Current evidence associates statin use with increased risk of type 2 diabetes (T2D). Mechanism are unclear. Statins may impact DNA methylation, a key regulator in gene expression. We conducted an epigenome-wide association study among 8313 Europeans (7163 never users and 1150 current statin users) from 7 cohorts to assess the association of statin use and DNA methylation in blood. After replication we found genome-wide associations of methylation sites annotated to DHCR24 (cg17901584, cg10177197), SC4MOL (cg05119988), and ABCG1 (cg06500161, cg27243685), which are involved in cholesterol, insulin and lipoprotein lipase pathways. Cg06500161 hypermethylation was related to decreased ABCG1 expression in two probes (P = 5 x 10-12 and 9 x 10-13), lower high density lipoprotein cholesterol (HDL, P = 0.002) and higher triglycerides (P = 1 x 10-4). Mendelian Randomization suggested that HDL and triglycerides might be a consequence of cg06500161 rather than a cause. Lower methylation of cg17901584 was associated with higher insulin (P = 0.006). Prevalent T2D was related to all sites except cg27243685 (P from 6 x 10-10 to 9 x 10-4). Only cg06500161 independently predicted incident T2D (P = 6 x 10-7), implicating that ABCG1 may be a causal factor for T2D as suggested by Mendelian Randomization (Figure 1). Our study is the first to provide evidence of DNA methylation as potential mechanism by which statin use can lead to adverse metabolic alterations and subsequently T2D.,
Department of Epidemiology