Abstract
The timing of daily fluctuations in blood glucose is tightly controlled by the circadian rhythm. DNA methylation accompanies the circadian clock, and aberrant DNA methylation has been associated with circadian disruption and hyperglycemia. However, the precise role of circadian genes methylation in glucose metabolism is unknown. Using a gene-set approach in monozygotic (MZ) twin pairs, we examined the joint effect of 77 CpGs in five core circadian genes (CLOCK, BMAL1, PER1, PER2, PER3) on glucose-related traits in 138 middle-aged, male-male MZ twins (69 pairs). DNA methylation was quantified by bisulfite pyrosequencing. We first conducted matched twin pair analysis to examine the association of single CpG methylation with glucose metabolism. We then performed gene-based and gene-set analyses by the truncated product method to examine the combined effect of DNA methylation at multiple CpGs in a gene or all five circadian genes as a pathway on glucose metabolism. Of the 77 assayed CpGs, only one site was individually associated with insulin resistance at FDR < 0.05. However, the joint effect of DNA methylation in all five circadian genes together showed a significant association with glucose metabolism. Our results may unravel a biological mechanism through which circadian rhythm regulates blood glucose, and highlight the importance of testing the joint effect of multiple CpGs in epigenetic analysis.
Highlights
Circadian rhythms regulate many vital biological processes including glucose metabolism and insulin secretion (Qian and Scheer, 2016)
Using a gene-set approach, the goal of this study is to examine the joint effect of DNA methylation at 77 CpG sites in five core circadian genes (CLOCK, BMAL1, PER1, PER2, PER3) on glucose metabolism in 69 MZ twin pairs participating in the Twins Heart Study (THS)
Using a gene-family approach, we demonstrated that altered DNA methylation in five circadian genes jointly contributed to glucose metabolism in a well-matched MZ twin sample
Summary
Circadian rhythms regulate many vital biological processes including glucose metabolism and insulin secretion (Qian and Scheer, 2016). The clock circadian regulator (CLOCK), brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (BMAL1), and period circadian clock (PER1/PER2/PER3) represent the core circadian genes in peripheral or central tissues (Kalsbeek et al, 2014) Genetic polymorphisms in these clock genes may be related to fasting glucose (Bouatia-Naji et al, 2009; Englund et al, 2009; Dupuis et al, 2010; Dashti et al, 2015), insulin resistance (Lyssenko et al, 2009; Dashti et al, 2015), obesity (Garaulet et al, 2014), and type 2 diabetes (Bouatia-Naji et al, 2009; Voight et al, 2010; Bonnefond et al, 2012; Gaulton et al, 2015). These results suggest that altered DNA methylation of circadian genes may play an important role in regulating glucose metabolism
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