. 2016 Jul 1;194(1):48-57.

doi: 10.1164/rccm.201510-2053OC.

Exome Array Analysis Identifies a Common Variant in IL27 Associated with Chronic Obstructive Pulmonary Disease

Brian D Hobbs^{1

2}, Margaret M Parker¹, Han Chen³, Taotao Lao¹, Megan Hardin^{1

2}, Dandi Qiao¹, Iwona Hawrylkiewicz⁴, Pawel Sliwinski⁴, Jae-Joon Yim⁵, Woo Jin Kim⁶, Deog Kyeom Kim⁷, Peter J Castaldi^{1

8}, Craig P Hersh^{1

2}, Jarrett Morrow¹, Bartolome R Celli², Victor M Pinto-Plata⁹, Gerald J Criner¹⁰, Nathaniel Marchetti¹¹, Raphael Bueno¹², Alvar Agustí¹³, Barry J Make¹⁴, James D Crapo¹⁴, Peter M Calverley¹⁵, Claudio F Donner¹⁶, David A Lomas¹⁷, Emiel F M Wouters¹⁸, Jorgen Vestbo¹⁹, Peter D Paré²⁰, Robert D Levy²⁰, Stephen I Rennard^{21

22}, Xiaobo Zhou¹, Nan M Laird⁵, Xihong Lin³, Terri H Beaty²³, Edwin K Silverman^{1

2}, Michael H Cho^{1

2}; NETT Genetics Investigators; ECLIPSE Investigators; COPDGene Investigators; International COPD Genetics Network Investigators

Affiliations

¹ 1 Channing Division of Network Medicine.
² 2 Division of Pulmonary and Critical Care Medicine.
³ 3 Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
⁴ 4 National Tuberculosis and Lung Disease Research Institute, Warsaw, Poland.
⁵ 5 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.
⁶ 6 Kangwon National University, Chuncheon, South Korea.
⁷ 7 Seoul National University Boramae Medical Center, Seoul, South Korea.
⁸ 8 Division of General Medicine and Primary Care, and.
⁹ 9 Department of Critical Care Medicine and Pulmonary Disease, Baystate Medical Center, Springfield, Massachusetts.
¹⁰ 10 Division of Pulmonary and Critical Care Medicine and.
¹¹ 11 Department of Thoracic Medicine and Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania.
¹² 12 Division of Thoracic Surgery, Brigham and Women's Hospital, Boston, Massachusetts.
¹³ 13 Thorax Institute, Hospital Clinic, IDIBAPS, University of Barcelona, CIBERES, Barcelona, Spain.
¹⁴ 14 National Jewish Health, Denver, Colorado.
¹⁵ 15 University of Liverpool, Liverpool, United Kingdom.
¹⁶ 16 Mondo Medico di I.F.I.M. srl, Multidisciplinary and Rehabilitation Outpatient Clinic, Borgomanero (NO), Italy.
¹⁷ 17 University College London, London, United Kingdom.
¹⁸ 18 University Hospital Maastricht, Maastricht, the Netherlands.
¹⁹ 19 University of Manchester, Manchester, United Kingdom.
²⁰ 20 University of British Columbia, Vancouver, British Columbia, Canada.
²¹ 21 Pulmonary and Critical Care Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
²² 22 Clinical Discovery Unit, AstraZeneca, Cambridge, United Kingdom; and.
²³ 23 Department of Epidemiology, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, Maryland.

PMID: 26771213
PMCID: PMC4960630
DOI: 10.1164/rccm.201510-2053OC

Exome Array Analysis Identifies a Common Variant in IL27 Associated with Chronic Obstructive Pulmonary Disease

Brian D Hobbs et al. Am J Respir Crit Care Med. 2016.

. 2016 Jul 1;194(1):48-57.

doi: 10.1164/rccm.201510-2053OC.

Authors

Affiliations

¹ 1 Channing Division of Network Medicine.
² 2 Division of Pulmonary and Critical Care Medicine.
³ 3 Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
⁴ 4 National Tuberculosis and Lung Disease Research Institute, Warsaw, Poland.
⁵ 5 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.
⁶ 6 Kangwon National University, Chuncheon, South Korea.
⁷ 7 Seoul National University Boramae Medical Center, Seoul, South Korea.
⁸ 8 Division of General Medicine and Primary Care, and.
⁹ 9 Department of Critical Care Medicine and Pulmonary Disease, Baystate Medical Center, Springfield, Massachusetts.
¹⁰ 10 Division of Pulmonary and Critical Care Medicine and.
¹¹ 11 Department of Thoracic Medicine and Surgery, Temple University School of Medicine, Philadelphia, Pennsylvania.
¹² 12 Division of Thoracic Surgery, Brigham and Women's Hospital, Boston, Massachusetts.
¹³ 13 Thorax Institute, Hospital Clinic, IDIBAPS, University of Barcelona, CIBERES, Barcelona, Spain.
¹⁴ 14 National Jewish Health, Denver, Colorado.
¹⁵ 15 University of Liverpool, Liverpool, United Kingdom.
¹⁶ 16 Mondo Medico di I.F.I.M. srl, Multidisciplinary and Rehabilitation Outpatient Clinic, Borgomanero (NO), Italy.
¹⁷ 17 University College London, London, United Kingdom.
¹⁸ 18 University Hospital Maastricht, Maastricht, the Netherlands.
¹⁹ 19 University of Manchester, Manchester, United Kingdom.
²⁰ 20 University of British Columbia, Vancouver, British Columbia, Canada.
²¹ 21 Pulmonary and Critical Care Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
²² 22 Clinical Discovery Unit, AstraZeneca, Cambridge, United Kingdom; and.
²³ 23 Department of Epidemiology, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, Maryland.

PMID: 26771213
PMCID: PMC4960630
DOI: 10.1164/rccm.201510-2053OC

Abstract

Rationale: 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.

Objectives: To identify coding variants associated with COPD.

Methods: 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.

Measurements and main results: 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.

Conclusions: 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.

Trial registration: ClinicalTrials.gov NCT00608764.

Keywords: IL-27; chronic obstructive pulmonary disease; exome; genetics.

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References

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Exome Array Analysis Identifies a Common Variant in IL27 Associated with Chronic Obstructive Pulmonary Disease

Affiliations

Exome Array Analysis Identifies a Common Variant in IL27 Associated with Chronic Obstructive Pulmonary Disease

Authors

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Abstract

References

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Grants and funding

LinkOut - more resources

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