DNA methylation of genes involved in lipid metabolism drives adiponectin levels and metabolic disease.

By identifying genomic regions involved in the regulation of adipokine levels and adipokine-mediated disease risk, we can improve our understanding of type 2 diabetes pathogenesis and inter-individual differences in metabolic risk.

通过识别参与调节脂肪因子水平和脂肪因子介导的疾病风险的基因组区域，我们可以提高对2型糖尿病发病机制和代谢风险个体间差异的理解。

Methods

We conducted an epigenome-wide meta-analysisof associations between serum adiponectin (n=2791) and leptin (n=3661) and leukocyte DNA methylation at over 400,000 CpG sites across five European cohorts.

我们在五个欧洲队列中进行了血清脂联素（n=2791）和瘦素（n=3661）与白细胞DNA甲基化在超过40万个CpG位点的全基因组关联研究。

The resulting methylation signatures were followed up using functional genomics, integrative analyses and causal inference methods.

结果的甲基化特征通过功能基因组学、综合分析和因果推断方法进行了后续研究。

Results

Our findings revealed robust associations with adiponectin at 73 CpGs and leptin at 211 CpGs.

我们的研究发现，在73个CpG位点与脂联素有强烈的关联，在211个CpG位点与瘦素有强烈的关联。

Many of the identified sites were also associated with risk factors for the metabolic syndrome and located in enhancers close to relevant transcription factor binding sites.

许多已识别的位点也与代谢综合征的风险因素有关，并且位于相关转录因子结合位点附近的增强子附近。

Integrative analyses additionally linked 35 of the adiponectin-associated CpGs to the expression of 46 genes, and 100 of the leptin-associated CpGs to the expression of 151 genes, with implicated genes enriched for lipid transport (e.g. ABCG1), metabolism (e.g. CPT1A) and biosynthesis (e.g. DHCR24).

综合分析进一步将35个与脂联素相关的CpG位点与46个基因的表达联系起来，以及将100个与瘦素相关的CpG位点与151个基因的表达联系起来，所涉及的基因富集于脂质运输（例如ABCG1）、代谢（例如CPT1A）和生物合成（例如DHCR24）相关通路。

Bidirectional two-sample Mendelian randomisation further identified two specific CpG sites as plausible drivers of both adiponectin levels and metabolic health: one annotated to ADIPOQ, the gene encoding adiponectin; and another linked to the expression of SREBF1, an established modifier of type 2 diabetes risk known to exert its effects via adiponectin.

双向两样本孟德尔随机化进一步确定了两个特定的CpG位点作为可能驱动脂联素水平和代谢健康的因素：一个注释到ADIPOQ基因，即编码脂联素的基因；另一个与SREBF1的表达相关，SREBF1是一个已知的2型糖尿病风险调节因子，已知通过脂联素发挥其效应。

conclusions/interpretation

Taken together, these large-scale and integrative analyses uncovered links between adipokines and widespread, yet functionally specific, differences in regulation of genes with a central role in type 2 diabetes and its risk factors.

综合这些大规模和综合性的分析，揭示了脂肪因子与2型糖尿病及其风险因素中起中心作用的基因调控的广泛而功能特异性的差异之间的联系。