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Article Dans Une Revue PLoS ONE Année : 2016

Association of Forced Vital Capacity with the Developmental Gene NCOR2

1 Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College, London
2 Leukocyte Biology, National Heart and Lung Institute, Imperial College London, London
3 Mammalian Genetics Laboratory
4 Respiratory Department, Royal Brompton and Harefield NHS Foundation Trust, London
5 Department of Epidemiology and Biostatistics, MRC-PHE (Medical Research Council–Public Health England) Centre for Environment and Health, School of Public Health, Imperial College London, London
6 Respiratory Epidemiology and Public Health
7 MRC-PHE Centre for Environment and Health, Imperial College, London
8 Univ. Grenoble Alpes, IAB, Team of Environmental Epidemiology applied to Reproduction and Respiratory Health, F-38000, Grenoble
9 Laboratory of Developmental Biology, Department of Medical Biochemistry and Molecular Biology, University of Oulu and Biocenter Oulu
10 Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester
11 University of Queensland Diamantina Institute, Translational Research Institute, Brisbane
12 MRC IEU - MRC Integrative Epidemiology Unit [Bristol, Royaume-Uni]
13 Department of Epidemiology, Erasmus University Medical Center, Rotterdam
14 Institut universitaire de cardiologie et de pneumologie de Québec, Department of Molecular Medicine, Laval University, Québec
15 Department of Pulmonary Diseases, University of Groningen, University Medical Center Groningen, Groningen
16 The University of British Columbia Center for Heart Lung Innovation, St-Paul's Hospital, Vancouver
17 Department of Health Sciences, University of Leicester, Leicester
18 INSERM, UMRS-946, Genetic Variation of Human Diseases Unit, Paris
19 Faculté de Médecine [Université Paris Diderot - Paris 7]
20 School of Social and Community Medicine, University of Bristol, Bristol
21 Université Paris Diderot, Sorbonne Paris Cité
22 Dept. of Internal Medicine, Clinical Research Center, Oulu University Hospital and Biocenter Oulu
23 Center for Life Course Epidemiology, Faculty of Medicine, P.O. Box 5000, FI-90014 University of Oulu, Oulu
24 Kajima Technical Research Institute
25 Respiratory Epidemiology, Occupational Medicine & Public Health [London]

Résumé

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<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.
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hal-04306309 , version 1 (24-11-2023)

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Cosetta Minelli, Charlotte H Dean, Matthew Hind, Alexessander Couto Alves, André F S Amaral, et al.. Association of Forced Vital Capacity with the Developmental Gene NCOR2. PLoS ONE, 2016, 11 (2), pp.e0147388. ⟨10.1371/journal.pone.0147388⟩. ⟨hal-04306309⟩
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