DNA methylation and the adverse metabolic outcomes of adiposity

Overweight and obesity affect ~1.5 billion people worldwide, and are major risk factors for type-2 diabetes (T2D), cardiovascular disease and related metabolic and inflammatory disturbances.1,2 Although the mechanisms linking adiposity to its clinical sequelae are poorly understood, recent studies suggest that adiposity may influence DNA methylation,3-6 a key regulator of gene expression and molecular phenotype.7 Here we use epigenome-wide association to show that body mass index (BMI, a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci at P<1x10-7, range P=9.2x10-8 to 6.0x10-46; N=10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find the methylation loci are enriched for functional genomic features in multiple tissues (P<0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P<9.0x10-6, range P=5.5x10-6 to 6.1x10-35, N=1,785 samples). The methylation loci identified highlight genes involved in lipid and lipoprotein metabolism, substrate transport, and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future type-2 diabetes (relative risk per 1SD increase in Methylation Risk Score: 2.3 [2.07-2.56]; P=1.1x10-54). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type-2 diabetes and other adverse clinical consequences of obesity.EGA study EGAS00001001922

全球约15亿人口受超重与肥胖问题困扰，其为2型糖尿病（type-2 diabetes, T2D）、心血管疾病及相关代谢与炎症紊乱的主要危险因素[1,2]。尽管将体脂与临床后遗症相关联的分子机制尚未阐明，但近期研究表明体脂可影响DNA甲基化（DNA methylation）[3-6]，而后者是基因表达与分子表型的关键调控因子[7]。本研究通过全表观基因组关联分析（epigenome-wide association）证实，作为体脂核心衡量指标的体质指数（body mass index, BMI）与广泛的DNA甲基化改变存在显著关联（共鉴定出187个遗传位点，P<1×10^-7，P值范围为9.2×10^-8至6.0×10^-46；样本量N=10261）。遗传关联分析结果显示，DNA甲基化改变主要是体脂状态导致的结果，而非其诱因。研究发现，上述甲基化位点在多种组织的功能基因组特征中显著富集（P<0.05）；同时哨兵甲基化标记（sentinel methylation markers）可在38个位点上识别基因表达特征（P<9.0×10^-6，P值范围为5.5×10^-6至6.1×10^-35，样本量N=1785）。本研究鉴定的甲基化位点所关联的基因，涉及脂质与脂蛋白代谢、底物转运及炎症通路等生物学过程。最后，本研究证实DNA甲基化异常可预测未来2型糖尿病的发生风险：甲基化风险评分（Methylation Risk Score）每增加1个标准差，相对风险为2.3 [2.07-2.56]；P=1.1×10^-54。本研究结果为体脂调控的生物学通路提供了全新见解，或可为开发预测与预防2型糖尿病及肥胖其他不良临床结局的新型策略提供支撑。本研究关联的EGA研究编号为EGAS00001001922。