Demographics of the COPD subjects for microarray analysis.

<p>Exacerbations were defined over a 3 year follow up; frequent denotes 2 or more exacerbations each year, zero denotes no exacerbations in any year, and intermediate denotes patients who did not fit the frequent or zero exacerbation phenotype. Blood counts are mean values (X10⁹ cells/L).</p><p>Demographics of the COPD subjects for microarray analysis.</p

Identification of a set of genes in blood associated with the frequent exacerbator phenotype; multivariate analysis using micro-array data 1 year follow up data (n = 106), followed by univariate analysis of 3 year follow up data (n = 46) and univariate analysis of a different population (n = 215) by PCR.

<p>FE =  frequent exacerbators; ZE  =  zero exacerbators.</p

Gene expression changes in the 6 gene panel identified by microarray analysis using the phenotype data after 1 year.

<p>The gene expression changes using the phenotype data after 3 years from the microarray population and PCR population are shown. Positive fold change  =  increase in frequent exacerbators compared to zero exacerbators, negative fold change  =  decrease in frequent exacerbators compared to zero exacerbators.</p><p>Gene expression changes in the 6 gene panel identified by microarray analysis using the phenotype data after 1 year.</p

The 10 most highly regulated genes in sputum and blood from microarray analysis; a positive fold change = increase in frequent exacerbators compared to zero exacerbators, a negative fold change = decrease in frequent exacerbators compared to zero exacerbators.

<p>Affy. ID  =  affymatrix identification number. There was no overlap between sputum and blood for highly expressed genes.</p><p>The 10 most highly regulated genes in sputum and blood from microarray analysis; a positive fold change  =  increase in frequent exacerbators compared to zero exacerbators, a negative fold change  =  decrease in frequent exacerbators compared to zero exacerbators.</p

Venn diagram showing the number of differentially regulated genes in blood (fold change +/−1.5 and p<0.01) between frequent exacerbators (F), the intermediate group (I), and zero exacerbators (Z); for example, F vs I denotes number of differentially regulated genes between frequent exacerbators and the intermediate group.

<p>Venn diagram showing the number of differentially regulated genes in blood (fold change +/−1.5 and p<0.01) between frequent exacerbators (F), the intermediate group (I), and zero exacerbators (Z); for example, F vs I denotes number of differentially regulated genes between frequent exacerbators and the intermediate group.</p

GeneGo pathway mapping of the microarray data for the comparison of zero vs frequent exacerbators; the 5 most highly regulated pathways are shown.

<p>The number of genes regulated within each pathway are shown.</p><p>GeneGo pathway mapping of the microarray data for the comparison of zero vs frequent exacerbators; the 5 most highly regulated pathways are shown.</p

Demographics of the COPD subjects for PCR analysis.

<p>Exacerbations were defined over a 3 year follow up; frequent denotes 2 or more exacerbations each year, zero denotes no exacerbations in any year, and intermediate denotes patients who did not fit the frequent or zero exacerbation phenotype. Blood counts are mean values (X10⁹ cells/L).</p><p>Demographics of the COPD subjects for PCR analysis.</p

Additional file 1: of Spirometric variability in smokers: transitions in COPD diagnosis in a five-year longitudinal study

Online Data Supplement. (DOCX 831 kb

Additional file 1: Stastical Methods. of Mortality and drug therapy in patients with chronic obstructive pulmonary disease: a network meta-analysis

(PDF 376 kb

DNA methylation profiling in human lung tissue identifies genes associated with COPD

<p>Chronic obstructive pulmonary disease (COPD) is a smoking-related disease characterized by genetic and phenotypic heterogeneity. Although association studies have identified multiple genomic regions with replicated associations to COPD, genetic variation only partially explains the susceptibility to lung disease, and suggests the relevance of epigenetic investigations. We performed genome-wide DNA methylation profiling in homogenized lung tissue samples from 46 control subjects with normal lung function and 114 subjects with COPD, all former smokers. The differentially methylated loci were integrated with previous genome-wide association study results. The top 535 differentially methylated sites, filtered for a minimum mean methylation difference of 5% between cases and controls, were enriched for CpG shelves and shores. Pathway analysis revealed enrichment for transcription factors. The top differentially methylated sites from the intersection with previous GWAS were in <i>CHRM1, GLT1D1</i>, and <i>C10orf11</i>; sorted by GWAS <i>P</i>-value, the top sites included <i>FRMD4A, THSD4</i>, and <i>C10orf11</i>. Epigenetic association studies complement genetic association studies to identify genes potentially involved in COPD pathogenesis. Enrichment for genes implicated in asthma and lung function and for transcription factors suggests the potential pathogenic relevance of genes identified through differential methylation and the intersection with a broader range of GWAS associations.</p