Journal article
Exome Array Analysis Identifies a Common Variant in IL27 Associated with Chronic Obstructive Pulmonary Disease
American journal of respiratory and critical care medicine, Vol.194(1), pp.48-57
07/01/2016
DOI: 10.1164/rccm.201510-2053OC
PMCID: PMC4960630
PMID: 26771213
Abstract
Chronic obstructive pulmonary disease (COPD) susceptibility is in part related to genetic variants. Most genetic studies have been focused on genome-wide common variants without a specific focus on coding variants, but common and rare coding variants may also affect COPD susceptibility.
To identify coding variants associated with COPD.
We tested nonsynonymous, splice, and stop variants derived from the Illumina HumanExome array for association with COPD in five study populations enriched for COPD. We evaluated single variants with a minor allele frequency greater than 0.5% using logistic regression. Results were combined using a fixed effects meta-analysis. We replicated novel single-variant associations in three additional COPD cohorts.
We included 6,004 control subjects and 6,161 COPD cases across five cohorts for analysis. Our top result was rs16969968 (P = 1.7 × 10(-14)) in CHRNA5, a locus previously associated with COPD susceptibility and nicotine dependence. Additional top results were found in AGER, MMP3, and SERPINA1. A nonsynonymous variant, rs181206, in IL27 (P = 4.7 × 10(-6)) was just below the level of exome-wide significance but attained exome-wide significance (P = 5.7 × 10(-8)) when combined with results from other cohorts. Gene expression datasets revealed an association of rs181206 and the surrounding locus with expression of multiple genes; several were differentially expressed in COPD lung tissue, including TUFM.
In an exome array analysis of COPD, we identified nonsynonymous variants at previously described loci and a novel exome-wide significant variant in IL27. This variant is at a locus previously described in genome-wide associations with diabetes, inflammatory bowel disease, and obesity and appears to affect genes potentially related to COPD pathogenesis.
Details
- Title: Subtitle
- Exome Array Analysis Identifies a Common Variant in IL27 Associated with Chronic Obstructive Pulmonary Disease
- Creators
- Brian D Hobbs - 2 Division of Pulmonary and Critical Care MedicineMargaret M Parker - 1 Channing Division of Network MedicineHan Chen - 3 Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MassachusettsTaotao Lao - 1 Channing Division of Network MedicineMegan Hardin - 2 Division of Pulmonary and Critical Care MedicineDandi Qiao - 1 Channing Division of Network MedicineIwona Hawrylkiewicz - 4 National Tuberculosis and Lung Disease Research Institute, Warsaw, PolandPawel Sliwinski - 4 National Tuberculosis and Lung Disease Research Institute, Warsaw, PolandJae-Joon Yim - 5 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South KoreaWoo Jin Kim - 6 Kangwon National University, Chuncheon, South KoreaDeog Kyeom Kim - 7 Seoul National University Boramae Medical Center, Seoul, South KoreaPeter J Castaldi - 8 Division of General Medicine and Primary Care, andCraig P Hersh - 2 Division of Pulmonary and Critical Care MedicineJarrett Morrow - 1 Channing Division of Network MedicineBartolome R Celli - 2 Division of Pulmonary and Critical Care MedicineVictor M Pinto-Plata - 9 Department of Critical Care Medicine and Pulmonary Disease, Baystate Medical Center, Springfield, MassachusettsGerald J Criner - 10 Division of Pulmonary and Critical Care Medicine andNathaniel Marchetti - 11 Department of Thoracic Medicine and Surgery, Temple University School of Medicine, Philadelphia, PennsylvaniaRaphael Bueno - 12 Division of Thoracic Surgery, Brigham and Women's Hospital, Boston, MassachusettsBarry J Make - 14 National Jewish Health, Denver, ColoradoJames D Crapo - 14 National Jewish Health, Denver, ColoradoPeter M Calverley - 15 University of Liverpool, Liverpool, United KingdomClaudio F Donner - 16 Mondo Medico di I.F.I.M. srl, Multidisciplinary and Rehabilitation Outpatient Clinic, Borgomanero (NO), ItalyDavid A Lomas - 17 University College London, London, United KingdomEmiel F M Wouters - 18 University Hospital Maastricht, Maastricht, the NetherlandsJorgen Vestbo - 19 University of Manchester, Manchester, United KingdomPeter D Paré - 20 University of British Columbia, Vancouver, British Columbia, CanadaRobert D Levy - 20 University of British Columbia, Vancouver, British Columbia, CanadaStephen I Rennard - 22 Clinical Discovery Unit, AstraZeneca, Cambridge, United Kingdom; andXiaobo Zhou - 1 Channing Division of Network MedicineNan M Laird - 5 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South KoreaXihong Lin - 3 Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MassachusettsTerri H Beaty - 23 Department of Epidemiology, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, MarylandEdwin K Silverman - 2 Division of Pulmonary and Critical Care MedicineMichael H Cho - 2 Division of Pulmonary and Critical Care MedicineNETT Genetics InvestigatorsECLIPSE InvestigatorsCOPDGene InvestigatorsInternational COPD Genetics Network Investigators
- Contributors
- Eric A Hoffman (Contributor) - University of Iowa, Radiology
- Resource Type
- Journal article
- Publication Details
- American journal of respiratory and critical care medicine, Vol.194(1), pp.48-57
- DOI
- 10.1164/rccm.201510-2053OC
- PMID
- 26771213
- PMCID
- PMC4960630
- NLM abbreviation
- Am J Respir Crit Care Med
- ISSN
- 1073-449X
- eISSN
- 1535-4970
- Publisher
- United States
- Grant note
- R01 HL127200 / NHLBI NIH HHS P01 HL083069 / NHLBI NIH HHS K01 HL129039 / NHLBI NIH HHS R33 HL120794 / NHLBI NIH HHS T32 HL007427 / NHLBI NIH HHS R01 HL084323 / NHLBI NIH HHS R01 HL089856 / NHLBI NIH HHS P01 HL114501 / NHLBI NIH HHS R21 HL120794 / NHLBI NIH HHS R01 HL124233 / NHLBI NIH HHS MR/N024842/1 / Medical Research Council R01 HL113264 / NHLBI NIH HHS P01 HL105339 / NHLBI NIH HHS K08 HL097029 / NHLBI NIH HHS R01 HL089897 / NHLBI NIH HHS K12 HL120004 / NHLBI NIH HHS
- Language
- English
- Date published
- 07/01/2016
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Radiology; Internal Medicine
- Record Identifier
- 9984051501102771
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