Introduction Therapeutic efficiency of glucagon-like peptide-1 (GLP-1) analog is about 50%–70% in type 2 diabetes mellitus (T2DM). Discovery of potential genetic biomarkers for prediction of treatment efficiency of GLP-1 analog before therapy is still necessary. We assess whether DNA methylation was associated with glycemic response to GLP-1 analog therapy in patients with poorly controlled T2DM. Research design and methods Genomic DNA was extracted from the peripheral blood of training (n=10) and validation (n=128) groups of patients with T2DM receiving GLP-1 analogs. DNA methylome was analyzed using Infinium Human Methylation EPIC Bead Chip in the training group. The candidate genes were examined using a pyrosequencing platform in the validation group. The association between DNA methylation status and glycemic response to GLP-1 was analyzed in these patients. Results The most differential methylation region between those with a good (responsive) and poor (unresponsive) glycemic response to GLP-1 analog therapy was located on chromosome 5q31.1 (135415693 to 135416613), the promoter of VTRNA2-1 in the training group. The methylation status of the VTRNA2-1 promoter was examined in the validation group via pyrosequencing reaction, and the hypomethylation of VTRNA2-1 (<40% methylation) was significantly associated with poor glycemic response to GLP-1 treatment (OR 2.757, 95% CI 1.240 to 6.130, p=0.011). Since the VTRNA2-1 promoter region was previously reported maternal imprinting extended to the adjacent centromeric CCCTC-binding factor site that contained an A/C polymorphism (rs2346018), which was associated with methylation density of VTRNA2-1 , this A/C polymorphism was also integrated to analyze association with glycemic response to GLP-1 analog therapy. In patients with the A allele of rs2346018 and hypomethylation (<40%) on the VTRNA2-1 promoter, the OR increased to 4.048 (95% CI 1.438 to 11.389, p=0.007). Conclusions The glycemic response to GLP-1 analog treatment is associated with the methylation status of the VTRNA2-1 promoter and polymorphism of rs2346018.

中文翻译：

---

穹窿 RNA 2-1 启动子的甲基化状态是 2 型糖尿病患者对胰高血糖素样肽 1 类似物治疗的血糖反应的预测因子

简介 胰高血糖素样肽-1 (GLP-1) 类似物在 2 型糖尿病 (T2DM) 中的治疗效率约为 50%–70%。在治疗前发现潜在的遗传生物标志物以预测 GLP-1 类似物的治疗效率仍然是必要的。我们评估 DNA 甲基化是否与控制不佳的 T2DM 患者对 GLP-1 类似物治疗的血糖反应有关。研究设计和方法 从接受 GLP-1 类似物的 T2DM 患者的训练组（n=10）和验证组（n=128）的外周血中提取基因组 DNA。在训练组中使用 Infinium Human Methylation EPIC Bead Chip 分析 DNA 甲基化组。在验证组中使用焦磷酸测序平台检查候选基因。在这些患者中分析了 DNA 甲基化状态与对 GLP-1 的血糖反应之间的关联。结果 对 GLP-1 类似物治疗的血糖反应良好（反应）和不良（无反应）的患者之间差异最大的甲基化区域位于训练组 VTRNA2-1 启动子的染色体 5q31.1（135415693 至 135416613）上. 通过焦磷酸测序反应在验证组中检测了 VTRNA2-1 启动子的甲基化状态，VTRNA2-1 的低甲基化（<40% 甲基化）与 GLP-1 治疗的低血糖反应显着相关（OR 2.757, 95% CI 1.240 至 6.130，p = 0.011）。由于先前报道了 VTRNA2-1 启动子区域的母体印记延伸到含有 A/C 多态性 (rs2346018) 的相邻着丝粒 CCCTC 结合因子位点，这与 VTRNA2-1 的甲基化密度相关，该 A/C 多态性也被整合以分析与 GLP-1 类似物治疗的血糖反应的关联。在具有 rs2346018 A 等位基因和 VTRNA2-1 启动子低甲基化（<40%）的患者中，OR 增加到 4.048（95% CI 1.438 至 11.389，p=0.007）。结论 GLP-1 类似物治疗的血糖反应与 VTRNA2-1 启动子的甲基化状态和 rs2346018 的多态性有关。