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. 2011;6(9):e24395.
doi: 10.1371/journal.pone.0024395. Epub 2011 Sep 16.

Genetics of sputum gene expression in chronic obstructive pulmonary disease

Weiliang Qiu  1 , Michael H Cho, John H Riley, Wayne H Anderson, Dave Singh, Per Bakke, Amund Gulsvik, Augusto A Litonjua, David A Lomas, James D Crapo, Terri H Beaty, Bartolome R Celli, Stephen Rennard, Ruth Tal-Singer, Steven M Fox, Edwin K Silverman, Craig P Hersh; ECLIPSE Investigators
Collaborators, Affiliations

Genetics of sputum gene expression in chronic obstructive pulmonary disease

Weiliang Qiu et al. PLoS One. 2011.

Abstract

Previous expression quantitative trait loci (eQTL) studies have performed genetic association studies for gene expression, but most of these studies examined lymphoblastoid cell lines from non-diseased individuals. We examined the genetics of gene expression in a relevant disease tissue from chronic obstructive pulmonary disease (COPD) patients to identify functional effects of known susceptibility genes and to find novel disease genes. By combining gene expression profiling on induced sputum samples from 131 COPD cases from the ECLIPSE Study with genomewide single nucleotide polymorphism (SNP) data, we found 4315 significant cis-eQTL SNP-probe set associations (3309 unique SNPs). The 3309 SNPs were tested for association with COPD in a genomewide association study (GWAS) dataset, which included 2940 COPD cases and 1380 controls. Adjusting for 3309 tests (p<1.5e-5), the two SNPs which were significantly associated with COPD were located in two separate genes in a known COPD locus on chromosome 15: CHRNA5 and IREB2. Detailed analysis of chromosome 15 demonstrated additional eQTLs for IREB2 mapping to that gene. eQTL SNPs for CHRNA5 mapped to multiple linkage disequilibrium (LD) bins. The eQTLs for IREB2 and CHRNA5 were not in LD. Seventy-four additional eQTL SNPs were associated with COPD at p<0.01. These were genotyped in two COPD populations, finding replicated associations with a SNP in PSORS1C1, in the HLA-C region on chromosome 6. Integrative analysis of GWAS and gene expression data from relevant tissue from diseased subjects has located potential functional variants in two known COPD genes and has identified a novel COPD susceptibility locus.

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Conflict of interest statement

Competing Interests: The authors have the following competing interests: Dr. Riley, Dr. Anderson, Dr. Tal-Singer, and Dr. Fox are full-time employees of GlaxoSmithKline. The International COPD Genetics Network and The ECLIPSE Study were funded by GlaxoSmithKline. Dr. Singh has received lectures fees, support for conference attendance, advisory board fees and research grants from a range of pharmaceutical companies including GSK, Chiesi Pharmaceuticals, AstraZeneca, Pfizer, CIPLA, Novartis, Forest, MSD, Boehringer and Allmiral. Dr. Lomas has received an educational grant, fees for speaking and acts as a consultant for GSK. Dr. Rennard has consulted for Able Associates, Adelphi Research, APT Pharma/Britnall, Aradigm, AstraZeneca, Boehringer-Ingelheim, Chiesi, CommonHealth, Consult Complete, and COPDForum, and has served on advisory boards for Almirall, Novartis, Nycomed, and Pfizer. Dr. Rennard has received lecture fees from American Thoracic Society, AstraZeneca, Boehringer-Ingelheim, California Allergy Society, and Creative Educational Concept, and has received industry-sponsored grants from AstraZeneca, Biomarck, Centocor, Mpex, and Nabi. Dr. Silverman has received grant support for two studies of COPD genetics and consulting fees from GlaxoSmithKline, and has received consulting fees from Astra-Zeneca. Dr. Silverman has also received honoraria from Wyeth, Bayer, GlaxoSmithKline, and Astra-Zeneca. Dr. Qiu, Dr. Cho, Dr. Bakke, Dr. Gulsvik, Dr. Litonjua, Dr. Crapo, Dr. Beaty, Dr. Celli, and Dr. Hersh do not report any conflicts of interest related to this manuscript. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Overview of integrative genomics data analysis.
*Combined genomewide association study (GWAS) = Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE), Bergen Norway, and National Emphysema Treatment Trial (NETT)-Normative Aging Study (NAS) . COPD = chronic obstructive pulmonary disease. eQTL = expression quantitative trait locus. FDR = false discovery rate. ICGN = International COPD Genetics Network. SNP = single nucleotide polymorphism.
Figure 2
Figure 2. Boxplots of sputum gene expression levels stratified by genotype in 131 Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) subjects with chronic obstructive pulmonary disease.
a) rs1265098 - PSORS1C3 (238997_at), p = 8.2e-5. b) rs13180 - IREB2 (1555476_at), p = 6.7e-9. c) rs1051730 - CHRNA5 (206533_at), p = 2.2e-4; LD bin 1 (see Table 4). d) rs6495306 - CHRNA5 (206533_at), p = 9.9e-6; LD bin 3 (see Table 4).
Figure 3
Figure 3. Detailed analysis of the chromosome 15q25 chronic obstructive pulmonary disease (COPD) locus.
a) Association between single nucleotide polymorphisms (SNPs) in the chromosome 15q25 COPD locus and expression levels of IREB2 (1555476_at), CHRNA5 (206533_at) and CHRNA3 (211587_x_at) in sputum samples from 131 Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) subjects. SNP rs numbers are listed in Table 4. b) Linkage disequilibrium r2 values between SNPs in the chromosome 15q25 COPD locus (listed in Table 4) in 131 ECLIPSE subjects.
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