Epigenome-wide association of DNA methylation markers in peripheral blood from Indian Asians and Europeans with incident type 2 diabetes: a nested case-control study.
Epigenome-wide association of DNA methylation markers in peripheral blood from Indian Asians and Europeans with incident type 2 diabetes: a nested case-control study.
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印度亚洲人和欧洲人与2型糖尿病的外周血液中DNA甲基化标志物的全基因组范围的关联：一项嵌套的病例对照研究。
DOI：
10.1016/s2213-8587(15)00127-8
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发表时间：
2015-07
期刊：
影响因子：
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通讯作者：
Kooner JS
中科院分区：
文献类型：
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作者：
Chambers JC;Loh M;Lehne B;Drong A;Kriebel J;Motta V;Wahl S;Elliott HR;Rota F;Scott WR;Zhang W;Tan ST;Campanella G;Chadeau-Hyam M;Yengo L;Richmond RC;Adamowicz-Brice M;Afzal U;Bozaoglu K;Mok ZY;Ng HK;Pattou F;Prokisch H;Rozario MA;Tarantini L;Abbott J;Ala-Korpela M;Albetti B;Ammerpohl O;Bertazzi PA;Blancher C;Caiazzo R;Danesh J;Gaunt TR;de Lusignan S;Gieger C;Illig T;Jha S;Jones S;Jowett J;Kangas AJ;Kasturiratne A;Kato N;Kotea N;Kowlessur S;Pitkäniemi J;Punjabi P;Saleheen D;Schafmayer C;Soininen P;Tai ES;Thorand B;Tuomilehto J;Wickremasinghe AR;Kyrtopoulos SA;Aitman TJ;Herder C;Hampe J;Cauchi S;Relton CL;Froguel P;Soong R;Vineis P;Jarvelin MR;Scott J;Grallert H;Bollati V;Elliott P;McCarthy MI;Kooner JS
占世界人口四分之一的印度亚洲人患2型糖尿病的风险很高。我们调查了DNA甲基化是否与印度亚洲人未来2型糖尿病发病率相关，以及印度亚洲人和欧洲人之间甲基化模式的差异是否与2型糖尿病风险大小的差异相关，并可用于预测2型糖尿病风险大小的差异。我们对来自伦敦生命科学前瞻性人群（LOLIPOP）研究的25372名参与者的8年随访中发现的患有2型糖尿病的印度亚洲人和欧洲人进行了DNA甲基化的巢式病例对照研究。患者于2002年5月1日至2008年9月12日期间招募。我们使用来自患有2型糖尿病的印度亚洲人和年龄匹配和性别匹配的印度亚洲对照的样本进行了表观基因组关联分析，然后对欧洲人的顶级信号进行了复制测试。对于发现和复制，在基线血液样本中测量DNA甲基化，该样本在2型糖尿病发作之前收集。表观基因组显著性设定为p<1 × 10−7。我们比较了基线时没有2型糖尿病的印度亚洲人和欧洲人之间的甲基化水平，以估计DNA甲基化对印度亚洲人未来2型糖尿病发病风险增加的潜在贡献。在平均随访8·5年（SD 1·8）的时间里，13 535名印度亚裔中有1608名（11·9%）和7066名欧洲人中有306名（4·3%）患上了2型糖尿病。印度裔亚洲人的2型糖尿病经年龄和性别校正的发病率比欧洲人高3.1倍（95%CI 2.8 - 3.6; p<0.0001），在校正肥胖、体力活动、2型糖尿病家族史和基线血糖测量后，仍高2.5倍（2.1 - 2.9; p<0.0001）。2型糖尿病患者和对照组之间甲基化水平的平均绝对差异范围为0.5%（SD 0.1）至1.1%（0.2）。5个位点的甲基化标记与未来2型糖尿病发病率相关;甲基化每增加1%的相对风险为1.09（95% CI 1.07 - 1.11; p= 1.3 × 10−17）对于ABCG 1，0.94（0·92-0·95; p=4·2 × 10−11）对于磷酸1，0·94（0·92-0·96; p=1·4 × 10 - 9）对于SOCS 3，1·07（1·04-1·09; p=2·1 × 10 - 10）对于SREBF 1，0·92（0·90-0·94; p=1·2 × 10 - 17）对于TXNIP。结合5个基因座的甲基化评分结果与未来2型糖尿病发病率相关（相对风险四分位数4 vs四分位数1 3·51，95% CI 2·79-4·42; p=1·3 × 10−26），并且独立于已确定的风险因素。印度亚洲人的甲基化评分高于欧洲人（p=1 × 10−34）。DNA甲基化可能为2型糖尿病的潜在途径提供新的见解，并为印度亚洲人2型糖尿病的风险分层和预防提供新的机会。欧盟、英国国家健康研究所、威康信托基金会、英国医学研究理事会、听力损失行动组织、英国生物技术和生物科学研究理事会、橡树基金会、经济和社会研究理事会、慕尼黑亥姆霍兹中心、德国环境健康研究中心、德国联邦教育和研究部、德国糖尿病研究中心、慕尼黑健康科学中心、北莱茵-威斯特伐利亚州科学研究部和德国联邦卫生部。
Indian Asians, who make up a quarter of the world’s population, are at high risk of developing type 2 diabetes. We investigated whether DNA methylation is associated with future type 2 diabetes incidence in Indian Asians and whether differences in methylation patterns between Indian Asians and Europeans are associated with, and could be used to predict, differences in the magnitude of risk of developing type 2 diabetes. We did a nested case-control study of DNA methylation in Indian Asians and Europeans with incident type 2 diabetes who were identified from the 8-year follow-up of 25 372 participants in the London Life Sciences Prospective Population (LOLIPOP) study. Patients were recruited between May 1, 2002, and Sept 12, 2008. We did epigenome-wide association analysis using samples from Indian Asians with incident type 2 diabetes and age-matched and sex-matched Indian Asian controls, followed by replication testing of top-ranking signals in Europeans. For both discovery and replication, DNA methylation was measured in the baseline blood sample, which was collected before the onset of type 2 diabetes. Epigenome-wide significance was set at p<1 × 10−7. We compared methylation levels between Indian Asian and European controls without type 2 diabetes at baseline to estimate the potential contribution of DNA methylation to increased risk of future type 2 diabetes incidence among Indian Asians. 1608 (11·9%) of 13 535 Indian Asians and 306 (4·3%) of 7066 Europeans developed type 2 diabetes over a mean of 8·5 years (SD 1·8) of follow-up. The age-adjusted and sex-adjusted incidence of type 2 diabetes was 3·1 times (95% CI 2·8–3·6; p<0·0001) higher among Indian Asians than among Europeans, and remained 2·5 times (2·1–2·9; p<0·0001) higher after adjustment for adiposity, physical activity, family history of type 2 diabetes, and baseline glycaemic measures. The mean absolute difference in methylation level between type 2 diabetes cases and controls ranged from 0·5% (SD 0·1) to 1·1% (0·2). Methylation markers at five loci were associated with future type 2 diabetes incidence; the relative risk per 1% increase in methylation was 1·09 (95% CI 1·07–1·11; p=1·3 × 10−17) for ABCG1, 0·94 (0·92–0·95; p=4·2 × 10−11) for PHOSPHO1, 0·94 (0·92–0·96; p=1·4 × 10−9) for SOCS3, 1·07 (1·04–1·09; p=2·1 × 10−10) for SREBF1, and 0·92 (0·90–0·94; p=1·2 × 10−17) for TXNIP. A methylation score combining results for the five loci was associated with future type 2 diabetes incidence (relative risk quartile 4 vs quartile 1 3·51, 95% CI 2·79–4·42; p=1·3 × 10−26), and was independent of established risk factors. Methylation score was higher among Indian Asians than Europeans (p=1 × 10−34). DNA methylation might provide new insights into the pathways underlying type 2 diabetes and offer new opportunities for risk stratification and prevention of type 2 diabetes among Indian Asians. The European Union, the UK National Institute for Health Research, the Wellcome Trust, the UK Medical Research Council, Action on Hearing Loss, the UK Biotechnology and Biological Sciences Research Council, the Oak Foundation, the Economic and Social Research Council, Helmholtz Zentrum Munchen, the German Research Center for Environmental Health, the German Federal Ministry of Education and Research, the German Center for Diabetes Research, the Munich Center for Health Sciences, the Ministry of Science and Research of the State of North Rhine-Westphalia, and the German Federal Ministry of Health.