DNA methylation sites associated with rate of COPD exacerbations

<bold>Background:</bold> Methylation at particular DNA sites has been shown to affect COPD development. However, the role of DNA methylation in COPD exacerbations is not yet clear. <bold>Objectives:</bold> To evaluate whether DNA methylation levels are associated with rate of COPD exacerbations. <bold>Methods:</bold> Within the prospective population–based Rotterdam Study, COPD patients who were assessed for both COPD exacerbations and whole-blood DNA methylation were included in the study. Whole-blood DNA methylation levels were measured with Illumina-Infinium Human Methylation 450K BeadChip. The discovery cohort included 66 COPD patients. Replication of the 10 top methylated sites was performed in an independent cohort of 88 subjects with COPD. Results of EWASs were pooled using sample-size weighted meta-analysis. <bold>Results:</bold> There were 60.6% of male participants in the discovery cohort and 53.4% in the replication cohort. The mean age was 64.5±9.1 years in the discovery cohort and 68.1±5.7 years in the replication cohort. We identified and replicated one DNA methylation site, cg25545920 located in the <italic>ARX</italic> gene on chromosome X, which was associated (P=1.89×10⁻⁰⁶) with rate of COPD exacerbations. EWAS meta-analysis of COPD exacerbation rate identified the same replicated DNA methylation site cg25545920 (P=3.09×10⁻⁰⁸; n=154) and a second DNA methylation site, cg08906631 located in the <italic>ZNF616</italic> gene on chromosome 19 (P=6.72×10⁻⁰⁸; n=154). <bold>Conclusion:</bold> This study identifies two methylation sites associated with rate of COPD exacerbations. Further replication studies are needed to confirm the findings and clarify their potential role in the pathophysiology of COPD exacerbations.