OBJECTIVE To investigate the role of epigenetics in statins' diabetogenic effect comparing DNA methylation (DNAm) between statin users and nonusers in an epigenome-wide association study in blood. RESEARCH DESIGN AND METHODS Five cohort studies' participants (n = 8,270) were classified as statin users when they were on statin therapy at the time of DNAm assessment with Illumina 450K or EPIC array or noncurrent users otherwise. Associations of DNAm with various outcomes like incident type 2 diabetes, plasma glucose, insulin, and insulin resistance (HOMA of insulin resistance [HOMA-IR]) as well as with gene expression were investigated. RESULTS Discovery (n = 6,820) and replication (n = 1,450) phases associated five DNAm sites with statin use: cg17901584 (1.12 × 10-25 [DHCR24]), cg10177197 (3.94 × 10-08 [DHCR24]), cg06500161 (2.67 × 10-23 [ABCG1]), cg27243685 (6.01 × 10-09 [ABCG1]), and cg05119988 (7.26 × 10-12 [SC4MOL]). Two sites were associated with at least one glycemic trait or type 2 diabetes. Higher cg06500161 methylation was associated with higher fasting glucose, insulin, HOMA-IR, and type 2 diabetes (odds ratio 1.34 [95% CI 1.22, 1.47]). Mediation analyses suggested that ABCG1 methylation partially mediates the effect of statins on high insulin and HOMA-IR. Gene expression analyses showed that statin exposure and ABCG1 methylation were associated with ABCG1 downregulation, suggesting epigenetic regulations of ABCG1 expression. Further, outcomes insulin and HOMA-IR were significantly associated with ABCG1 expression. CONCLUSIONS This study sheds light on potential mechanisms linking statins with type 2 diabetes risk, providing evidence on DNAm partially mediating statins' effects on insulin traits. Further efforts shall disentangle the molecular mechanisms through which statins may induce DNAm changes, potentially leading to ABCG1 epigenetic regulation.

中文翻译：

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他汀类药物治疗与 2 型糖尿病之间的表观遗传联系。


目的 通过血液表观基因组关联研究，比较他汀类药物使用者和非使用者之间的 DNA 甲基化 (DNAm)，探讨表观遗传学在他汀类药物致糖尿病效应中的作用。研究设计和方法 五项队列研究的参与者 (n = 8,270) 在使用 Illumina 450K 或 EPIC 阵列进行 DNAm 评估时被归类为他汀类药物使用者，否则被归类为非当前使用者。研究了 DNAm 与各种结果（如 2 型糖尿病、血浆葡萄糖、胰岛素和胰岛素抵抗（胰岛素抵抗的 HOMA [HOMA-IR]）以及基因表达等结果的关联。结果 发现 (n = 6,820) 和复制 (n = 1,450) 阶段将五个 DNAm 位点与他汀类药物的使用相关：cg17901584 (1.12 × 10-25 [DHCR24])、cg10177197 (3.94 × 10-08 [DHCR24])、cg06500161 (2.67) × 10-23 [ABCG1]）、cg27243685（6.01 × 10-09 [ABCG1]）和 cg05119988（7.26 × 10-12 [SC4MOL]）。两个位点与至少一种血糖特征或 2 型糖尿病相关。较高的 cg06500161 甲基化与较高的空腹血糖、胰岛素、HOMA-IR 和 2 型糖尿病相关（比值比 1.34 [95% CI 1.22, 1.47]）。中介分析表明 ABCG1 甲基化部分介导他汀类药物对高胰岛素和 HOMA-IR 的影响。基因表达分析表明，他汀类药物暴露和 ABCG1 甲基化与 ABCG1 下调相关，表明 ABCG1 表达的表观遗传调控。此外，胰岛素和 HOMA-IR 的结果与 ABCG1 表达显着相关。结论 这项研究揭示了他汀类药物与 2 型糖尿病风险之间的潜在机制，为 DNAm 部分介导他汀类药物对胰岛素特性的影响提供了证据。 进一步的努力将解开他汀类药物可能诱导 DNAm 变化的分子机制，从而可能导致 ABCG1 表观遗传调控。