@article{ba093ee7e76a459ab96da124a211d99a,
title = "Physical Activity, Television Viewing Time, and DNA Methylation in Peripheral Blood",
abstract = "Introduction Physical activity may affect health via DNA methylation. The epigenetic influences of sedentary behaviors such as television viewing are unknown. We performed a genomewide study of DNA methylation in peripheral blood in relation to physical activity and television viewing time.Methods DNA methylation was measured using the Illumina Infinium HumanMethylation450K BeadChip array in blood samples collected at baseline (N = 5513) and follow-up (N = 1249) from participants in the Melbourne Collaborative Cohort Study. At baseline, times per week of leisure-time physical activity were self-reported. At follow-up, the International Physical Activity Questionnaire was used to assess MET-hours per week of total and leisure-time physical activity and hours per day of television viewing time. Linear mixed models were used to assess associations between physical activity and television viewing measures and DNA methylation at individual CpG sites, adjusted for potential confounders and batch effects.Results At follow-up, total physical activity was associated with DNA methylation at cg10266336 (P = 6.0 x 10(-9)), annotated to the SAA2 gene. Weaker evidence of associations (P <1.0 x 10(-5)) were observed for an additional 14 CpG sites with total physical activity, for 7 CpG sites with leisure-time physical activity, and for 9 CpG sites with television viewing time. Changes in leisure-time physical activity between baseline and follow-up were associated with methylation changes (P <0.05) at four of the seven CpG sites with weaker evidence of cross-sectional associations with leisure-time physical activity.Conclusion Physical activity and television viewing may be associated with blood DNA methylation, a potential pathway to chronic disease development. Further research using accelerometer data and larger sample sizes is warranted.",
keywords = "PHYSICAL ACTIVITY, TELEVISION VIEWING, DNA METHYLATION, EPIGENETIC, PERIPHERAL BLOOD, EPIGENOME-WIDE ASSOCIATION, NF-KAPPA-B, PROMOTER METHYLATION, GENE-EXPRESSION, SEDENTARY TIME, RISK, EXERCISE, CANCER, LIFE, EDUCATION",
author = "{van Roekel}, {Eline H.} and Pierre-Antoine Dugue and Chol-Hee Jung and Joo, {Jihoon E.} and Enes Makalic and Wong, {Ee Ming} and English, {Dallas R.} and Southey, {Melissa C.} and Giles, {Graham G.} and Lynch, {Brigid M.} and Milne, {Roger L.}",
note = "Funding Information: In this first EWAS of physical activity and television viewing time, we found a cross-sectional association between total physical activity and methylation at one CpG site, and weaker evidence of association for an additional 14 CpG sites with total physical activity, 7 CpG sites with leisure-time physical activity, and 9 (nonoverlapping) CpG sites with television viewing time. Changes in leisure-time physical activity between baseline and follow-up were associated with methylation changes at four of the seven CpG sites with weaker evidence of cross-sectional associations with leisure-time physical activity. These findings require replication. Nevertheless, our results are in line with observational and intervention research findings that physical activity may affect blood DNA methylation ( 7 ) and suggest that television viewing time may also be associated with DNA methylation, independently of moderate to vigorous physical activity. There is some overlap between our findings and those reported in a gene ontology meta-analysis ( 29 ), which summarized results of observational and intervention studies investigating associations of exercise with DNA methylation in humans. For leisure-time physical activity, we found weak evidence of a cross-sectional and a longitudinal association with methylation at cg27283993, annotated to KLF6 , a tumor suppressor gene involved in colon cancer development ( 30 ). The meta-analysis included a study ( 31 ) of skeletal muscle samples in men, reporting that a 6-month endurance exercise intervention decreased DNA methylation at two CpG sites annotated to KLF6 , and increased mRNA expression of KLF6 . Further, an animal study reported increased KLF6 expression in adipose tissue after exercise ( 32 ). For total physical activity, associations appeared mainly driven by doing some versus no activity. Specifically, doing some versus no total physical activity was associated with methylation at cg10266336, annotated to the SAA2 gene. This gene codes for serum amyloid A-2 protein, which is secreted in response to inflammatory cytokines ( 33 ) and is implicated in cardiovascular disease development ( 34 ). One intervention study reported upregulated SAA2 transcription in skeletal muscle in response to resistance exercise in postmenopausal women ( 35 ). We also observed weaker evidence of total physical activity with methylation at cg00939211, annotated to the SNIP1 gene, coding for smad nuclear interacting protein 1, which influences transforming growth factor-β (TGF-β) and nuclear factor kappa-B (NF-κB) signaling ( 36,37 ). TGF-β and NF-κB signaling are known to play an important role in cancer development ( 38,39 ) and can be activated in blood by exercise ( 40,41 ). Television viewing time showed weak evidence of association with methylation at cg07141142, annotated to the ZMAT3 gene, which influences p53-mediated growth inhibitory signaling that is associated with cancer development ( 42 ). Pathway analysis also identified cancer-related pathways including “ECM–receptor interaction,” “microRNAs in cancer,” and “p53 signaling pathway.” Again, there is some consistency with previous results from the gene ontology meta-analysis on exercise and DNA methylation ( 29 ) that identified microRNA-associated and tumor suppressor gene networks to be involved. In our analysis, greater television viewing time was mostly associated with higher methylation levels, whereas for physical activity, no clear pattern in direction of associations was observed. Further research is required to replicate our findings and investigate whether and how these may affect gene expression. An important strength of our study was the large sample size, although it may still have been insufficient to detect associations at the significance threshold. Because ours is the first EWAS of physical activity and television viewing time to date, we also applied a more liberal cutoff point ( P < 1.0 × 10 −5 ) for findings that warrant follow-up. Other strengths included the longitudinal analysis and adjustment for several potential confounders. A limitation of our study included the use of self-reported physical activity data, which may have resulted in measurement error. We had a crude measure of physical activity at baseline and in our longitudinal analysis, which could have limited statistical power. At follow-up, we used data from the comprehensive IPAQ, which has good test–retest reliability but poor to moderate criterion validity ( 43 ). The reliability for the identified CpG sites was relatively low, and measurement error may have reduced statistical power. Nevertheless, in a previous study using the same data, we replicated many previously reported BMI-associated CpG sites and identified hundreds of novel associations that were replicated in independent populations ( 12 ), which is indirect evidence for the validity and reliability of our data. We observed some inflation in test statistics for total physical activity, whereas none was found for the individual continuous and dichotomous variables. Inflation was still observed after adjusting for 10 methylation-based principal components (results not shown) ( 27 ); we cannot explain these findings. Some CpG sites with weaker evidence of associations with leisure-time and total physical activity showed opposite directions of associations for the dichotomous and continuous variable, which may indicate spurious findings and require further investigation. In conclusion, we observed generally weak evidence of cross-sectional associations between physical activity and television viewing time and DNA methylation in peripheral blood, and that changes in physical activity over approximately a decade may be associated with methylation changes. Studies with accelerometer data and with larger sample sizes will be necessary to replicate our findings. Mechanistic research is needed to investigate whether DNA methylation may be a biological mechanism linking physical activity and sedentary behavior to chronic disease development. The MCCS was made possible by the contribution of many people, including the original investigators, the teams that recruited the participants and continue working on follow-up, and the many thousands of Melbourne residents who continue to participate in the study. This work was supported by the Australian National Health and Medical Research Council (NHMRC) (grant no. 1088405). MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by the Australian NHMRC grant nos. 209057 and 396414 and by infrastructure provided by the Cancer Council Victoria. Cases were ascertained through the Victorian Cancer Registry and the Australian Cancer Database (Australian Institute of Health and Welfare). The nested case–control methylation studies were supported by the NHMRC grant nos. 1011618, 1026892, 1027505, 1050198, 1043616, and 1074383. EHvR was supported by an Endeavour Research Fellowship from the Department of Education and Training of the Australian Government (6059-2017). MCS is an NHMRC Senior Research Fellow (1061177). BML is funded by a National Breast Cancer Foundation Fellowship (ECF-15-012). The study sponsors were not involved in the study design; in the collection, analysis, and interpretation of the data; in the writing of the report; and in the decision to submit the article for publication. The results of the present study do not constitute endorsement by the American College of Sports Medicine. The authors declared no conflicts of interest. The authors declare that the results of the study are presented clearly and honestly, and without fabrication, falsification, or inappropriate data manipulation. Publisher Copyright: {\textcopyright} 2019 by the American College of Sports Medicine.",
year = "2019",
month = mar,
doi = "10.1249/MSS.0000000000001827",
language = "English",
volume = "51",
pages = "490--498",
journal = "Medicine and Science in Sports and Exercise",
issn = "0195-9131",
publisher = "LIPPINCOTT WILLIAMS & WILKINS",
number = "3",
}