Epigenome-wide association study of adiposity and future risk of obesity-related diseases
Epigenome-wide association study of adiposity and future risk of obesity-related diseases
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DOI：
10.1038/s41366-018-0064-7
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发表时间：
2018-12-01
影响因子：
4.9
通讯作者：
Chadeau-Hyam, Marc
中科院分区：
文献类型：
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作者：
Campanella, Gianluca;Gunter, Marc J.;Chadeau-Hyam, Marc
肥胖是一些常见慢性疾病的危险因素，如乳腺癌和结直肠癌、代谢和心血管疾病；然而，这些关系的生物学基础尚不完全清楚。为了探讨肥胖与这些疾病的关系，我们研究了外周血白细胞（PBL） DNA甲基化标记物与肥胖的关系，以及它们对乳腺癌、结直肠癌和心肌梗死发生风险的影响。方法在荟萃分析框架内分析来自4个欧洲人群队列的1941名个体的DNA甲基化谱（Illumina Infinium HumanMethylation450 BeadChip）与体重指数、腰围、腰臀比和腰高比的关系。在这些个体的一个子集中，还可以获得全基因组基因表达水平、葡萄糖和脂质代谢生物标志物的数据。在358个个体中进行了与所有肥胖测量相关的甲基化标记的验证。最后，我们在发现人群的相关亚群中调查了肥胖相关甲基化标记与乳腺癌、结直肠癌和心肌梗死的关系。结果我们确定了40个CpG位点，其甲基化水平与至少一种肥胖测量相关。其中，ABCG1中的一个CpG位点（cg06500161）与所有四种肥胖测量（P = 9.07x10（-8）至3.27x10(-1)8）和ABCG1全长亚型转录活性较低（P = 6.00x10(-7)），较高的甘油三酯水平（P = 5.37 x10(-9)）和较高的甘油三酯与高密度脂蛋白胆固醇比值（P =1.03x10(-1)）相关。在40个信息丰富且与肥胖相关的CpG位点中，两个（在IL2RB和FGF18中）与结直肠癌显著相关（负相关，P < 1.6x10(-3)）， 1号染色体上的一个基因间位点与心肌梗死负相关（P < 1.25x10(-3)），独立于肥胖和既定危险因素。结论表观遗传变化，特别是DNA甲基化模式的改变，可能是肥胖和肥胖相关疾病交叉的中间生物标志物，并可能为潜在的生物学机制提供线索。
Background Obesity is an established risk factor for several common chronic diseases such as breast and colorectal cancer, metabolic and cardiovascular diseases; however, the biological basis for these relationships is not fully understood. To explore the association of obesity with these conditions, we investigated peripheral blood leucocyte (PBL) DNA methylation markers for adiposity and their contribution to risk of incident breast and colorectal cancer and myocardial infarction.Methods DNA methylation profiles (Illumina Infinium HumanMethylation450 BeadChip) from 1941 individuals from four population-based European cohorts were analysed in relation to body mass index, waist circumference, waist-hip and waist height ratio within a meta-analytical framework. In a subset of these individuals, data on genome-wide gene expression level, biomarkers of glucose and lipid metabolism were also available. Validation of methylation markers associated with all adiposity measures was performed in 358 individuals. Finally, we investigated the association of obesity-related methylation marks with breast, colorectal cancer and myocardial infarction within relevant subsets of the discovery population.Results We identified 40 CpG loci with methylation levels associated with at least one adiposity measure. Of these, one CpG locus (cg06500161) in ABCG1 was associated with all four adiposity measures (P = 9.07x10(-8) to 3.27x10(-1)8) and lower transcriptional activity of the full-length isoform of ABCG1 (P = 6.00x10(-7)), higher triglyceride levels (P = 5.37 x10(-9)) and higher triglycerides-to-HDL cholesterol ratio (P =1.03x10(-1)). Of the 40 informative and obesity-related CpG loci, two (in IL2RB and FGF18) were significantly associated with colorectal cancer (inversely, P < 1.6x10(-3)) and one intergenic locus on chromosome 1 was inversely associated with myocardial infarction (P < 1.25x10(-3)), independently of obesity and established risk factors.Conclusion Our results suggest that epigenetic changes, in particular altered DNA methylation patterns, may be an intermediate biomarker at the intersection of obesity and obesity-related diseases, and could offer clues as to underlying biological mechanisms.