marciante, K. (Kristin), Obeidat, M. (Ma'en), Postma, D.S. (Dirkje), Aldrich, M.C. (Melinda), Brusselle, G.G. (Guy), Chen, T.H., Eiriksdottir, G. (Gudny), Franceschini, N. (Nora), Heinrich, J. (Joachim), Rotter, J.I. (Jerome), Wijmenga, C. (Cisca), Williams, O.D. (Dale), Hofman, A. (Albert), Laurie, C.C. (Cathy), Lumley, T. (Thomas), Morrison, A.C. (Alanna), Joubert, B.R. (Bonnie), Rivadeneira Ramirez, F. (Fernando), Couper, D.J. (David), Kritchevsky, S.B. (Stephen), Liu, Y. (YongMei), Wjst, M. (Matthias), Wain, L.V. (Louise), Vonk, J.M. (Judith), Uitterlinden, A.G. (André), Rochat, T. (Thierry), Rich, S.S. (Stephen), Psaty, B.M. (Bruce), O'Connor, G.T. (George), North, K.E. (Kari), Mirel, D. (Daniel), Meibohm, B. (Bernd), Launer, L.J. (Lenore), Khaw, K-T. (Kay-Tee), Hartikainen, A.L., Hammond, C.J. (Christopher), Gläser, S. (Sven), Marchini, J. (Jonathan), Kraft, P. (Peter), Wareham, N.J. (Nick), Völzke, H. (Henry), Stricker, B.H.Ch. (Bruno), Spector, T.D. (Timothy), Probst-Hensch, N.M. (Nicole M.), Jarvis, D.L. (Deborah), Jarvelin, M.-R. (Marjo-Riitta), Heckbert, S.R. (Susan), Gudnason, V. (Vilmundur), Boezen, H.M. (Marike), Barr, R.G. (Graham), Cassano, P.A. (Patricia), Strachan, D.P. (David), Fornage, M. (Myriam), Hall, I.P. (Ian), Dupuis, J. (Josée), Tobin, M.D. (Martin), London, S.J. (Stephanie), Bentley, A.R. (Amy), Hancock, D.B. (Dana), Artigas, M.S., Gharib, S.A. (Sina), Henry, A. (Amanda), Manichaikul, A. (Ani), Ramasamy, A. (Adaikalavan), Loth, D.W. (Daan), Imboden, M. (Medea), Koch, B. (Beate), McArdle, W.L. (Wendy), Smith, A.V. (Davey), Smolonska, J. (Joanna), Sood, A. (Akshay), Tang, W. (Wenbo), Wilk, J.B. (Jemma), Zhai, G. (Guangju), Zhao, J.H. (Jing Hua), Aschard, H. (Hugues), Burkart, K.M. (Kristin), Curjuric, I. (Ivan), Eijgelsheim, M. (Mark), Elliott, P. (Paul), Gu, X. (Xiangjun), Harris, T.B. (Tamara), Janson, C. (Christer), Homuth, G. (Georg), Hysi, P.G. (Pirro), Liu, J. (Jason), Loehr, L.R. (Laura), Lohman, K. (Kurt), Loos, R.J.F. (Ruth), Manning, A.K. (Alisa), Marciante, K. (Kristin), Obeidat, M. (Ma'en), Postma, D.S. (Dirkje), Aldrich, M.C. (Melinda), Brusselle, G.G. (Guy), Chen, T.H., Eiriksdottir, G. (Gudny), Franceschini, N. (Nora), Heinrich, J. (Joachim), Rotter, J.I. (Jerome), Wijmenga, C. (Cisca), Williams, O.D. (Dale), Hofman, A. (Albert), Laurie, C.C. (Cathy), Lumley, T. (Thomas), Morrison, A.C. (Alanna), Joubert, B.R. (Bonnie), Rivadeneira Ramirez, F. (Fernando), Couper, D.J. (David), Kritchevsky, S.B. (Stephen), Liu, Y. (YongMei), Wjst, M. (Matthias), Wain, L.V. (Louise), Vonk, J.M. (Judith), Uitterlinden, A.G. (André), Rochat, T. (Thierry), Rich, S.S. (Stephen), Psaty, B.M. (Bruce), O'Connor, G.T. (George), North, K.E. (Kari), Mirel, D. (Daniel), Meibohm, B. (Bernd), Launer, L.J. (Lenore), Khaw, K-T. (Kay-Tee), Hartikainen, A.L., Hammond, C.J. (Christopher), Gläser, S. (Sven), Marchini, J. (Jonathan), Kraft, P. (Peter), Wareham, N.J. (Nick), Völzke, H. (Henry), Stricker, B.H.Ch. (Bruno), Spector, T.D. (Timothy), Probst-Hensch, N.M. (Nicole M.), Jarvis, D.L. (Deborah), Jarvelin, M.-R. (Marjo-Riitta), Heckbert, S.R. (Susan), Gudnason, V. (Vilmundur), Boezen, H.M. (Marike), Barr, R.G. (Graham), Cassano, P.A. (Patricia), Strachan, D.P. (David), Fornage, M. (Myriam), Hall, I.P. (Ian), Dupuis, J. (Josée), Tobin, M.D. (Martin), London, S.J. (Stephanie), and Bentley, A.R. (Amy)

Published
2012
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19. Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction

Author

Wilk, J.B. (Jemma), Shrine, N.R.G. (Nick), Loehr, L.R. (Laura), Zhao, J.H. (Jing Hua), Manichaikul, A. (Ani), Lopez, L.M. (Lorna), Smith, A.V. (Davey), Heckbert, S.R. (Susan), Smolonska, J. (Joanna), Tang, W. (Wenbo), Loth, D.W. (Daan), Curjuric, I. (Ivan), Hui, J. (Jennie), Cho, M.H. (Michael), Latourelle, J.C. (Jeanne), Henry, A. (Amanda), Aldrich, M.C. (Melinda), Bakke, A.B. (Arnold B.), Beaty, T.H. (Terri), Bentley, A.R. (Amy), Borecki, I.B. (Ingrid), Brusselle, G.G. (Guy), Burkart, K.M. (Kristin), Chen, T.H., Couper, D.J. (David), Crapo, R.O. (Robert), Davies, G. (Gail), Dupuis, J. (Josée), Franceschini, N. (Nora), Gulsvik, A. (Amund), Hancock, D.B. (Dana), Harris, T.B. (Tamara), Hofman, A. (Albert), Imboden, M. (Medea), James, A.L. (Alan), Khaw, K-T. (Kay-Tee), Lahousse, L. (Lies), Launer, L.J. (Lenore), Litonjua, A.A. (Augusto), Liu, Y. (YongMei), Lohman, K. (Kurt), Lomas, D.J. (David John), Lumley, T. (Thomas), Marciante, K. (Kristin), McArdle, W.L. (Wendy), Meibohm, B. (Bernd), Morrison, A.C. (Alanna), Musk, A.W. (Arthur), Myers, R.H. (Richard), North, K.E. (Kari), Postma, D.S. (Dirkje), Psaty, B.M. (Bruce), Rich, S.S. (Stephen), Rivadeneira Ramirez, F. (Fernando), Rochat, T. (Thierry), Rotter, J.I. (Jerome), Soler Artigas, M. (Maria), Starr, J.M. (John), Uitterlinden, A.G. (André), Wareham, N.J. (Nick), Wijmenga, C. (Cisca), Zanen, P. (Pieter), Province, M.A. (Mike), Silverman, E. (Edwin), Deary, I.J. (Ian), Palmer, C. (Cameron), Cassano, P.A. (Patricia), Gudnason, V. (Vilmundur), Barr, R.G. (Graham), Loos, R.J.F. (Ruth), Strachan, D.P. (David), London, S.J. (Stephanie), Boezen, H.M. (Marike), Probst-Hensch, N. (Nicole), Gharib, S.A. (Sina), Hall, I.P. (Ian), O'Connor, G.T. (George), Tobin, M.D. (Martin), Stricker, B.H.Ch. (Bruno), Wilk, J.B. (Jemma), Shrine, N.R.G. (Nick), Loehr, L.R. (Laura), Zhao, J.H. (Jing Hua), Manichaikul, A. (Ani), Lopez, L.M. (Lorna), Smith, A.V. (Davey), Heckbert, S.R. (Susan), Smolonska, J. (Joanna), Tang, W. (Wenbo), Loth, D.W. (Daan), Curjuric, I. (Ivan), Hui, J. (Jennie), Cho, M.H. (Michael), Latourelle, J.C. (Jeanne), Henry, A. (Amanda), Aldrich, M.C. (Melinda), Bakke, A.B. (Arnold B.), Beaty, T.H. (Terri), Bentley, A.R. (Amy), Borecki, I.B. (Ingrid), Brusselle, G.G. (Guy), Burkart, K.M. (Kristin), Chen, T.H., Couper, D.J. (David), Crapo, R.O. (Robert), Davies, G. (Gail), Dupuis, J. (Josée), Franceschini, N. (Nora), Gulsvik, A. (Amund), Hancock, D.B. (Dana), Harris, T.B. (Tamara), Hofman, A. (Albert), Imboden, M. (Medea), James, A.L. (Alan), Khaw, K-T. (Kay-Tee), Lahousse, L. (Lies), Launer, L.J. (Lenore), Litonjua, A.A. (Augusto), Liu, Y. (YongMei), Lohman, K. (Kurt), Lomas, D.J. (David John), Lumley, T. (Thomas), Marciante, K. (Kristin), McArdle, W.L. (Wendy), Meibohm, B. (Bernd), Morrison, A.C. (Alanna), Musk, A.W. (Arthur), Myers, R.H. (Richard), North, K.E. (Kari), Postma, D.S. (Dirkje), Psaty, B.M. (Bruce), Rich, S.S. (Stephen), Rivadeneira Ramirez, F. (Fernando), Rochat, T. (Thierry), Rotter, J.I. (Jerome), Soler Artigas, M. (Maria), Starr, J.M. (John), Uitterlinden, A.G. (André), Wareham, N.J. (Nick), Wijmenga, C. (Cisca), Zanen, P. (Pieter), Province, M.A. (Mike), Silverman, E. (Edwin), Deary, I.J. (Ian), Palmer, C. (Cameron), Cassano, P.A. (Patricia), Gudnason, V. (Vilmundur), Barr, R.G. (Graham), Loos, R.J.F. (Ruth), Strachan, D.P. (David), London, S.J. (Stephanie), Boezen, H.M. (Marike), Probst-Hensch, N. (Nicole), Gharib, S.A. (Sina), Hall, I.P. (Ian), O'Connor, G.T. (George), Tobin, M.D. (Martin), and Stricker, B.H.Ch. (Bruno)

Abstract

Rationale: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known. Objectives: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic ofCOPD assessedby spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases. Methods: Fif

Published
2012
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20. Occupational exposure to dusts, gases, and fumes and incidence of chronic obstructive pulmonary disease in the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults

Author

Risk Assessment of Toxic and Immunomodulatory Agents, Dep IRAS, Mehta, A.J., Miedinger, D., Keidel, D., Bettschart, R., Bircher, A., Bridevaux, P.O., Curjuric, I, Kromhout, H., Rochat, T., Rothe, T., Russi, E.W., Schikowski, T., Schindler, C., Schwartz, J., Turk, A., Vermeulen, R., Probst-Hensch, N., Künzli, N., Risk Assessment of Toxic and Immunomodulatory Agents, Dep IRAS, Mehta, A.J., Miedinger, D., Keidel, D., Bettschart, R., Bircher, A., Bridevaux, P.O., Curjuric, I, Kromhout, H., Rochat, T., Rothe, T., Russi, E.W., Schikowski, T., Schindler, C., Schwartz, J., Turk, A., Vermeulen, R., Probst-Hensch, N., and Künzli, N.

Published
2012

21. Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function

Author

Hancock, DB, Artigas, MS, Gharib, SA, Henry, A, Manichaikul, A, Ramasamy, A, Loth, Daan, Imboden, M, Koch, B, McArdle, WL, Smith, AV, Smolonska, J, Sood, A, Tang, WB, Wilk, JB, Zhai, GJ, Zhao, JH, Aschard, H, Burkart, KM, Curjuric, I, Eijgelsheim, Mark, Elliott, P, Gu, XJ, Harris, TB, Janson, C, Homuth, G, Hysi, PG, Liu, JZ, Loehr, LR, Lohman, K, Loos, RJF, Manning, AK, Marciante, KD, Obeidat, M, Postma, DS, Aldrich, MC, Brusselle, Guy, Chen, TH, Eiriksdottir, G, Franceschini, N, Heinrich, J (Joachim), Rotter, JI, Wijmenga, C, Williams, OD, Bentley, AR, Hofman, Bert, Laurie, CC, Lumley, T, Morrison, AC, Joubert, BR, Rivadeneira, Fernando, Couper, DJ, Kritchevsky, SB, Liu, YM, Wjst, M, Wain, LV, Vonk, JM, Uitterlinden, André, Rochat, T, Rich, SS, Psaty, BM, O'Connor, GT, North, KE, Mirel, DB, Meibohm, B, Launer, LJ (Lenore), Khaw, KT, Hartikainen, AL, Hammond, CJ, Glaser, S, Marchini, J, Kraft, P, Wareham, NJ, Volzke, H, Stricker, Bruno, Spector, TD, Probst-Hensch, NM, Jarvis, D, Jarvelin, MR, Heckbert, SR, Gudnason, V, Boezen, M, Barr, RG, Cassano, PA, Strachan, DP, Fornage, M, Hall, IP, Dupuis, J, Tobin, MD, London, SJ, Hancock, DB, Artigas, MS, Gharib, SA, Henry, A, Manichaikul, A, Ramasamy, A, Loth, Daan, Imboden, M, Koch, B, McArdle, WL, Smith, AV, Smolonska, J, Sood, A, Tang, WB, Wilk, JB, Zhai, GJ, Zhao, JH, Aschard, H, Burkart, KM, Curjuric, I, Eijgelsheim, Mark, Elliott, P, Gu, XJ, Harris, TB, Janson, C, Homuth, G, Hysi, PG, Liu, JZ, Loehr, LR, Lohman, K, Loos, RJF, Manning, AK, Marciante, KD, Obeidat, M, Postma, DS, Aldrich, MC, Brusselle, Guy, Chen, TH, Eiriksdottir, G, Franceschini, N, Heinrich, J (Joachim), Rotter, JI, Wijmenga, C, Williams, OD, Bentley, AR, Hofman, Bert, Laurie, CC, Lumley, T, Morrison, AC, Joubert, BR, Rivadeneira, Fernando, Couper, DJ, Kritchevsky, SB, Liu, YM, Wjst, M, Wain, LV, Vonk, JM, Uitterlinden, André, Rochat, T, Rich, SS, Psaty, BM, O'Connor, GT, North, KE, Mirel, DB, Meibohm, B, Launer, LJ (Lenore), Khaw, KT, Hartikainen, AL, Hammond, CJ, Glaser, S, Marchini, J, Kraft, P, Wareham, NJ, Volzke, H, Stricker, Bruno, Spector, TD, Probst-Hensch, NM, Jarvis, D, Jarvelin, MR, Heckbert, SR, Gudnason, V, Boezen, M, Barr, RG, Cassano, PA, Strachan, DP, Fornage, M, Hall, IP, Dupuis, J, Tobin, MD, and London, SJ

Abstract

Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV1), and its ratio to forced vital capacity (FEV1/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV1 and FEV1/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P-JMA = 5.00 x 10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P-JMA = 4.35 x 10(-9)), and KCNJ2 and SOX9 (smallest P-JMA = 1.28 x 10(-8)) were associated with FEV1/FVC or FEV1 in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.

Published
2012

22. Serum bilirubin is associated with lung function in a Swiss general population sample

Author

Curjuric, I., primary, Imboden, M., additional, Adam, M., additional, Bettschart, R. W., additional, Gerbase, M. W., additional, Kunzli, N., additional, Rochat, T., additional, Rohrer, L., additional, Rothe, T. B., additional, Schwartz, J., additional, Stolz, D., additional, Tschopp, J.-M., additional, von Eckardstein, A., additional, Kronenberg, F., additional, and Probst-Hensch, N. M., additional

Published
2013
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23. Authors' response

Author

Probst-Hensch, N. M., primary, Curjuric, I., additional, Bridevaux, P.-O., additional, Kunzli, N., additional, Schindler, C., additional, and Rochat, T., additional

Published
2010
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24. Prevalence of airflow obstruction in smokers and never-smokers in Switzerland

Author

Bridevaux, P.-O., primary, Probst-Hensch, N. M., additional, Schindler, C., additional, Curjuric, I., additional, Felber Dietrich, D., additional, Braendli, O., additional, Brutsche, M., additional, Burdet, L., additional, Frey, M., additional, Gerbase, M. W., additional, Ackermann-Liebrich, U., additional, Pons, M., additional, Tschopp, J.-M., additional, Rochat, T., additional, and Russi, E. W., additional

Published
2010
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25. Longitudinal change of prebronchodilator spirometric obstruction and health outcomes: results from the SAPALDIA cohort

Author

Probst-Hensch, N. M., primary, Curjuric, I., additional, Pierre-Olivier, B., additional, Ackermann-Liebrich, U., additional, Bettschart, R. W., additional, Brandli, O., additional, Brutsche, M., additional, Burdet, L., additional, Gerbase, M. W., additional, Knopfli, B., additional, Kunzli, N., additional, Pons, M. G., additional, Schindler, C., additional, Tschopp, J.-M., additional, Rochat, T., additional, and Russi, E. W., additional

Published
2009
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27. Decreased PM10 exposure attenuates age-related lung function decline: genetic variants in p53, p21, and CCND1 modify this effect.

Author

Imboden M, Schwartz J, Schindler C, Curjuric I, Berger W, Liu SLJ, Russi EW, Ackermann-Liebrich U, Rochat T, Probst-Hensch NM, and SAPALDIA Team

Abstract

BACKGROUND: Decreasing exposure to airborne particulates was previously associated with reduced age-related decline in lung function. However, whether the benefit from improved air quality depends on genetic background is not known. Recent evidence points to the involvement of the genes p53 and p21 and of the cell cycle control gene cyclin D1 (CCND1) in the response of bronchial cells to air pollution. OBJECTIVE: We determined in 4,326 participants of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) whether four single-nucleotide polymorphisms in three genes [CCND1 (rs9344 [P242P], rs667515), p53 (rs1042522 [R72P]), and p21 (rs1801270 [S31R])] modified the previously observed attenuation of the decline in the forced expiratory flow between 25% and 75% of the forced vital capacity (FEF(25-75)) associated with improved air quality. METHODS: Subjects of the prospective population-based SAPALDIA cohort were assessed in 1991 and 2002 by spirometry, questionnaires, and biological sample collection for genotyping. We assigned spatially resolved concentrations of particulate matter with aerodynamic diameter < or = 10 microm (PM(10)) to each participant's residential history 12 months before the baseline and follow-up assessments. RESULTS: The effect of diminishing PM(10) exposure on FEF(25-75) decline appeared to be modified by p53 R72P, CCND1 P242P, and CCND1 rs667515. For example, a 10-microg/m(3) decline in average PM(10) exposure over an 11-year period attenuated the average annual decline in FEF(25-75) by 21.33 mL/year (95% confidence interval, 10.57-32.08) among participants homozygous for the CCND1 (P242P) GG genotype, by 13.72 mL/year (5.38-22.06) among GA genotypes, and by 6.00 mL/year (-4.54 to 16.54) among AA genotypes. CONCLUSIONS: Our results suggest that cell cycle control genes may modify the degree to which improved air quality may benefit respiratory function in adults. [ABSTRACT FROM AUTHOR]

Published
2009
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28. 49 Errors in drug-therapy reported to a national poisons information centre

Author

Curjuric, I, Guirguis, M, Kupferschmidt, H, and Meier-Abt, PJ

Subjects
Medication errors -- Demographic aspects, Toxicology -- Research, Poison control centers -- Reports, Environmental issues, Health, Pharmaceuticals and cosmetics industries
Abstract

Objective: Errors in medicine have received increased awareness in recent years. This is especially true for errors caused by medical professionals. In contrast, errors caused by non-professionals have received less [...]

Published
2002

29. Characterization of source-specific air pollution exposure for a large population-based swiss cohort (SAPALDIA)

Author

Liu LJS, Curjuric I, Keidel D, Heldstab J, Kunzli N, Bayer-Oglesby L, Ackermann-Liebrich U, Schindler C, and SAPALDIA Team

Abstract

BACKGROUND: Although the dispersion model approach has been used in some epidemiologic studies to examine health effects of traffic-specific air pollution, no study has evaluated the model predictions vigorously. METHODS: We evaluated total and traffic-specific particulate matter < 10 and < 2.5 microm in aero-dynamic diameter (PM(10), PM(2.5)), nitrogren dioxide, and nitrogen oxide concentrations predicted by Gaussian dispersion models against fixed-site measurements at different locations, including traffic-impacted, urban-background, and alpine settings between and across cities. The model predictions were then used to estimate individual subjects' historical and cumulative exposures with a temporal trend model. RESULTS: Modeled PM(10) and NO(2) predicted at least 55% and 72% of the variability of the measured PM(10) and NO(2), respectively. Traffic-specific pollution estimates correlated with the NO(x) measurements (R(2) >or=0.77) for background sites but not for traffic sites. Regional background PM(10) accounted for most PM(10) mass in all cities. Whereas traffic PM(10) accounted for < 20% of the total PM(10), it varied significantly within cities. The modeling error for PM(10) was similar within and between cities. Traffic NO(x) accounted for the majority of NO(x) mass in urban areas, whereas background NO(x) accounted for the majority of NO(x) in rural areas. The within-city NO(2) modeling error was larger than that between cities. CONCLUSIONS: The dispersion model predicted well the total PM(10), NO(x), and NO(2) and traffic-specific pollution at background sites. However, the model underpredicted traffic NO(x) and NO(2) at traffic sites and needs refinement to reflect local conditions. The dispersion model predictions for PM(10) are suitable for examining individual exposures and health effects within and between cities. [ABSTRACT FROM AUTHOR]

Published
2007
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31. Adult onset asthma and interaction between genes and active tobacco smoking : The GABRIEL consortium

Author

Vonk, J. M., Scholtens, S., Postma, D. S., Moffatt, M. F., Jarvis, D., Ramasamy, A., Wjst, M., Omenaas, E. R., Bouzigon, E., Demenais, F., Nadif, R., Siroux, V., Polonikov, A. V., Solodilova, M., Ivanov, V. P., Curjuric, I., Imboden, M., Kumar, A., Probst-Hensch, N., Ogorodova, L. M., Puzyrev, V. P., Bragina, E. Yu, Freidin, M. B., Nolte, I. M., Farrall, A. M., Cookson, W. O. C. M., Strachan, D. P., Koppelman, G. H., and Boezen, H. M.

Subjects
3. Good health

35. Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function

Author

Hancock, D. B., Soler, Artigas, Gharib, S. A., Henry, A., Manichaikul, A., Ramasamy, A., Loth, D. W., Imboden, M., Koch, B., McArdle, W., Smith, A. V., Smolonska, J., Sood, A., Tang, W., Wilk, J. B., Zhai, G., Zhao, J. H., Aschard, H., Burkart, K. M., Curjuric, I., Eijgelsheim, M., Elliott, P., Gu, X., Harris, T. B., Janson, C., Homuth, G., Hysi, P., Liu, J. Z., Loehr, L. R., Lohman, K., Loos, R., Manning, A. K., Marciante, K. D., Obeidat, M., Postma, D., Aldrich, M., Brusselle, G. G., Chen, T. H., Eiriksdottir, G., Franceschini, N., Heinrich, J., Rotter, J. I., Wijmenga, C., Williams, O. D., Bentley, A. R., Hofman, A., Laurie, C., Lumley, T., Morrison, A. C., Joubert, B. R., Rivadeneira, F., Couper, D. J., Kritchevsky, S. B., Liu, Y., Wjst, M., Wain, L. V., Vonk, J. M., Uitterlinden, A., Rochat, T., Rich, S. S., Psaty, B. M., O'Connor, G. T., North, K. E., Mirel, D. B., Meibohm, B., Launer, L. J., Khaw, K. T., Hartikainen, A. L., Hammond, C. J., Gläser, S., Marchini, J., Kraft, P., Wareham, N. J., Völzke, H., Stricker, B. H. C., Spector, T. D., Probst-Hensch, N. M., Jarvis, D., Jarvelin, M. R., Heckbert, S. R., Gudnason, V., Boezen, H. M., Barr, R. G., Cassano, P. A., Strachan, D. P., Fornage, M., Hall, I. P., Dupuis, J., Tobin, M. D., and London, S. J.

Subjects
3. Good health

38. Determinants of change in airway reactivity over 11 years in the SAPALDIA population study

Author

Ivan Curjuric, Christian Schindler, Margaret W. Gerbase, Marco Pons, E. Zemp, Natalia Kunzli, Ursula Ackermann-Liebrich, T. Rochat, Julien Vincent G. A. Schwartz, Pierre-Olivier Bridevaux, Martin Brutsche, Robert Bettschart, Martin Frey, Bruno H Knöpfli, Julia Dratva, University of Zurich, and Curjuric, I

Subjects
Lung Diseases, Male, Questionnaires, Pediatrics, Bronchial Provocation Tests/methods, Cohort Studies, Atopy, 11124 Institute of Medical Molecular Genetics, 0302 clinical medicine, Surveys and Questionnaires, 540 Chemistry, Prevalence, 030212 general & internal medicine, Methacholine Chloride, 10038 Institute of Clinical Chemistry, ddc:616, 2. Zero hunger, education.field_of_study, Smoking, Middle Aged, Methacholine Chloride/diagnostic use, Cohort, Population study, Female, medicine.symptom, Switzerland, medicine.drug, Cohort study, Adult, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Spirometry/methods, Population, 610 Medicine & health, Bronchial Provocation Tests, Lung Diseases/pathology, 03 medical and health sciences, Respiratory Hypersensitivity, Hypersensitivity, medicine, Humans, education, Aged, business.industry, medicine.disease, 030228 respiratory system, Spirometry, Respiratory Hypersensitivity/pathology, 2740 Pulmonary and Respiratory Medicine, 570 Life sciences, biology, Methacholine, business, Weight gain, Body mass index, Demography
Abstract

We investigated determinants of change in bronchial reactivity in the Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA), a population-based cohort with wide age range (29-72 yrs at follow-up). The role of sex, age, atopic status, smoking and body mass index (BMI) on percentage change in bronchial reactivity slope from the baseline value was analysed in 3,005 participants with methacholine tests in 1991 and 2002, and complete covariate data. Slope was defined as percentage decline in forced expiratory volume in 1 s from its maximal value per micromole of methacholine. Bronchial hyperreactivity prevalence fell from 14.3 to 12.5% during follow-up. Baseline age was nonlinearly associated with change in reactivity slope: participants aged

Published
2011
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39. Comment on: Wiser et al. Ovarian cancer in Switzerland: incidence and treatment according to hospital registry data. Swiss Med Wkly.2018;148:w14647.

Author

Feller A, Bopp M, Lorez M, Zellweger U, Adam M, Curjuric I, Staehelin K, Perren A, Bergeron Y, Rapiti E, Mousavi M, Diebold J, Dyntar D, Bulliard JL, Maspoli Conconi M, Bordoni A, Konzelmann I, Wagner U, and Rohrmann S

Subjects
Female, Humans, Incidence, Registries, Switzerland, Carcinoma, Ovarian Epithelial, Ovarian Neoplasms
Published
2020
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40. Author Correction: Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis.

Author

Waage J, Standl M, Curtin JA, Jessen LE, Thorsen J, Tian C, Schoettler N, Flores C, Abdellaoui A, Ahluwalia TS, Alves AC, Amaral AFS, Antó JM, Arnold A, Barreto-Luis A, Baurecht H, van Beijsterveldt CEM, Bleecker ER, Bonàs-Guarch S, Boomsma DI, Brix S, Bunyavanich S, Burchard EG, Chen Z, Curjuric I, Custovic A, den Dekker HT, Dharmage SC, Dmitrieva J, Duijts L, Ege MJ, Gauderman WJ, Georges M, Gieger C, Gilliland F, Granell R, Gui H, Hansen T, Heinrich J, Henderson J, Hernandez-Pacheco N, Holt P, Imboden M, Jaddoe VWV, Jarvelin MR, Jarvis DL, Jensen KK, Jónsdóttir I, Kabesch M, Kaprio J, Kumar A, Lee YA, Levin AM, Li X, Lorenzo-Diaz F, Melén E, Mercader JM, Meyers DA, Myers R, Nicolae DL, Nohr EA, Palviainen T, Paternoster L, Pennell CE, Pershagen G, Pino-Yanes M, Probst-Hensch NM, Rüschendorf F, Simpson A, Stefansson K, Sunyer J, Sveinbjornsson G, Thiering E, Thompson PJ, Torrent M, Torrents D, Tung JY, Wang CA, Weidinger S, Weiss S, Willemsen G, Williams LK, Ober C, Hinds DA, Ferreira MA, Bisgaard H, Strachan DP, and Bønnelykke K

Abstract

In the version of this article initially published, in Fig. 3, the y-axis numbering did not match the log scale indicated in the axis label. The error has been corrected in the HTML and PDF version of the article.

Published
2018
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41. Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis.

Author

Waage J, Standl M, Curtin JA, Jessen LE, Thorsen J, Tian C, Schoettler N, Flores C, Abdellaoui A, Ahluwalia TS, Alves AC, Amaral AFS, Antó JM, Arnold A, Barreto-Luis A, Baurecht H, van Beijsterveldt CEM, Bleecker ER, Bonàs-Guarch S, Boomsma DI, Brix S, Bunyavanich S, Burchard EG, Chen Z, Curjuric I, Custovic A, den Dekker HT, Dharmage SC, Dmitrieva J, Duijts L, Ege MJ, Gauderman WJ, Georges M, Gieger C, Gilliland F, Granell R, Gui H, Hansen T, Heinrich J, Henderson J, Hernandez-Pacheco N, Holt P, Imboden M, Jaddoe VWV, Jarvelin MR, Jarvis DL, Jensen KK, Jónsdóttir I, Kabesch M, Kaprio J, Kumar A, Lee YA, Levin AM, Li X, Lorenzo-Diaz F, Melén E, Mercader JM, Meyers DA, Myers R, Nicolae DL, Nohr EA, Palviainen T, Paternoster L, Pennell CE, Pershagen G, Pino-Yanes M, Probst-Hensch NM, Rüschendorf F, Simpson A, Stefansson K, Sunyer J, Sveinbjornsson G, Thiering E, Thompson PJ, Torrent M, Torrents D, Tung JY, Wang CA, Weidinger S, Weiss S, Willemsen G, Williams LK, Ober C, Hinds DA, Ferreira MA, Bisgaard H, Strachan DP, and Bønnelykke K

Subjects
Allergens genetics, Case-Control Studies, Genetic Variation genetics, Genome-Wide Association Study methods, Humans, Phenotype, Risk, Genetic Loci genetics, Genetic Predisposition to Disease genetics, Genome, Human genetics, HLA Antigens genetics, Rhinitis, Allergic genetics
Abstract

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries 1,2 . To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis.

Published
2018
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42. Alpha-1 antitrypsin deficiency: From the lung to the heart?

Author

Curjuric I, Imboden M, Bettschart R, Caviezel S, Dratva J, Pons M, Rothe T, Schmidt-Trucksäss A, Stolz D, Thun GA, von Eckardstein A, Kronenberg F, Ferrarotti I, and Probst-Hensch NM

Subjects
Aged, Blood Pressure genetics, Carotid Artery Diseases blood, Carotid Artery Diseases diagnostic imaging, Carotid Artery Diseases genetics, Carotid Intima-Media Thickness, Female, Genetic Predisposition to Disease, Humans, Hypertension blood, Hypertension diagnosis, Hypertension genetics, Male, Mendelian Randomization Analysis, Middle Aged, Phenotype, Pulmonary Disease, Chronic Obstructive blood, Pulmonary Disease, Chronic Obstructive diagnosis, Pulmonary Disease, Chronic Obstructive genetics, Risk Assessment, Risk Factors, Switzerland, alpha 1-Antitrypsin blood, alpha 1-Antitrypsin Deficiency blood, alpha 1-Antitrypsin Deficiency diagnosis, alpha 1-Antitrypsin Deficiency genetics, Carotid Artery Diseases etiology, Hypertension etiology, Mutation, Pulmonary Disease, Chronic Obstructive etiology, alpha 1-Antitrypsin genetics, alpha 1-Antitrypsin Deficiency complications
Abstract

Background and Aims: Alpha-1 antitrypsin (A1AT) is the most abundant serine protease inhibitor in human blood and exerts important anti-inflammatory and immune-modulatory effects. In combination with smoking or other long-term noxious exposures such as occupational dust and fumes, genetic A1AT deficiency can cause chronic obstructive pulmonary disease, a condition with elevated cardiovascular risk. The effects of A1AT deficiency on cardiovascular risk have hardly been studied today., Methods: Using data from 2614 adults from the population-based SAPALDIA cohort, we tested associations of serum A1AT and SERPINA1 mutations with carotid intima-media thickness (CIMT, measured by B-mode ultrasonography) or self-reported arterial hypertension or cardiovascular disease in multiple regression models using a Mendelian Randomization like analysis design. Mutations Pi-S and Pi-Z were coded as ordinal genotype score (MM, MS, MZ/SS, SZ and ZZ), according to their progressive biological impact., Results: Serum A1AT concentration presented a u-shaped association with CIMT. At the lower end of the A1AT distribution, an analogous, linear association between SERPINA1 score and higher CIMT was observed, resulting in an estimated 1.2% (95%-confidence interval -0.1-2.5) increase in CIMT per unit (p = 0.060). Genotype score was significantly associated with arterial hypertension with an odds ratio (OR) of 1.2 (1.0-1.5) per unit (p = 0.028). The association with cardiovascular disease was not significant (OR 1.3 (0.9-1.9))., Conclusions: Our results support a possible causal relationship between genetic A1AT deficiency and increased cardiovascular risk, which needs to be better taken into account for the management of affected patients and first-degree relatives., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Published
2018
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43. Hypertension, diabetes and lifestyle in the long-term - Results from a Swiss population-based cohort.

Author

Walther D, Curjuric I, Dratva J, Schaffner E, Quinto C, Schmidt-Trucksäss A, Eze IC, Burdet L, Pons M, Gerbase MW, Imboden M, Schindler C, and Probst-Hensch N

Subjects
Alcohol Drinking, Body Mass Index, Cohort Studies, Exercise, Female, Humans, Longitudinal Studies, Male, Obesity, Sex Factors, Smoking, Surveys and Questionnaires, Switzerland epidemiology, Diabetes Mellitus, Type 2 epidemiology, Hypertension epidemiology, Life Style
Abstract

Healthy lifestyles are integral in preventing and treating common cardiovascular and metabolic diseases. The aim of this study was to observe smoking habits, alcohol intake, physical activity and body mass index over a 10-year period in a population-based cohort, particularly focusing on participants with hypertension and type 2 diabetes mellitus. Included were 4155 participants from the first (2001-2003) and second (2010-2011) follow-ups of the Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults (SAPALDIA). Information was collected via health questionnaire; height and weight were measured. In a healthy lifestyle score one point was attributed per criterion; non-smoking, low risk alcohol consumption, BMI<25kg/m 2 , and regular physical activity. Overall in 2010-2011, 16.4% were smokers, 7.7% had at risk alcohol consumption, 25.5% were physically inactive and 57.8% were overweight or obese. Both those with hypertension and diabetes had lower mean healthy lifestyle scores than those without disease. Women with incident hypertension from 2001 to 2011 had lower odds of improving their healthy lifestyle score during this time period compared to those without this disease. In contrast, women with incident diabetes had higher odds of lifestyle score improvement. In men, neither hypertension nor diabetes was associated with change in lifestyle score. Our findings suggest that, irrespective of disease status, preventative attention is needed, particularly in regards to physical activity and bodyweight. These needs could be met by population-based interventions, a necessary and suitable option in both preventing and treating the non-communicable disease epidemic which currently faces countries worldwide., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Published
2017
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44. Genes Interacting with Occupational Exposures to Low Molecular Weight Agents and Irritants on Adult-Onset Asthma in Three European Studies.

Author

Rava M, Ahmed I, Kogevinas M, Le Moual N, Bouzigon E, Curjuric I, Dizier MH, Dumas O, Gonzalez JR, Imboden M, Mehta AJ, Tubert-Bitter P, Zock JP, Jarvis D, Probst-Hensch NM, Demenais F, and Nadif R

Subjects
Adult, Asthma epidemiology, Europe epidemiology, Female, Humans, Male, Middle Aged, Molecular Weight, NF-kappa B genetics, Polymorphism, Single Nucleotide, Irritants analysis, Occupational Diseases epidemiology, Occupational Exposure statistics & numerical data, Particulate Matter analysis
Abstract

Background: The biological mechanisms by which cleaning products and disinfectants-an emerging risk factor-affect respiratory health remain incompletely evaluated. Studying genes by environment interactions (G × E) may help identify new genes related to adult-onset asthma., Objectives: We identified interactions between genetic polymorphisms of a large set of genes involved in the response to oxidative stress and occupational exposures to low molecular weight (LMW) agents or irritants on adult-onset asthma., Methods: Our data came from three large European cohorts: Epidemiological Family-based Study of the Genetics and Environment of Asthma (EGEA), Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults (SAPALDIA), and European Community Respiratory Health Survey in Adults (ECRHS). A candidate pathway-based strategy identified 163 genes involved in the response to oxidative stress and potentially related to exposures to LMW agents/irritants. Occupational exposures were evaluated using an asthma job-exposure matrix and job-specific questionnaires for cleaners and healthcare workers. Logistic regression models were used to detect G × E interactions, adjusted for age, sex, and population ancestry, in 2,599 adults (mean age, 47 years; 60% women, 36% exposed, 18% asthmatics). p-Values were corrected for multiple comparisons., Results: Ever exposure to LMW agents/irritants was associated with current adult-onset asthma [OR = 1.28 (95% CI: 1.04, 1.58)]. Eight single nucleotide polymorphism (SNP) by exposure interactions at five loci were found at p < 0.005: PLA2G4A (rs932476, chromosome 1), near PLA2R1 (rs2667026, chromosome 2), near RELA (rs931127, rs7949980, chromosome 11), PRKD1 (rs1958980, rs11847351, rs1958987, chromosome 14), and PRKCA (rs6504453, chromosome 17). Results were consistent across the three studies and after accounting for smoking., Conclusions: Using a pathway-based selection process, we identified novel genes potentially involved in adult asthma by interaction with occupational exposure. These genes play a role in the NF-κB pathway, which is involved in inflammation. Citation: Rava M, Ahmed I, Kogevinas M, Le Moual N, Bouzigon E, Curjuric I, Dizier MH, Dumas O, Gonzalez JR, Imboden M, Mehta AJ, Tubert-Bitter P, Zock JP, Jarvis D, Probst-Hensch NM, Demenais F, Nadif R. 2017. Genes interacting with occupational exposures to low molecular weight agents and irritants on adult-onset asthma in three European studies. Environ Health Perspect 125:207-214; http://dx.doi.org/10.1289/EHP376., Competing Interests: Glaxo Wellcome and Glaxo France, producers of asthma medication, partially funded the local studies (Bergen and Paris, respectively) in ECHRS II. The authors declare they have no other actual or potential competing financial interests.

Published
2017
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45. Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis.

Author

Paternoster L, Standl M, Waage J, Baurecht H, Hotze M, Strachan DP, Curtin JA, Bønnelykke K, Tian C, Takahashi A, Esparza-Gordillo J, Alves AC, Thyssen JP, den Dekker HT, Ferreira MA, Altmaier E, Sleiman PM, Xiao FL, Gonzalez JR, Marenholz I, Kalb B, Yanes MP, Xu CJ, Carstensen L, Groen-Blokhuis MM, Venturini C, Pennell CE, Barton SJ, Levin AM, Curjuric I, Bustamante M, Kreiner-Møller E, Lockett GA, Bacelis J, Bunyavanich S, Myers RA, Matanovic A, Kumar A, Tung JY, Hirota T, Kubo M, McArdle WL, Henderson AJ, Kemp JP, Zheng J, Smith GD, Rüschendorf F, Bauerfeind A, Lee-Kirsch MA, Arnold A, Homuth G, Schmidt CO, Mangold E, Cichon S, Keil T, Rodríguez E, Peters A, Franke A, Lieb W, Novak N, Fölster-Holst R, Horikoshi M, Pekkanen J, Sebert S, Husemoen LL, Grarup N, de Jongste JC, Rivadeneira F, Hofman A, Jaddoe VW, Pasmans SG, Elbert NJ, Uitterlinden AG, Marks GB, Thompson PJ, Matheson MC, Robertson CF, Ried JS, Li J, Zuo XB, Zheng XD, Yin XY, Sun LD, McAleer MA, O'Regan GM, Fahy CM, Campbell LE, Macek M, Kurek M, Hu D, Eng C, Postma DS, Feenstra B, Geller F, Hottenga JJ, Middeldorp CM, Hysi P, Bataille V, Spector T, Tiesler CM, Thiering E, Pahukasahasram B, Yang JJ, Imboden M, Huntsman S, Vilor-Tejedor N, Relton CL, Myhre R, Nystad W, Custovic A, Weiss ST, Meyers DA, Söderhäll C, Melén E, Ober C, Raby BA, Simpson A, Jacobsson B, Holloway JW, Bisgaard H, Sunyer J, Hensch NMP, Williams LK, Godfrey KM, Wang CA, Boomsma DI, Melbye M, Koppelman GH, Jarvis D, McLean WI, Irvine AD, Zhang XJ, Hakonarson H, Gieger C, Burchard EG, Martin NG, Duijts L, Linneberg A, Jarvelin MR, Noethen MM, Lau S, Hübner N, Lee YA, Tamari M, Hinds DA, Glass D, Brown SJ, Heinrich J, Evans DM, and Weidinger S

Subjects
Case-Control Studies, Dermatitis, Atopic pathology, Humans, Immunity, Innate genetics, Risk Factors, T-Lymphocytes cytology, T-Lymphocytes immunology, T-Lymphocytes metabolism, Dermatitis, Atopic ethnology, Dermatitis, Atopic genetics, Ethnicity genetics, Genetic Loci, Genetic Markers genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Polymorphism, Single Nucleotide genetics
Abstract

Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis.

Published
2015
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46. Modification of the association between PM10 and lung function decline by cadherin 13 polymorphisms in the SAPALDIA cohort: a genome-wide interaction analysis.

Author

Imboden M, Kumar A, Curjuric I, Adam M, Thun GA, Haun M, Tsai MY, Pons M, Bettschart R, Turk A, Rochat T, Künzli N, Schindler C, Kronenberg F, and Probst-Hensch NM

Subjects
Adolescent, Adult, Air Pollution adverse effects, Cadherins metabolism, Cohort Studies, Female, Genome, Genotype, Humans, Male, Middle Aged, Particle Size, Respiratory Physiological Phenomena, Air Pollutants toxicity, Cadherins genetics, Particulate Matter toxicity, Pulmonary Ventilation drug effects, Pulmonary Ventilation genetics
Abstract

Background: Both air pollution and genetic variation have been shown to affect lung function. Their interaction has not been studied on a genome-wide scale to date., Objectives: We aimed to identify, in an agnostic fashion, genes that modify the association between long-term air pollution exposure and annual lung function decline in an adult population-based sample., Methods: A two-stage genome-wide interaction study was performed. The discovery (n = 763) and replication (n = 3,896) samples were derived from the multi-center SAPALDIA cohort (Swiss Cohort Study on Air Pollution and Lung Disease in Adults). Annual rate of decline in the forced mid-expiratory flow (FEF25-75%) was the main end point. Multivariate linear regression analyses were used to identify potential multiplicative interactions between genotypes and 11-year cumulative PM10 exposure., Results: We identified a cluster of variants intronic to the CDH13 gene as the only locus with genome-wide significant interactions. The strongest interaction was observed for rs2325934 (p = 8.8 × 10(-10)). Replication of the interaction between this CDH13 variant and cumulative PM10 exposure on annual decline in FEF25-75% was successful (p = 0.008). The interaction was not sensitive to adjustment for smoking or body weight., Conclusions: CDH13 is functionally linked to the adipokine adiponectin, an inflammatory regulator. Future studies need to confirm the interaction and assess how the result relates to previously observed interactions between air pollution and obesity on respiratory function.

Published
2015
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47. Human leukocyte antigen class II variants and adult-onset asthma: does occupational allergen exposure play a role?

Author

Smit LA, Strachan DP, Vermeulen R, de Bakker PI, Demenais F, Dumas O, Carsin AE, Cullinan P, Curjuric I, Ghosh RE, Heederik D, Imboden M, Jarvis D, Lathrop M, Le Moual N, Mehta A, Miedinger D, Sigsgaard T, Siroux V, Vernez D, Zock JP, Kauffmann F, Probst-Hensch N, Kogevinas M, and Bouzigon E

Subjects
Adolescent, Adult, Alleles, Asthma physiopathology, Cohort Studies, Europe, Female, Genome-Wide Association Study, Genotype, HLA-DQ Antigens genetics, HLA-DQ beta-Chains genetics, HLA-DRB1 Chains genetics, Histocompatibility Antigens Class II immunology, Humans, Male, Middle Aged, Molecular Weight, Odds Ratio, Polymorphism, Single Nucleotide, Young Adult, Allergens immunology, Asthma genetics, Asthma immunology, Histocompatibility Antigens Class II genetics, Occupational Exposure
Abstract

Recently, a locus centred on rs9273349 in the HLA-DQ region emerged from genome-wide association studies of adult-onset asthma. We aimed to further investigate the role of human leukocyte antigen (HLA) class II in adult-onset asthma and a possible interaction with occupational exposures. We imputed classical HLA-II alleles from 7579 single-nucleotide polymorphisms in 6025 subjects (1202 with adult-onset asthma) from European cohorts: ECRHS, SAPALDIA, EGEA and B58C, and from surveys of bakers and agricultural workers. Based on an asthma-specific job-exposure matrix, 2629 subjects had ever been exposed to high molecular weight (HMW) allergens. We explored associations between 23 common HLA-II alleles and adult-onset asthma, and tested for gene-environment interaction with occupational exposure to HMW allergens. Interaction was also tested for rs9273349. Marginal associations of classical HLA-II alleles and adult-onset asthma were not statistically significant. Interaction was detected between the DPB1*03:01 allele and exposure to HMW allergens (p = 0.009), in particular to latex (p = 0.01). In the unexposed group, the DPB1*03:01 allele was associated with adult-onset asthma (OR 0.67, 95%CI 0.53-0.86). HMW allergen exposures did not modify the association of rs9273349 with adult-onset asthma. Common classical HLA-II alleles were not marginally associated with adult-onset asthma. The association of latex exposure and adult-onset asthma may be modified by DPB1*03:01., (©ERS 2014.)

Published
2014
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48. Common genes underlying asthma and COPD? Genome-wide analysis on the Dutch hypothesis.

Author

Smolonska J, Koppelman GH, Wijmenga C, Vonk JM, Zanen P, Bruinenberg M, Curjuric I, Imboden M, Thun GA, Franke L, Probst-Hensch NM, Nürnberg P, Riemersma RA, van Schayck CP, Loth DW, Brusselle GG, Stricker BH, Hofman A, Uitterlinden AG, Lahousse L, London SJ, Loehr LR, Manichaikul A, Barr RG, Donohue KM, Rich SS, Pare P, Bossé Y, Hao K, van den Berge M, Groen HJ, Lammers JW, Mali W, Boezen HM, and Postma DS

Subjects
Adolescent, Adult, Aged, Female, Humans, Male, Middle Aged, Netherlands, Polymorphism, Single Nucleotide, Risk Factors, Young Adult, Asthma genetics, Genome-Wide Association Study, Pulmonary Disease, Chronic Obstructive genetics
Abstract

Asthma and chronic obstructive pulmonary disease (COPD) are thought to share a genetic background ("Dutch hypothesis"). We investigated whether asthma and COPD have common underlying genetic factors, performing genome-wide association studies for both asthma and COPD and combining the results in meta-analyses. Three loci showed potential involvement in both diseases: chr2p24.3, chr5q23.1 and chr13q14.2, containing DDX1, COMMD10 (both participating in the nuclear factor (NF) κβ pathway) and GNG5P5, respectively. Single nucleotide polymorphisms (SNPs) rs9534578 in GNG5P5 reached genome-wide significance after first replication phase (p=9.96×10(-9)). The second replication phase, in seven independent cohorts, provided no significant replication. Expression quantitative trait loci (eQTL) analysis in blood cells and lung tissue on the top 20 associated SNPs identified two SNPs in COMMD10 that influenced gene expression. Inflammatory processes differ in asthma and COPD and are mediated by NF-κβ, which could be driven by the same underlying genes, COMMD10 and DDX1. None of the SNPs reached genome-wide significance. Our eQTL studies support a functional role for two COMMD10 SNPs, since they influence gene expression in both blood cells and lung tissue. Our findings suggest that there is either no common genetic component in asthma and COPD or, alternatively, different environmental factors, e.g. lifestyle and occupation in different countries and continents, which may have obscured the genetic common contribution., (The content of this work is not subject to copyright. Designand branding are ©ERS 2014.)

Published
2014
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49. Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.

Author

Tang W, Kowgier M, Loth DW, Soler Artigas M, Joubert BR, Hodge E, Gharib SA, Smith AV, Ruczinski I, Gudnason V, Mathias RA, Harris TB, Hansel NN, Launer LJ, Barnes KC, Hansen JG, Albrecht E, Aldrich MC, Allerhand M, Barr RG, Brusselle GG, Couper DJ, Curjuric I, Davies G, Deary IJ, Dupuis J, Fall T, Foy M, Franceschini N, Gao W, Gläser S, Gu X, Hancock DB, Heinrich J, Hofman A, Imboden M, Ingelsson E, James A, Karrasch S, Koch B, Kritchevsky SB, Kumar A, Lahousse L, Li G, Lind L, Lindgren C, Liu Y, Lohman K, Lumley T, McArdle WL, Meibohm B, Morris AP, Morrison AC, Musk B, North KE, Palmer LJ, Probst-Hensch NM, Psaty BM, Rivadeneira F, Rotter JI, Schulz H, Smith LJ, Sood A, Starr JM, Strachan DP, Teumer A, Uitterlinden AG, Völzke H, Voorman A, Wain LV, Wells MT, Wilk JB, Williams OD, Heckbert SR, Stricker BH, London SJ, Fornage M, Tobin MD, O'Connor GT, Hall IP, and Cassano PA

Subjects
Adult, Female, Humans, Longitudinal Studies, Male, Chromosomes, Human, Pair 11 genetics, Gene Expression Regulation, Genetic Loci, Genome-Wide Association Study, Respiration genetics
Abstract

Background: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function., Methods: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis., Results: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively., Conclusions: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.

Published
2014
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50. Serum bilirubin is associated with lung function in a Swiss general population sample.

Author

Curjuric I, Imboden M, Adam M, Bettschart RW, Gerbase MW, Künzli N, Rochat T, Rohrer L, Rothe TB, Schwartz J, Stolz D, Tschopp JM, von Eckardstein A, Kronenberg F, and Probst-Hensch NM

Subjects
Adolescent, Adult, Biomarkers blood, Body Mass Index, Cohort Studies, Female, Forced Expiratory Volume, Genotype, Humans, Linear Models, Lung physiology, Lung physiopathology, Male, Middle Aged, Respiration Disorders blood, Respiratory Function Tests, Smoking adverse effects, Spirometry, Switzerland, Vital Capacity, Young Adult, Bilirubin blood, Respiration Disorders genetics, Respiration Disorders physiopathology
Abstract

Bilirubin is a strong antioxidant. Increased serum levels have been associated with lower respiratory disease and mortality risk. We studied the association of bilirubin with lung function in the Swiss study on Air Pollution and Lung Disease in adults (SAPALDIA) cohort. Associations between natural logarithmised bilirubin and forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC and mean forced expiratory flow between 25%-75% of FVC (FEF25-75%) were tested using multiple linear regression in the whole study population (n=4195) and strata of ever-smoking and high body mass index (BMI, defined by the highest distribution quartile). Associations were retested with single nucleotide polymorphism rs6742078, a genetic determinant of bilirubin. High bilirubin levels were significantly associated with higher FEV1/FVC and FEF25-75% overall. Upon stratification, significant associations persisted in ever-smokers, amounting to 1.1% (95% CI 0.1-2.2%) increase in FEV1/FVC, and 116.2 mL·s(-1) (95% CI -15.9-248.4 mL·s(-1)) in FEF25-75% per interquartile range of bilirubin exposure in smokers with high BMI. Associations were positive but nonsignificant in never-smokers with high BMI. Similarly, rs6742078 genotype TT was associated with increased FEV1/FVC and FEF25-75%. Our results suggest a possible protective role of bilirubin on lung tissue, which could be important for prevention and therapy.

Published
2014
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