Kriebel Jennifer, Herder Christian, Rathmann Wolfgang, Wahl Simone, Kunze Sonja, Molnos Sophie, Volkova Nadezda, Schramm Katharina, Carstensen-Kirberg Maren, Waldenberger Melanie, Gieger Christian, Peters Annette, Illig Thomas, Prokisch Holger, Roden Michael, Grallert Harald
Research Unit of Molecular Epidemiology, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany.
Institute of Epidemiology II, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany.
PLoS One. 2016 Mar 28;11(3):e0152314. doi: 10.1371/journal.pone.0152314. eCollection 2016.
Epigenetic regulation has been postulated to affect glucose metabolism, insulin sensitivity and the risk of type 2 diabetes. Therefore, we performed an epigenome-wide association study for measures of glucose metabolism in whole blood samples of the population-based Cooperative Health Research in the Region of Augsburg F4 study using the Illumina HumanMethylation 450 BeadChip. We identified a total of 31 CpG sites where methylation level was associated with measures of glucose metabolism after adjustment for age, sex, smoking, and estimated white blood cell proportions and correction for multiple testing using the Benjamini-Hochberg (B-H) method (four for fasting glucose, seven for fasting insulin, 25 for homeostasis model assessment-insulin resistance [HOMA-IR]; B-H-adjusted p-values between 9.2x10(-5) and 0.047). In addition, DNA methylation at cg06500161 (annotated to ABCG1) was associated with all the aforementioned phenotypes and 2-hour glucose (B-H-adjusted p-values between 9.2x10(-5) and 3.0x10(-3)). Methylation status of additional three CpG sites showed an association with fasting insulin only after additional adjustment for body mass index (BMI) (B-H-adjusted p-values = 0.047). Overall, effect strengths were reduced by around 30% after additional adjustment for BMI, suggesting that this variable has an influence on the investigated phenotypes. Furthermore, we found significant associations between methylation status of 21 of the aforementioned CpG sites and 2-hour insulin in a subset of samples with seven significant associations persisting after additional adjustment for BMI. In a subset of 533 participants, methylation of the CpG site cg06500161 (ABCG1) was inversely associated with ABCG1 gene expression (B-H-adjusted p-value = 1.5x10(-9)). Additionally, we observed an enrichment of the top 1,000 CpG sites for diabetes-related canonical pathways using Ingenuity Pathway Analysis. In conclusion, our study indicates that DNA methylation and diabetes-related traits are associated and that these associations are partially BMI-dependent. Furthermore, the interaction of ABCG1 with glucose metabolism is modulated by epigenetic processes.
表观遗传调控被认为会影响葡萄糖代谢、胰岛素敏感性和2型糖尿病风险。因此，我们在基于人群的奥格斯堡地区合作健康研究F4研究的全血样本中，使用Illumina HumanMethylation 450 BeadChip进行了一项全表观基因组关联研究，以检测葡萄糖代谢指标。我们共鉴定出31个CpG位点，在对年龄、性别、吸烟情况以及估计的白细胞比例进行调整，并使用Benjamini-Hochberg（B-H）方法进行多重检验校正后，这些位点的甲基化水平与葡萄糖代谢指标相关（空腹血糖相关4个，空腹胰岛素相关7个，稳态模型评估胰岛素抵抗[HOMA-IR]相关25个；B-H校正p值在9.2×10⁻⁵至0.047之间）。此外，cg06500161（注释为ABCG1）处的DNA甲基化与上述所有表型以及2小时血糖相关（B-H校正p值在9.2×10⁻⁵至3.0×10⁻³之间）。另外三个CpG位点的甲基化状态仅在对体重指数（BMI）进行额外调整后与空腹胰岛素相关（B-H校正p值 = 0.047）。总体而言，在对BMI进行额外调整后，效应强度降低了约30%，表明该变量对所研究的表型有影响。此外，我们发现上述21个CpG位点的甲基化状态与2小时胰岛素之间存在显著关联，在对BMI进行额外调整后，仍有7个显著关联存在于一个样本子集中。在一个533名参与者的子集中，CpG位点cg06500161（ABCG1）的甲基化与ABCG1基因表达呈负相关（B-H校正p值 = 1.5×10⁻⁹）。此外，我们使用Ingenuity Pathway Analysis观察到糖尿病相关经典通路的前1000个CpG位点存在富集。总之，我们的研究表明DNA甲基化与糖尿病相关性状有关，且这些关联部分依赖于BMI。此外，ABCG1与葡萄糖代谢的相互作用受表观遗传过程调控。
