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Eur J Hum Genet. 2018 May;26(5):709-722. doi: 10.1038/s41431-017-0089-8. Epub 2018 Feb 8.

Understanding the role of the chromosome 15q25.1 in COPD through epigenetics and transcriptomics.

Author information

1
Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands.
2
Pfizer University of Granada, GENYO Centre for Genomics and Oncological Research, Andalusian Region Government, Granada, Spain.
3
Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
4
Department of Bioanalysis Pharmaceutical Care Unit, Ghent University Hospital, Ghent, Belgium.
5
Department of Epidemiology University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
6
Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, Groningen, The Netherlands.
7
Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
8
Department of Pulmonology University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
9
Centre for Heart Lung Innovation, University of British Columbia, Vancouver, BC, Canada.
10
Department of Molecular Medicine, Laval University, Institut universitaire de cardiologie et de pneumologie de Québec, Quebec, QC, Canada.
11
Genetics and Pharmacogenomics (GpGx), Merck Research Laboratories, Seattle, WA, USA.
12
Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.
13
Department of Respiratory Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.
14
Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands. n.amin@erasmusmc.nl.

Abstract

Chronic obstructive pulmonary disease (COPD) is a major health burden in adults and cigarette smoking is considered the most important environmental risk factor of COPD. Chromosome 15q25.1 locus is associated with both COPD and smoking. Our study aims at understanding the mechanism underlying the association of chromosome 15q25.1 with COPD through epigenetic and transcriptional variation in a population-based setting. To assess if COPD-associated variants in 15q25.1 are methylation quantitative trait loci, epigenome-wide association analysis of four genetic variants, previously associated with COPD (P < 5 × 10-8) in the 15q25.1 locus (rs12914385:C>T-CHRNA3, rs8034191:T>C-HYKK, rs13180:C>T-IREB2 and rs8042238:C>T-IREB2), was performed in the Rotterdam study (n = 1489). All four variants were significantly associated (P < 1.4 × 10-6) with blood DNA methylation of IREB2, CHRNA3 and PSMA4, of which two, including IREB2 and PSMA4, were also differentially methylated in COPD cases and controls (P < 0.04). Further additive and multiplicative effects of smoking were evaluated and no significant effect was observed. To evaluate if these four genetic variants are expression quantitative trait loci, transcriptome-wide association analysis was performed in 1087 lung samples. All four variants were also significantly associated with differential expression of the IREB2 3'UTR in lung tissues (P < 5.4 × 10-95). We conclude that regulatory mechanisms affecting the expression of IREB2 gene, such as DNA methylation, may explain the association between genetic variants in chromosome 15q25.1 and COPD, largely independent of smoking.

PMID:
29422661
PMCID:
PMC5945654
DOI:
10.1038/s41431-017-0089-8
[Indexed for MEDLINE]
Free PMC Article

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