Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity.
Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity.
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全基因组范围的体重指数研究和肥胖的不利结果。
DOI：
10.1038/nature20784
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发表时间：
2017-01-05
期刊：
影响因子：
64.8
通讯作者：
Chambers JC
中科院分区：
文献类型：
--
作者：
Wahl S;Drong A;Lehne B;Loh M;Scott WR;Kunze S;Tsai PC;Ried JS;Zhang W;Yang Y;Tan S;Fiorito G;Franke L;Guarrera S;Kasela S;Kriebel J;Richmond RC;Adamo M;Afzal U;Ala-Korpela M;Albetti B;Ammerpohl O;Apperley JF;Beekman M;Bertazzi PA;Black SL;Blancher C;Bonder MJ;Brosch M;Carstensen-Kirberg M;de Craen AJ;de Lusignan S;Dehghan A;Elkalaawy M;Fischer K;Franco OH;Gaunt TR;Hampe J;Hashemi M;Isaacs A;Jenkinson A;Jha S;Kato N;Krogh V;Laffan M;Meisinger C;Meitinger T;Mok ZY;Motta V;Ng HK;Nikolakopoulou Z;Nteliopoulos G;Panico S;Pervjakova N;Prokisch H;Rathmann W;Roden M;Rota F;Rozario MA;Sandling JK;Schafmayer C;Schramm K;Siebert R;Slagboom PE;Soininen P;Stolk L;Strauch K;Tai ES;Tarantini L;Thorand B;Tigchelaar EF;Tumino R;Uitterlinden AG;van Duijn C;van Meurs JB;Vineis P;Wickremasinghe AR;Wijmenga C;Yang TP;Yuan W;Zhernakova A;Batterham RL;Smith GD;Deloukas P;Heijmans BT;Herder C;Hofman A;Lindgren CM;Milani L;van der Harst P;Peters A;Illig T;Relton CL;Waldenberger M;Järvelin MR;Bollati V;Soong R;Spector TD;Scott J;McCarthy MI;Elliott P;Bell JT;Matullo G;Gieger C;Kooner JS;Grallert H;Chambers JC
超重和肥胖影响着全球约15亿人，是2型糖尿病（T2D）、心血管疾病以及相关代谢和炎症紊乱的主要危险因素。尽管将肥胖与其临床后遗症联系起来的机制尚不清楚，但最近的研究表明，肥胖可能影响DNA甲基化，而DNA甲基化是基因表达和分子表型的关键调节因子。在这里，我们使用表观基因组关联来显示体重指数（BMI，肥胖的关键指标）与DNA甲基化的广泛变化相关（187个遗传位点，P<1x10-7，范围P=9.2x10-8至6.0x10-46； N=10,261个样本）。遗传关联分析表明，DNA甲基化的改变主要是肥胖的结果，而不是原因。我们发现甲基化位点在多个组织中丰富，具有功能基因组特征（P<0.05），并且哨兵甲基化标记识别了38个位点的基因表达特征（P<9 × 10-6，范围P=5.5 × 10-6至6.1 × 10-35， N=1,785个样本）。甲基化位点确定了涉及脂质和脂蛋白代谢、底物运输和炎症途径的重点基因。最后，我们发现DNA甲基化的干扰可以预测未来的2型糖尿病（甲基化风险评分每增加1SD的相对风险：2.3 [2.07-2.56]；P=1.1x10-54）。我们的研究结果为肥胖影响的生物学途径提供了新的见解，并可能为预测和预防2型糖尿病和肥胖的其他不良临床后果提供新的策略。
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. Although the mechanisms linking adiposity to its clinical sequelae are poorly understood, recent studies suggest that adiposity may influence DNA methylation, a key regulator of gene expression and molecular phenotype. 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.
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