Epigenome-wide association study of incident type 2 diabetes: a meta-analysis of five prospective European cohorts.
Epigenome-wide association study of incident type 2 diabetes: a meta-analysis of five prospective European cohorts.
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DOI：
10.1007/s00125-022-05652-2
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发表时间：
2022-05
期刊：
影响因子：
8.2
通讯作者：
Snieder H
中科院分区：
文献类型：
--
作者：
Fraszczyk E;Spijkerman AMW;Zhang Y;Brandmaier S;Day FR;Zhou L;Wackers P;Dollé MET;Bloks VW;Gào X;Gieger C;Kooner J;Kriebel J;Picavet HSJ;Rathmann W;Schöttker B;Loh M;Verschuren WMM;van Vliet-Ostaptchouk JV;Wareham NJ;Chambers JC;Ong KK;Grallert H;Brenner H;Luijten M;Snieder H
2型糖尿病是一种复杂的代谢性疾病，在全球范围内发病率不断增加。使用表观遗传标记物改善对2型糖尿病的预测，可以帮助针对那些风险最高的人进行预防。本研究的目的是通过结合来自五个前瞻性欧洲队列的表观全基因组关联研究（EWAS）结果，确定偶发2型糖尿病的预测性甲基化标志物。我们对2型糖尿病诊断前7-10年收集的血液中的EWAS进行了荟萃分析。用Illumina Infinium甲基化阵列测量DNA甲基化。共纳入来自5个纵向队列的1250例病例和1950例对照：杜廷赫姆、ESTHER、KORA 1、KORA 2和EPIC-Norfolk。DNA甲基化与2型糖尿病发病之间的关系采用稳健的线性回归进行研究，并对潜在的混杂因素进行调整。使用METAL对队列水平的个体CpG EWAS估计值进行逆方差固定效应荟萃分析。甲基GSA R包用于基因集富集分析。在一组印度亚洲人（LOLIPOP，UK）中进行全基因组显著CpG位点的确认。荟萃分析确定了76个CpG位点，与对照个体相比，2型糖尿病患者的甲基化差异（p值<1.1 × 10−7）。76个CpG位点中的64个（84.2%）通过在独立的印度亚洲人队列中的方向一致性效应和p值<0.05而被证实。然而，在调整基线BMI后，只有4个CpG位点保持全基因组显著性，并且将76个CpG甲基化风险评分添加到包括2型糖尿病的既定预测因子（年龄，性别，BMI和HbA 1c）的预测模型中，未显示改善（AUC 0.757 vs 0.753）。全表观基因组结果的基因集富集分析清楚地显示了与胰岛素信号传导、脂质稳态和炎症相关的过程的富集。通过结合五个欧洲队列的结果，从而显著增加研究样本量，我们确定了76个与2型糖尿病相关的CpG位点。在一个独立的印度亚洲人队列中复制64个CpG表明，DNA甲基化水平与2型糖尿病发病率之间的关联是稳健的，并且与种族无关。我们的数据还表明，BMI部分解释了DNA甲基化与2型糖尿病之间的关联。需要进一步的研究来阐明潜在的生物学机制，并确定差异甲基化CpG位点在2型糖尿病发展中的潜在因果作用。在线版本包含同行评审但未经编辑的补充材料，可通过10.1007/s 00125 -022-05652-2获得。
Type 2 diabetes is a complex metabolic disease with increasing prevalence worldwide. Improving the prediction of incident type 2 diabetes using epigenetic markers could help tailor prevention efforts to those at the highest risk. The aim of this study was to identify predictive methylation markers for incident type 2 diabetes by combining epigenome-wide association study (EWAS) results from five prospective European cohorts. We conducted a meta-analysis of EWASs in blood collected 7–10 years prior to type 2 diabetes diagnosis. DNA methylation was measured with Illumina Infinium Methylation arrays. A total of 1250 cases and 1950 controls from five longitudinal cohorts were included: Doetinchem, ESTHER, KORA1, KORA2 and EPIC-Norfolk. Associations between DNA methylation and incident type 2 diabetes were examined using robust linear regression with adjustment for potential confounders. Inverse-variance fixed-effects meta-analysis of cohort-level individual CpG EWAS estimates was performed using METAL. The methylGSA R package was used for gene set enrichment analysis. Confirmation of genome-wide significant CpG sites was performed in a cohort of Indian Asians (LOLIPOP, UK). The meta-analysis identified 76 CpG sites that were differentially methylated in individuals with incident type 2 diabetes compared with control individuals (p values <1.1 × 10−7). Sixty-four out of 76 (84.2%) CpG sites were confirmed by directionally consistent effects and p values <0.05 in an independent cohort of Indian Asians. However, on adjustment for baseline BMI only four CpG sites remained genome-wide significant, and addition of the 76 CpG methylation risk score to a prediction model including established predictors of type 2 diabetes (age, sex, BMI and HbA1c) showed no improvement (AUC 0.757 vs 0.753). Gene set enrichment analysis of the full epigenome-wide results clearly showed enrichment of processes linked to insulin signalling, lipid homeostasis and inflammation. By combining results from five European cohorts, and thus significantly increasing study sample size, we identified 76 CpG sites associated with incident type 2 diabetes. Replication of 64 CpGs in an independent cohort of Indian Asians suggests that the association between DNA methylation levels and incident type 2 diabetes is robust and independent of ethnicity. Our data also indicate that BMI partly explains the association between DNA methylation and incident type 2 diabetes. Further studies are required to elucidate the underlying biological mechanisms and to determine potential causal roles of the differentially methylated CpG sites in type 2 diabetes development. The online version contains peer-reviewed but unedited supplementary material available at 10.1007/s00125-022-05652-2.
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影响因子：
30.8
作者：
Mahajan A;Taliun D;Thurner M;Robertson NR;Torres JM;Rayner NW;Payne AJ;Steinthorsdottir V;Scott RA;Grarup N;Cook JP;Schmidt EM;Wuttke M;Sarnowski C;Mägi R;Nano J;Gieger C;Trompet S;Lecoeur C;Preuss MH;Prins BP;Guo X;Bielak LF;Below JE;Bowden DW;Chambers JC;Kim YJ;Ng MCY;Petty LE;Sim X;Zhang W;Bennett AJ;Bork-Jensen J;Brummett CM;Canouil M;Ec Kardt KU;Fischer K;Kardia SLR;Kronenberg F;Läll K;Liu CT;Locke AE;Luan J;Ntalla I;Nylander V;Schönherr S;Schurmann C;Yengo L;Bottinger EP;Brandslund I;Christensen C;Dedoussis G;Florez JC;Ford I;Franco OH;Frayling TM;Giedraitis V;Hackinger S;Hattersley AT;Herder C;Ikram MA;Ingelsson M;Jørgensen ME;Jørgensen T;Kriebel J;Kuusisto J;Ligthart S;Lindgren CM;Linneberg A;Lyssenko V;Mamakou V;Meitinger T;Mohlke KL;Morris AD;Nadkarni G;Pankow JS;Peters A;Sattar N;Stančáková A;Strauch K;Taylor KD;Thorand B;Thorleifsson G;Thorsteinsdottir U;Tuomilehto J;Witte DR;Dupuis J;Peyser PA;Zeggini E;Loos RJF;Froguel P;Ingelsson E;Lind L;Groop L;Laakso M;Collins FS;Jukema JW;Palmer CNA;Grallert H;Metspalu A;Dehghan A;Köttgen A;Abecasis GR;Meigs JB;Rotter JI;Marchini J;Pedersen O;Hansen T;Langenberg C;Wareham NJ;Stefansson K;Gloyn AL;Morris AP;Boehnke M;McCarthy MI
通讯作者：
McCarthy MI
影响因子：
4.4
作者：
Mittelstraß K;Waldenberger M
通讯作者：
Waldenberger M
影响因子：
3.5
作者：
Kulkarni, Hemant;Kos, Mark Z.;Carless, Melanie A.
通讯作者：
Carless, Melanie A.
影响因子：
120.7
作者：
Mokdad, AH;Ford, ES;Marks, JS
通讯作者：
Marks, JS
影响因子：
3.5
作者：
McCarthy, Mark I.;Hirschhorn, Joel N.
通讯作者：
Hirschhorn, Joel N.