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.
| Original language | English |
|---|---|
| Pages (from-to) | 709-722 |
| Number of pages | 14 |
| Journal | European Journal of Human Genetics |
| Volume | 26 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 1 May 2018 |
Bibliographical note
Funding Information:Funding This study is sponsored by grant number 4.1.13.007 of Lung Foundation (Longfonds), the Netherlands. DAvdP, KdJ and NA are supported by grant number 4.1.13.007 of Lung Foundation. IN is supported by the ERAWEB scholarship. The Rotterdam Study is funded by Erasmus Medical Centre and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The EWAS data was funded by the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, and by the Netherlands Organization for Scientific Research (NWO; project number 184021007). The Lung eQTL study at Laval University was supported by the Chaire de pneumologie de la Fon-dation JD Bégin de l’Université Laval, the Fondation de l’Institut universitaire de cardiologie et de pneumologie de Québec, the Respiratory Health Network of the FRQS, the Canadian Institutes of Health Research (MOP − 123369), and the Cancer Research Society and Read for the Cure. YB holds a Canada Research Chair in Genomics of Heart and Lung Diseases. The sponsors of this study played no role in the design of the study; in data collection, analysis, and interpretation; or in the writing and submission of the manuscript.
Funding Information:
Conflict of interest LL reports personal fees from Boehringer Ingel-heim GmbH, non-financial support from Novartis, grants from AstraZeneca, grants and non-financial support from European Respiratory Society, grants and non-financial support from Belgian Respiratory Society, outside the submitted work. MvdB reports research grants paid to The University from Chiesi, GlaxoSmithKline (GSK), Astra Zeneca and TEVA, outside the submitted work. DCN is employed by Merck & Co. The University of Groningen has received money for Professor D. Postma regarding a grant for research from Astra Zeneca, Chiesi, Genentec, GSK and Roche. Fees for consultancies were given to the University of Groningen by Astra Zeneca, Boehringer Ingelheim, Chiesi, GSK, Takeda and TEVA. The other authors declare that they have no conflict of interest.
Funding Information:
Acknowledgements The generation and management of the Illumina 450K methylation array data (EWAS data) and the Illumina exome chip v1.0 array data for the Rotterdam Study were executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The Exome chip array data set was funded by the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, from the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO)-sponsored Netherlands Consortium for Healthy Aging (NCHA; project no. 050-060-810); the Netherlands Organization for Scientific Research (NWO; project number 184021007) and by the Rainbow Project (RP10; Netherlands Exome Chip Project) of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL; www.bbmri.nl). We thank Ms. Mila Jhamai, Ms. Sarah Higgins and Mr. Marijn Verkerk for their help in creating the exome chip database, and Carolina Medina-Gomez, Lennard Karsten and Linda Broer for QC and variant calling. We thank Michael Verbiest, Mila Jhamai, Sarah Higgins, Marijn Verkerk and Lisette Stolk for their help in creating the methylation database. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The authors would like to thank the staff at the Respiratory Health Network Tissue Bank of the FRQS for their valuable assistance with the Lung eQTL dataset at Laval University. We would like to acknowledge members of the BIOS consortium (https://www.bbmri.nl/?p=259).
Publisher Copyright:
© 2018 European Society of Human Genetics.
Funding
Funding This study is sponsored by grant number 4.1.13.007 of Lung Foundation (Longfonds), the Netherlands. DAvdP, KdJ and NA are supported by grant number 4.1.13.007 of Lung Foundation. IN is supported by the ERAWEB scholarship. The Rotterdam Study is funded by Erasmus Medical Centre and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The EWAS data was funded by the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, and by the Netherlands Organization for Scientific Research (NWO; project number 184021007). The Lung eQTL study at Laval University was supported by the Chaire de pneumologie de la Fon-dation JD Bégin de l’Université Laval, the Fondation de l’Institut universitaire de cardiologie et de pneumologie de Québec, the Respiratory Health Network of the FRQS, the Canadian Institutes of Health Research (MOP − 123369), and the Cancer Research Society and Read for the Cure. YB holds a Canada Research Chair in Genomics of Heart and Lung Diseases. The sponsors of this study played no role in the design of the study; in data collection, analysis, and interpretation; or in the writing and submission of the manuscript. Conflict of interest LL reports personal fees from Boehringer Ingel-heim GmbH, non-financial support from Novartis, grants from AstraZeneca, grants and non-financial support from European Respiratory Society, grants and non-financial support from Belgian Respiratory Society, outside the submitted work. MvdB reports research grants paid to The University from Chiesi, GlaxoSmithKline (GSK), Astra Zeneca and TEVA, outside the submitted work. DCN is employed by Merck & Co. The University of Groningen has received money for Professor D. Postma regarding a grant for research from Astra Zeneca, Chiesi, Genentec, GSK and Roche. Fees for consultancies were given to the University of Groningen by Astra Zeneca, Boehringer Ingelheim, Chiesi, GSK, Takeda and TEVA. The other authors declare that they have no conflict of interest. Acknowledgements The generation and management of the Illumina 450K methylation array data (EWAS data) and the Illumina exome chip v1.0 array data for the Rotterdam Study were executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The Exome chip array data set was funded by the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, from the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO)-sponsored Netherlands Consortium for Healthy Aging (NCHA; project no. 050-060-810); the Netherlands Organization for Scientific Research (NWO; project number 184021007) and by the Rainbow Project (RP10; Netherlands Exome Chip Project) of the Biobanking and Biomolecular Research Infrastructure Netherlands (BBMRI-NL; www.bbmri.nl). We thank Ms. Mila Jhamai, Ms. Sarah Higgins and Mr. Marijn Verkerk for their help in creating the exome chip database, and Carolina Medina-Gomez, Lennard Karsten and Linda Broer for QC and variant calling. We thank Michael Verbiest, Mila Jhamai, Sarah Higgins, Marijn Verkerk and Lisette Stolk for their help in creating the methylation database. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The authors would like to thank the staff at the Respiratory Health Network Tissue Bank of the FRQS for their valuable assistance with the Lung eQTL dataset at Laval University. We would like to acknowledge members of the BIOS consortium (https://www.bbmri.nl/?p=259).
| Funders | Funder number |
|---|---|
| BBMRI-NL | |
| Belgian Respiratory Society | |
| Lung Foundation | |
| Netherlands Consortium for Healthy Aging | 050-060-810 |
| Netherlands Genomics Initiative | |
| Read for the Cure | |
| Research Institute for Diseases in the Elderly | |
| Université Laval | |
| European Respiratory Society | |
| Cancer Research Society | |
| Fondation Institut Universitaire de Cardiologie et de Pneumologie de Québec | |
| Canadian Institutes of Health Research | MOP − 123369 |
| Canadian Institutes of Health Research | |
| Fonds de Recherche du Québec - Santé | |
| European Commission | |
| ZonMw | |
| Erasmus Universiteit Rotterdam | |
| Ministerie van Volksgezondheid, Welzijn en Sport | |
| Erasmus Medisch Centrum | |
| Ministerie van Onderwijs, Cultuur en Wetenschap | |
| Nederlandse Organisatie voor Wetenschappelijk Onderzoek | 184021007 |
| Nederlandse Organisatie voor Wetenschappelijk Onderzoek |
