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Regular moderate-vigorous physical activity (MVPA) reduces the risk of cardiovascular and other chronic diseases, among other important benefits at all life stages. It is hypothesized that physical activity may alter disease risk via epigenetic modifications, including potentially long-standing changes in DNA methylation as previous research has shown epigenetic changes following exercise interventions. Most existing reports examine global methylation or study acute exercise effects on DNA methylation. To our knowledge, there are no published epigenome-wide association studies (EWAS) of habitual MVPA. In this analysis, we tested associations between leisure time MVPA and genome-wide variation in CpG methylation, an epigenetic mark, in 2,601 African American participants (1,663 women; mean age 56.6 years) in the Atherosclerosis Risk in Communities (ARIC) study. The Illumina HM450K Bead Chip was used to measure methylation in 471,035 CpG sites in stored frozen leukocyte samples, from visit 2 (1990-1992) or 3 (1993-1995). Linear regression models tested the cross-sectional association of DNA methylation M-value with self-reported leisure time MVPA at the visit of sample collection, modeled as minutes of MVPA per week and by category based on the AHA guidelines for physical activity in adults (none, less than 150, or at least 150 minutes MVPA per week), adjusting for age, sex, body mass index, education, alcohol use in grams per week, smoking status, cancer status, white blood cell count, imputed cell-type proportions using the Houseman method, and batch effects with the top 30 HM450K built-in nonnegative control probe principal components. Three CpGs, cg08269485, cg20272155, and cg08966208, upstream of the cathepsin D encoding gene, CTSD, were observed to be significantly inversely associated (q<0.05, FDR) with MVPA minutes/week. This is a strongly imprinted genomic region (chr11p15.5) and the region has also been reported to include DNA methylation variants that changed in response to an exercise training intervention. Additionally, 163 CpGs that we identified in the literature to be associated with habitual MVPA were also tested using the same models. One CpG, cg07863043, upstream of the adenomatosis polyposis coli gene, APC, in the 5q22.2 genomic region, was observed to be significantly positively associated with achieving at least 150 minutes of MVPA per week compared to none (q=0.0001, FDR). APC encodes a tumor suppressor protein that is an antagonist of the Wnt signaling pathway, and is involved in carcinogenesis and embryonic development. Replication in other populations is ongoing to confirm these findings as well as to identify additional physical activity-related DNA methylation variants.