Exome Array Analysis Identifies a Common Variant in IL27 Associated with Chronic Obstructive Pulmonary Disease
Brian D Hobbs, Margaret M Parker, Han Chen, Taotao Lao, Megan Hardin, Dandi Qiao, Iwona Hawrylkiewicz, Pawel Sliwinski, Jae-Joon Yim, Woo Jin Kim, Deog Kyeom Kim, Peter J Castaldi, Craig P Hersh, Jarrett Morrow, Bartolome R Celli, Victor M Pinto-Plata, Gerald J Criner, Nathaniel Marchetti, Raphael Bueno, Alvar Agustí, Barry J Make, James D Crapo, Peter M Calverley, Claudio F Donner, David A Lomas, Emiel F M Wouters, Jorgen Vestbo, Peter D Paré, Robert D Levy, Stephen I Rennard, Xiaobo Zhou, Nan M Laird, Xihong Lin, Terri H Beaty, Edwin K Silverman, Michael H Cho, NETT Genetics Investigators, ECLIPSE Investigators, COPDGene Investigators, International COPD Genetics Network Investigators, Brian D Hobbs, Margaret M Parker, Han Chen, Taotao Lao, Megan Hardin, Dandi Qiao, Iwona Hawrylkiewicz, Pawel Sliwinski, Jae-Joon Yim, Woo Jin Kim, Deog Kyeom Kim, Peter J Castaldi, Craig P Hersh, Jarrett Morrow, Bartolome R Celli, Victor M Pinto-Plata, Gerald J Criner, Nathaniel Marchetti, Raphael Bueno, Alvar Agustí, Barry J Make, James D Crapo, Peter M Calverley, Claudio F Donner, David A Lomas, Emiel F M Wouters, Jorgen Vestbo, Peter D Paré, Robert D Levy, Stephen I Rennard, Xiaobo Zhou, Nan M Laird, Xihong Lin, Terri H Beaty, Edwin K Silverman, Michael H Cho, NETT Genetics Investigators, ECLIPSE Investigators, COPDGene Investigators, International COPD Genetics Network Investigators
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.
Source: PubMed