Novel epigenetic determinants of type 2 diabetes in Mexican-American families
Novel epigenetic determinants of type 2 diabetes in Mexican-American families
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DOI：
10.1093/hmg/ddv232
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发表时间：
2015-09-15
影响因子：
3.5
通讯作者：
Carless, Melanie A.
中科院分区：
文献类型：
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作者：
Kulkarni, Hemant;Kos, Mark Z.;Carless, Melanie A.
虽然DNA甲基化现在被认为是复杂疾病的重要介质，但DNA甲基化在多大程度上解释了此类疾病的遗传基础尚不清楚。在代表美国少数高风险人群的大家庭中，我们旨在描述表观基因组DNA甲基化在2型糖尿病（T2 D）中的作用。使用Illumina人类甲基化450 BeadChip阵列，我们测试了850个墨西哥裔美国人家系中446356个位点的DNA甲基化与T2 D相关的年龄、性别和表型性状的相关性。稳健的统计分析表明：（i）15%的甲基化组具有显著的遗传性，中位遗传率为0.14;（ii）14%的CpG位点的DNA甲基化与附近的序列变异相关;（iii）22%和3%的常染色体CpG位点分别与年龄和性别相关;（iv）53个CpG位点与T2 D易感性、空腹血糖和胰岛素抵抗显著相关;（v）五个CpG位点的DNA甲基化水平，映射到三个充分表征的基因（TXNIP，ABCG 1和SAMD 12）独立地解释了7.8%的T2 D（vi）甲基化在这五个位点的遗传可能性是不太可能受到相邻的DNA序列变异的影响。我们的研究确定了墨西哥裔美国人T2 D风险的新表观遗传指标，这些人患这种疾病的风险增加。这些结果为T2 D的潜在治疗靶点提供了新的见解。
Although DNA methylation is now recognized as an important mediator of complex diseases, the extent to which the genetic basis of such diseases is accounted for by DNA methylation is unknown. In the setting of large, extended families representing a minority, high-risk population of the USA, we aimed to characterize the role of epigenome-wide DNA methylation in type 2 diabetes (T2D). Using Illumina Human Methylation 450 BeadChip arrays, we tested for association of DNA methylation at 446 356 sites with age, sex and phenotypic traits related to T2D in 850 pedigreed Mexican-American individuals. Robust statistical analyses showed that (i) 15% of the methylome is significantly heritable, with a median heritability of 0.14; (ii) DNA methylation at 14% of CpG sites is associated with nearby sequence variants; (iii) 22% and 3% of the autosomal CpG sites are associated with age and sex, respectively; (iv) 53 CpG sites were significantly associated with liability to T2D, fasting blood glucose and insulin resistance; (v) DNA methylation levels at five CpG sites, mapping to three well-characterized genes (TXNIP, ABCG1 and SAMD12) independently explained 7.8% of the heritability of T2D (vi) methylation at these five sites was unlikely to be influenced by neighboring DNA sequence variation. Our study has identified novel epigenetic indicators of T2D risk in Mexican Americans who have increased risk for this disease. These results provide new insights into potential treatment targets of T2D.