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

Nedeljkovic, I; Lahousse, L; Carnero-Montoro, E; Faiz, A; Vonk, JM; de Jong, K; van der Plaat, DA; van Diemen, CC; van den Berge, M; Obeidat, M; Bossé, Y; Nickle, DC; Uitterlinden, AG; van Meurs, JBJ; Stricker, BHC; Brusselle, GG; Postma, DS; Boezen, HM; van Duijn, CM; Amin, N

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

Nedeljkovic, I Lahousse, L Carnero-Montoro, E Faiz, A

Vonk, JM de Jong, K van der Plaat, DA van Diemen, CC van den Berge, M Obeidat, M Bossé, Y Nickle, DC Uitterlinden, AG van Meurs, JBJ Stricker, BHC Brusselle, GG Postma, DS Boezen, HM van Duijn, CM Amin, N

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Publication Type:: Journal Article
Citation:: Human Molecular Genetics, 2018, 27 (2), pp. 396 - 405
Issue Date:: 2018-01-15

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Field	Value	Language
dc.contributor.author	Nedeljkovic, I	en_US
dc.contributor.author	Lahousse, L	en_US
dc.contributor.author	Carnero-Montoro, E	en_US
dc.contributor.author	Faiz, A https://orcid.org/0000-0003-1740-3538	en_US
dc.contributor.author	Vonk, JM	en_US
dc.contributor.author	de Jong, K	en_US
dc.contributor.author	van der Plaat, DA	en_US
dc.contributor.author	van Diemen, CC	en_US
dc.contributor.author	van den Berge, M	en_US
dc.contributor.author	Obeidat, M	en_US
dc.contributor.author	Bossé, Y	en_US
dc.contributor.author	Nickle, DC	en_US
dc.contributor.author	Uitterlinden, AG	en_US
dc.contributor.author	van Meurs, JBJ	en_US
dc.contributor.author	Stricker, BHC	en_US
dc.contributor.author	Brusselle, GG	en_US
dc.contributor.author	Postma, DS	en_US
dc.contributor.author	Boezen, HM	en_US
dc.contributor.author	van Duijn, CM	en_US
dc.contributor.author	Amin, N	en_US
dc.date.available	2017-10-25	en_US
dc.date.issued	2018-01-15	en_US
dc.identifier.citation	Human Molecular Genetics, 2018, 27 (2), pp. 396 - 405	en_US
dc.identifier.issn	0964-6906	en_US
dc.identifier.uri	http://hdl.handle.net/10453/128489
dc.description.abstract	© The Author 2017. 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.	en_US
dc.relation.ispartof	Human Molecular Genetics	en_US
dc.relation.isbasedon	10.1093/hmg/ddx390	en_US
dc.subject.classification	Genetics & Heredity	en_US
dc.subject.mesh	Chromosomes, Human, Pair 19	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Pulmonary Disease, Chronic Obstructive	en_US
dc.subject.mesh	Genetic Predisposition to Disease	en_US
dc.subject.mesh	rab4 GTP-Binding Proteins	en_US
dc.subject.mesh	Chromosome Mapping	en_US
dc.subject.mesh	Smoking	en_US
dc.subject.mesh	DNA Methylation	en_US
dc.subject.mesh	Gene Expression	en_US
dc.subject.mesh	Epigenesis, Genetic	en_US
dc.subject.mesh	Polymorphism, Single Nucleotide	en_US
dc.subject.mesh	Quantitative Trait Loci	en_US
dc.subject.mesh	Adult	en_US
dc.subject.mesh	Aged	en_US
dc.subject.mesh	Middle Aged	en_US
dc.subject.mesh	Female	en_US
dc.subject.mesh	Male	en_US
dc.subject.mesh	Genetic Variation	en_US
dc.subject.mesh	Genome-Wide Association Study	en_US
dc.subject.mesh	Hypoxia-Inducible Factor-Proline Dioxygenases	en_US
dc.title	COPD GWAS variant at 19q13.2 in relation with DNA methylation and gene expression	en_US
dc.type	Journal Article
utslib.citation.volume	2	en_US
utslib.citation.volume	27	en_US
utslib.for	0604 Genetics	en_US
utslib.for	1102 Cardiorespiratory Medicine and Haematology	en_US
utslib.for	06 Biological Sciences	en_US
utslib.for	11 Medical and Health Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	closed_access
pubs.issue	2	en_US
pubs.publication-status	Published	en_US
pubs.volume	27	en_US

Abstract:

© The Author 2017. 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.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/128489