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Leveraging DNA methylation signatures in peripheral blood as predictors of impaired respiratory function and chronic obstructive pulmonary disease.

Research output: Contribution to conferencePaper

Abstract

The causes of poor respiratory function and chronic obstructive pulmonary disease (COPD) are still incompletely understood. It is clear however, that both genes and the environment play an important role. DNA methylation is under both genetic and environmental control. We therefore hypothesised that investigation of differential methylation associated with these phenotypes would improve prediction of, and permit mechanistic insights into COPD. We investigated genome-wide differential DNA methylation patterns using the recently released 850K Illumina EPIC array. Epigenome-wide association studies (EWAS) of respiratory function and COPD were performed in peripheral blood samples from the Generation Scotland: Scottish Family Health Study cohort (GS:SFHS; N=3,791; 274 COPD cases and 2,928 controls). In independent COPD incidence data (N=150), significantly differentially methylated sites (p<3.6×10−8) were evaluated for their added predictive power to a model including the clinical variables, age, sex, height and smoking history using receiver operating characteristic analysis. The Lothian Birth Cohort 1936 (LBC1936) was used to replicate results from the EWAS (N=895) and prediction analyses (N=178). To our knowledge, this is the largest single cohort EWAS of respiratory function and COPD to date. We identified 29 respiratory function and/or COPD associated differentially methylated sites. A significant improvement in discrimination between COPD cases and controls (p<0.05) in independent GS:SFHS (p=0.014) and LBC1936 (p=0.018) datasets was observed when differentially methylated sites were incorporated in a clinical model. The differentially methylated sites mapped to genes involved in alternative splicing, JAK-STAT signalling, and axon guidance. Identification of novel differentially methylated sites has provided novel mechanistic insights and supported previous hypotheses into impaired respiratory function, and improved the prediction of COPD risk. However, future longitudinal studies, with serial measurements of DNA methylation are warranted to evaluate the causal significance of the identified associations, and to assess the utility of DNA methylation profiling in the clinical management of COPD.

    Research areas

  • epigenome-wide association study, respiratory function, COPD, Pathway analysis, Functional annotation, integated omics analysis, COPD gene expression, alternatice splicing, JAK-Stat, Axon guidance, incident COPD, prediction, cinical value

ID: 81065124