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Association of forced vital capacity with the developmental gene NCOR2 |
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| Author: | Minelli, Cosetta1; Dean, Charlotte H.2,3; Hind, Matthew4; |
| Organizations: |
1Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College, London, United Kingdom 2Leukocyte Biology, National Heart and Lung Institute, Imperial College London, London, United Kingdom 3Mammalian Genetics Unit, MRC Harwell, Oxon, United Kingdom
4Respiratory Department, Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom
5Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom 6MRC-PHE Centre for Environment & Health, London, United Kingdom 7Univ. Grenoble Alpes, IAB, Team of Environmental Epidemiology applied to Reproduction and Respiratory Health, F-38000, Grenoble, France 8INSERM, IAB, Team of Environmental Epidemiology applied to Reproduction and Respiratory Health, F-38000, Grenoble, France 9CHU de Grenoble, IAB, Team of Environmental Epidemiology applied to Reproduction and Respiratory Health, F-38000, Grenoble, France 10Biocenter Oulu, University of Oulu, Oulu, Finland 11Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, United Kingdom 12University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia 13MRC Integrative Epidemiology Unit, University of Bristol, Bristol, United Kingdom 14Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands 15Institut universitaire de cardiologie et de pneumologie de Québec, Department of Molecular Medicine, Laval University, Québec, Canada 16Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands 17The University of British Columbia Center for Heart Lung Innovation, St-Paul’s Hospital, Vancouver, Canada 18Department of Health Sciences, University of Leicester, Leicester, United Kingdom 19INSERM, UMRS-946, Genetic Variation of Human Diseases Unit, Paris, France 20Univ. Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d’Hématologie, F-75007, Paris, France 21School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom 22SpiroMeta consortium, Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, United Kingdom 23CHARGE consortium, Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, United States of America 24Center for Life Course Epidemiology, Faculty of Medicine, P.O. Box 5000, FI-90014 University of Oulu, Oulu, Finland 25Unit of Primary Care, Oulu University Hospital, Kajaanintie 50, P.O. Box 20, FI-90220, Oulu, 90029 OYS, Finland |
| Format: | article |
| Version: | published version |
| Access: | open |
| Online Access: | PDF Full Text (PDF, 0.3 MB) |
| Persistent link: | http://urn.fi/urn:nbn:fi-fe2019050814737 |
| Language: | English |
| Published: |
Public Library of Science,
2016
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| Publish Date: | 2019-05-08 |
| Description: |
AbstractBackground: 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<0.002; 0.05/25), with a nominal p-value considered as suggestive evidence. For SNPs with evidence of replication, effects on the expression levels of nearby genes in lung tissue were tested in 1,111 lung samples (Lung eQTL consortium), with further functional investigation performed using public epigenomic profiling data (ENCODE). Results: NCOR2-rs12708369 showed strong replication in children (p = 0.0002), with replication unavailable in adults due to low imputation quality. This intronic variant is in a strong transcriptional enhancer element in lung fibroblasts, but its eQTL effects could not be tested due to low imputation quality in the eQTL dataset. SERPINE2-rs6754561 replicated at nominal level in both adults (p = 0.036) and children (p = 0.045), while WNT16-rs2707469 replicated at nominal level only in adults (p = 0.026). The eQTL analyses showed association of WNT16-rs2707469 with expression levels of the nearby gene CPED1. We found no statistically significant eQTL effects for SERPINE2-rs6754561. Conclusions: We have identified a new gene, NCOR2, in the retinoic acid signalling pathway pointing to a role of vitamin A metabolism in the regulation of FVC. Our findings also support SERPINE2, a COPD gene with weak previous evidence of association with FVC, and suggest WNT16 as a further promising candidate. see all
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| Series: |
PLoS one |
| ISSN: | 1932-6203 |
| ISSN-E: | 1932-6203 |
| ISSN-L: | 1932-6203 |
| Article number: | e0147388 |
| DOI: | 10.1371/journal.pone.0147388 |
| OADOI: | https://oadoi.org/10.1371/journal.pone.0147388 |
| Type of Publication: |
A1 Journal article – refereed |
| Field of Science: |
3142 Public health care science, environmental and occupational health 3111 Biomedicine |
| Subjects: | |
| EU Grant Number: |
(633595) DYNAHEALTH - Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging |
| Copyright information: |
© 2016 Minelli et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
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https://creativecommons.org/licenses/by/4.0/ |