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1. Limited overlap in significant hits between genome-wide association studies on two airflow obstruction definitions in the same population

Author

Plaat, D.A.D., Vonk, J.M. (Judith), Lahousse, L. (Lies), de Jong, K., Faiz, A., Nedeljkovic, I., Amin, N. (Najaf), Diemen, C.C. (Cleo) van, Brusselle, G.G. (Guy), Bossé, Y. (Yohan), Brandsma, CA, Hao, K. (Ke), Pare, P.D., Duijn, C.M., Postma, D.S. (Dirkje), Boezen, H.M. (Marike), Plaat, D.A.D., Vonk, J.M. (Judith), Lahousse, L. (Lies), de Jong, K., Faiz, A., Nedeljkovic, I., Amin, N. (Najaf), Diemen, C.C. (Cleo) van, Brusselle, G.G. (Guy), Bossé, Y. (Yohan), Brandsma, CA, Hao, K. (Ke), Pare, P.D., Duijn, C.M., Postma, D.S. (Dirkje), and Boezen, H.M. (Marike)

Abstract

Background: Airflow obstruction is a hallmark of chronic obstructive pulmonary disease (COPD), and is defined as either the ratio between forced expiratory volume in one second and forced vital capacity (FEV1/FVC) < 70% or < lower limit of normal (LLN). This study aimed to assess the overlap between genome-wide association studies (GWAS) on airflow obstruction using these two definitions in the same population stratified by smoking. Methods: GWASes were performed in the LifeLines Cohort Study for both airflow obstruction definitions in never-smokers (NS = 5071) and ever-smokers (ES = 4855). The FEV1/FVC < 70% models were adjusted for sex, age, and height; FEV1/FVC < LLN models were not adjusted. Ever-smokers models were additionally adjusted for pack-years and current-smoking. The overlap in significantly associated SNPs between the two definitions and never/ever-smokers was assessed using several p-value thresholds. To quantify the agreement, the Pearson correlation coefficient was calculated between the p-values and ORs. Replication was performed in the Vlagtwedde-Vlaardingen study (NS = 432, ES = 823). The overlapping SNPs with p < 10− 4 were validated in the Vlagtwedde-Vlaardingen and Rotterdam Study cohorts (NS = 1966, ES = 3134) and analysed for expression quantitative trait loci (eQTL) in lung tissue (n = 1087). Results: In the LifeLines cohort, 96% and 93% of the never- and ever-smokers were classified concordantly based on the two definitions. 26 and 29% of the investigated SNPs were overlapping at p < 0.05 in never- and eversmokers, respectively. At p < 10− 4 the overlap was 4% and 6% respectively, which could be change findings as shown by simulation studies. The effect estimates of the SNPs of the two definitions correlated strongly, but the p-values showed more variation and correlated only moderately. Similar observations were made in the Vlagtwedde-Vlaardingen study. Two overlapping SNPs in never-smokers (NFYC and FABP7) had the same direction of effe

Published
2019
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2. Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function

Author

Wyss, A.B. (Annah B.), Sofer, T. (Tamar), Lee, M.K. (Mi Kyeong), Terzikhan, N. (Natalie), Nguyen, J.N. (Jennifer N.), Lahousse, L. (Lies), Latourelle, J.C. (Jeanne), Smith, A.V. (Albert), Bartz, T.M. (Traci M.), Feitosa, M.F. (Mary Furlan), Gao, W. (Wei), Ahluwalia, T.S. (Tarunveer Singh), Tang, W. (Wenbo), Oldmeadow, C. (Christopher), Duan, Q. (Qing), Jong, K. (Kim) de, Wojczynski, M.K. (Mary ), Wang, X.-Q. (Xin-Qun), Noordam, R. (Raymond), Hartwig, F.P. (Fernando Pires), Jackson, V.E. (Victoria E.), Wang, T. (Tianyuan), Obeidat, M. (Ma’en), Hobbs, B.D. (Brian D.), Huan, T. (Tianxiao), Gui, H. (Hongsheng), Parker, M.M. (Margaret M.), Hu, D. (Donglei), Mogil, L.S. (Lauren S.), Kichaev, G. (Gleb), Jin, J. (Jianping), Graff, M.J. (Maud J.L.), Harris, T.B. (Tamara), Kalhan, R. (Ravi), Heckbert, S.R. (Susan), Paternoster, L. (Lavinia), Burkart, K.M. (Kristin), Liu, Y. (YongMei), Holliday, E.G. (Elizabeth), Wilson, J.F. (James), Vonk, J.M. (Judith), Sanders, J.L. (Jason L.), Barr, R.G. (Graham), Mutsert, R. (Reneé) de, Menezes, A.M.B. (Ana Maria Baptista), Adams, H.H.H. (Hieab), Van Den Berge, M. (Maarten), Joehanes, R. (Roby), Levin, A.M. (Albert M.), Liberto, J. (Jennifer), Launer, L.J. (Lenore), Morrison, A.C. (Alanna), Sitlani, C.M. (Colleen), Celedón, J.C. (Juan C.), Kritchevsky, S.B. (Stephen), Scott, R.J. (Rodney J.), Christensen, K. (Kaare), Rotter, J.I. (Jerome I.), Bonten, T.N. (Tobias N.), Wehrmeister, F.C. (Fernando C.), Bossé, Y. (Yohan), Xiao, S. (Shujie), Oh, S. (Sam), Franceschini, N. (Nora), Brody, J.A. (Jennifer A.), Kaplan, R.C. (Robert), Lohman, K. (Kurt), McEvoy, M. (Mark), Province, M.A. (Mike), Rosendaal, F.R. (Frits), Taylor, K.D. (Kent), Nickle, D.C. (David C.), Williams, L.K. (L. Keoki), Burchard, E.G. (Esteban), Wheeler, H.E. (Heather), Sin, D.D. (Don D.), Gudnason, V. (Vilmundur), North, K.E. (Kari), Fornage, M. (Myriam), Psaty, B.M. (Bruce M.), Myers, R.H. (Richard), O’Connor, G. (George), Hansen, T. (Torben), Laurie, C.C. (Cathy C.), Cassano, P.A. (Patricia), Sung, J. (Joohon), Kim, W.J. (Woo Jin), Attia, J. (John), Lange, L.A. (Leslie), Boezen, H.M. (Marike), Thyagarajan, B. (Bharat), Rich, S.S. (Stephen), Mook-Kanamori, D.O. (Dennis O.), Horta, B.L. (Bernardo Lessa), Uitterlinden, A.G. (André), Im, H.K. (Hae Kyung), Cho, M.H. (Michael H.), Brusselle, G.G. (Guy), Gharib, S.A. (Sina), Dupuis, J. (Josée), Manichaikul, A. (Ani), London, S.J. (Stephanie J.), Wyss, A.B. (Annah B.), Sofer, T. (Tamar), Lee, M.K. (Mi Kyeong), Terzikhan, N. (Natalie), Nguyen, J.N. (Jennifer N.), Lahousse, L. (Lies), Latourelle, J.C. (Jeanne), Smith, A.V. (Albert), Bartz, T.M. (Traci M.), Feitosa, M.F. (Mary Furlan), Gao, W. (Wei), Ahluwalia, T.S. (Tarunveer Singh), Tang, W. (Wenbo), Oldmeadow, C. (Christopher), Duan, Q. (Qing), Jong, K. (Kim) de, Wojczynski, M.K. (Mary ), Wang, X.-Q. (Xin-Qun), Noordam, R. (Raymond), Hartwig, F.P. (Fernando Pires), Jackson, V.E. (Victoria E.), Wang, T. (Tianyuan), Obeidat, M. (Ma’en), Hobbs, B.D. (Brian D.), Huan, T. (Tianxiao), Gui, H. (Hongsheng), Parker, M.M. (Margaret M.), Hu, D. (Donglei), Mogil, L.S. (Lauren S.), Kichaev, G. (Gleb), Jin, J. (Jianping), Graff, M.J. (Maud J.L.), Harris, T.B. (Tamara), Kalhan, R. (Ravi), Heckbert, S.R. (Susan), Paternoster, L. (Lavinia), Burkart, K.M. (Kristin), Liu, Y. (YongMei), Holliday, E.G. (Elizabeth), Wilson, J.F. (James), Vonk, J.M. (Judith), Sanders, J.L. (Jason L.), Barr, R.G. (Graham), Mutsert, R. (Reneé) de, Menezes, A.M.B. (Ana Maria Baptista), Adams, H.H.H. (Hieab), Van Den Berge, M. (Maarten), Joehanes, R. (Roby), Levin, A.M. (Albert M.), Liberto, J. (Jennifer), Launer, L.J. (Lenore), Morrison, A.C. (Alanna), Sitlani, C.M. (Colleen), Celedón, J.C. (Juan C.), Kritchevsky, S.B. (Stephen), Scott, R.J. (Rodney J.), Christensen, K. (Kaare), Rotter, J.I. (Jerome I.), Bonten, T.N. (Tobias N.), Wehrmeister, F.C. (Fernando C.), Bossé, Y. (Yohan), Xiao, S. (Shujie), Oh, S. (Sam), Franceschini, N. (Nora), Brody, J.A. (Jennifer A.), Kaplan, R.C. (Robert), Lohman, K. (Kurt), McEvoy, M. (Mark), Province, M.A. (Mike), Rosendaal, F.R. (Frits), Taylor, K.D. (Kent), Nickle, D.C. (David C.), Williams, L.K. (L. Keoki), Burchard, E.G. (Esteban), Wheeler, H.E. (Heather), Sin, D.D. (Don D.), Gudnason, V. (Vilmundur), North, K.E. (Kari), Fornage, M. (Myriam), Psaty, B.M. (Bruce M.), Myers, R.H. (Richard), O’Connor, G. (George), Hansen, T. (Torben), Laurie, C.C. (Cathy C.), Cassano, P.A. (Patricia), Sung, J. (Joohon), Kim, W.J. (Woo Jin), Attia, J. (John), Lange, L.A. (Leslie), Boezen, H.M. (Marike), Thyagarajan, B. (Bharat), Rich, S.S. (Stephen), Mook-Kanamori, D.O. (Dennis O.), Horta, B.L. (Bernardo Lessa), Uitterlinden, A.G. (André), Im, H.K. (Hae Kyung), Cho, M.H. (Michael H.), Brusselle, G.G. (Guy), Gharib, S.A. (Sina), Dupuis, J. (Josée), Manichaikul, A. (Ani), and London, S.J. (Stephanie J.)

Abstract

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lu

Published
2018
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3. COPD GWAS variant at 19q13.2 in relation with DNA methylation and gene expression

Author

Prokić, I. (Ivana), Lahousse, L. (Lies), Carnero-Montoro, E. (Elena), Faiz, A. (Alen), Vonk, J.M. (Judith), Jong, K. (Kim) de, van der Plaat, D.A. (Diana A.), Diemen, C.C. (Cleo) van, Van Den Berge, M. (Maarten), Obeidat, M. (Ma'en), Bossé, Y. (Yohan), Nickle, D.C. (David C.), Uitterlinden, A.G. (André), Meurs, J.B.J. (Joyce) van, Stricker, B.H.Ch. (Bruno), Brusselle, G.G. (Guy), Postma, D.S. (Dirkje S.), Boezen, H.M. (Marike), Duijn, C.M. (Cornelia) van, Amin, N. (Najaf), Prokić, I. (Ivana), Lahousse, L. (Lies), Carnero-Montoro, E. (Elena), Faiz, A. (Alen), Vonk, J.M. (Judith), Jong, K. (Kim) de, van der Plaat, D.A. (Diana A.), Diemen, C.C. (Cleo) van, Van Den Berge, M. (Maarten), Obeidat, M. (Ma'en), Bossé, Y. (Yohan), Nickle, D.C. (David C.), Uitterlinden, A.G. (André), Meurs, J.B.J. (Joyce) van, Stricker, B.H.Ch. (Bruno), Brusselle, G.G. (Guy), Postma, D.S. (Dirkje S.), Boezen, H.M. (Marike), Duijn, C.M. (Cornelia) van, and Amin, N. (Najaf)

Abstract

Chronic obstructive pulmonary disease (COPD) is among the major health burdens in adults. While cigarette smoking is the leading risk factor, a growing number of genetic variations have been discovered to influence disease susceptibility. Epigenetic modifications may mediate the response of the genome to smoking and regulate gene expression. Chromosome 19q13.2 region is associated with both smoking and COPD, yet its functional role is unclear. Our study aimed to determine whether rs7937 (RAB4B, EGLN2), a top genetic variant in 19q13.2 region identified in genome-wide association studies of COPD, is associated with differential DNA methylation in blood (N=1490) and gene expression in blood (N=721) and lungs (N=1087). We combined genetic and epigenetic data from the Rotterdam Study (RS) to perform the epigenome-wide association analysis of rs7937. Further, we used genetic and transcriptomic data from blood (RS) and from lung tissue (Lung expression quantitative trait loci mapping study), to perform the transcriptome-wide association study of rs7937. Rs7937 was significantly (FDR < 0.05) and consistently associated with differential DNA methylation in blood at 4 CpG sites in cis, independent of smoking. One methylation site (cg11298343-EGLN2) was also associated with COPD (P=0.001). Additionally, rs7937 was associated with gene expression levels in blood in cis (EGLN2), 42% mediated through cg11298343, and in lung tissue, in cis and trans (NUMBL, EGLN2, DNMT3A, LOC101929709 and PAK2). Our results suggest that changes of DNA methylation and gene expression may be intermediate steps between genetic variants and COPD, but further causal studies in lung tissue should confirm this hypothesis.

Published
2018
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4. Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis

Author

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

Abstract

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

Published
2017
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5. Association of Forced Vital Capacity with the Developmental Gene NCOR2

Author

Minelli, C. (Cosetta), Dean, C. H. (Charlotte H.), Hind, M. (Matthew), Alves, A. C. (Alexessander Couto), Amaral, A. F. (André F. S.), Siroux, V. (Valerie), Huikari, V. (Ville), Soler Artigas, M. (María), Evans, D. M. (David M.), Loth, D. W. (Daan W.), Bossé, Y. (Yohan), Postma, D. S. (Dirkje S.), Sin, D. (Don), Thompson, J. (John), Demenais, F. (Florence), Henderson, J. (John), S. c. (SpiroMeta consortium), C. c. (CHARGE consortium), Bouzigon, E. (Emmanuelle), Jarvis, D. (Deborah), Järvelin, M.-R. (Marjo-Riitta), Burney, P. (Peter), School of Medicine / Public Health, and Latzin, Philipp

Subjects
Adult, Male, General Science & Technology, CHARGE consortium, Organogenesis, Quantitative Trait Loci, lcsh:Medicine, Young Adult, Clinical Research, Forced Expiratory Volume, Genetics, 2.1 Biological and endogenous factors, Humans, SpiroMeta consortium, Developmental, Nuclear Receptor Co-Repressor 2, Aetiology, Polymorphism, lcsh:Science, Lung, Genetic Association Studies, Aged, Gene Expression Profiling, lcsh:R, Single Nucleotide, Middle Aged, Genes, Respiratory, lcsh:Q, Female, Genome-Wide Association Study
Abstract

Article, Background Forced Vital Capacity (FVC) is an important predictor of all-cause mortality in the absence of chronic respiratory conditions. Epidemiological evidence highlights the role of early life factors on adult FVC, pointing to environmental exposures and genes affecting lung development as risk factors for low FVC later in life. Although highly heritable, a small number of genes have been found associated with FVC, and we aimed at identifying further genetic variants by focusing on lung development genes. Methods Per-allele effects of 24,728 SNPs in 403 genes involved in lung development were tested in 7,749 adults from three studies (NFBC1966, ECRHS, EGEA). The most significant SNP for the top 25 genes was followed-up in 46,103 adults (CHARGE and SpiroMeta consortia) and 5,062 children (ALSPAC). Associations were considered replicated if the replication p-value survived Bonferroni correction (p, published version, peerReviewed

Published
2016

6. Molecular mechanisms underlying variations in lung function: A systems genetics analysis

Author

Obeidat, M. (Ma'en), Hao, K. (Ke), Bossé, Y. (Yohan), Nickle, D.C. (David), Nie, Y. (Yunlong), Postma, D.S. (Dirkje), Laviolette, M. (Michel), Sandford, A. (Andrew), Daley, D. (Denise), Hogg, J.C. (James), Elliott, W.M., Fishbane, N. (Nick), Timens, W. (Wim), Hysi, P.G. (Pirro), Kaprio, J. (Jaakko), Wilson, J.F. (James F), Hui, J. (Jennie), Rawal, R. (Rajesh), Schulz, H. (Holger), Stubbe, B. (Beate), Hayward, C. (Caroline), Polasek, O. (Ozren), Jarvelin, M.-R. (Marjo-Riitta), Zhao, J.H. (Jing Hua), Jarvis, D.L. (Deborah L.), Kähönen, M. (Mika), Franceschini, N. (Nora), North, K.E. (Kari), Loth, D.W. (Daan), Brusselle, G.G. (Guy), Smith, A.V. (Davey), Gudnason, V. (Vilmundur), Bartz, T.M. (Traci M.), Wilk, J.B. (Jemma), O'Connor, G.T. (George), Cassano, P.A. (Patricia), Tang, W. (Wenbo), Wain, L.V. (Louise), Artigas, M.S., Gharib, S.A. (Sina), Strachan, D.P. (David P.), Sin, D.D., Tobin, M.D. (Martin), London, S.J. (Stephanie J.), Hall, I.P. (Ian), Paré, P.D. (Peter), Obeidat, M. (Ma'en), Hao, K. (Ke), Bossé, Y. (Yohan), Nickle, D.C. (David), Nie, Y. (Yunlong), Postma, D.S. (Dirkje), Laviolette, M. (Michel), Sandford, A. (Andrew), Daley, D. (Denise), Hogg, J.C. (James), Elliott, W.M., Fishbane, N. (Nick), Timens, W. (Wim), Hysi, P.G. (Pirro), Kaprio, J. (Jaakko), Wilson, J.F. (James F), Hui, J. (Jennie), Rawal, R. (Rajesh), Schulz, H. (Holger), Stubbe, B. (Beate), Hayward, C. (Caroline), Polasek, O. (Ozren), Jarvelin, M.-R. (Marjo-Riitta), Zhao, J.H. (Jing Hua), Jarvis, D.L. (Deborah L.), Kähönen, M. (Mika), Franceschini, N. (Nora), North, K.E. (Kari), Loth, D.W. (Daan), Brusselle, G.G. (Guy), Smith, A.V. (Davey), Gudnason, V. (Vilmundur), Bartz, T.M. (Traci M.), Wilk, J.B. (Jemma), O'Connor, G.T. (George), Cassano, P.A. (Patricia), Tang, W. (Wenbo), Wain, L.V. (Louise), Artigas, M.S., Gharib, S.A. (Sina), Strachan, D.P. (David P.), Sin, D.D., Tobin, M.D. (Martin), London, S.J. (Stephanie J.), Hall, I.P. (Ian), and Paré, P.D. (Peter)

Abstract

Background: Lung function measures reflect the physiological state of the lung, and are essential to the diagnosis of chronic obstructive pulmonary disease (COPD). The SpiroMeta-CHARGE consortium undertook the largest genome-wide association study (GWAS) so far (n=48 201) for forced expiratory volume in 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC) in

Published
2015
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7. Susceptibility to chronic mucus hypersecretion, a genome wide association study

Author

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

Abstract

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

Published
2014
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