Heritable rather than age-related environmental and stochastic factors dominate variation in DNA methylation of the human IGF2/H19 locus
Heritable rather than age-related environmental and stochastic factors dominate variation in DNA methylation of the human IGF2/H19 locus
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DOI：
10.1093/hmg/ddm010
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发表时间：
2007-03-01
影响因子：
3.5
通讯作者：
Slagboom, P. Eline
中科院分区：
文献类型：
--
作者：
Heijmans, Bastiaan T.;Kremer, Dennis;Slagboom, P. Eline
表观遗传变异可能会显着导致常见疾病的风险。目前，对表观遗传变异的程度和原因知之甚少。在这里，我们研究了可遗传影响的贡献以及环境和随机因素对IGF2/H19基因座DNA甲基化变化的综合作用。此外，我们测试了该基因座是否受到年龄相关的表观遗传模式的变性，如先前建议的全球甲基化所建议。我们使用最近开发的基于质谱的方法测量了196个青少年和176个中年双胞胎的H19和IGF2差异甲基化区（DMR）的甲基化。我们观察到跨个体DNA甲基化的实质性变化，强调DNA甲基化是一种定量性状。对单卵和双卵双胞胎的数据分析表明，这种变异的很大一部分可以归因于可遗传的因素。对于H19 DMR，单个CpG位点的甲基化在20％至74％之间，IGF2 DMR在57％至97％之间变化。值得注意的是，环境和随机因子对DNA甲基化的综合影响在中年龄远不及青春期，这表明该基因座甲基化模式的年龄相关变性的作用有限。 IGF2/H19基因座中的单核苷酸多态性与IGF2 DMR的DNA甲基化显着相关（P = 0.004）。初步分析表明H19 DMR甲基化与体型之间存在关联（P <0.05）。我们的研究表明，IGF2/H19基因座的DNA甲基化的变化主要取决于CIS中的可遗传因素和单核苷酸多态性（SNP），而不是随着年龄而发生的环境和随机因素的累积效应。
Epigenetic variation may significantly contribute to the risk of common disease. Currently, little is known about the extent and causes of epigenetic variation. Here, we investigated the contribution of heritable influences and the combined effect of environmental and stochastic factors to variation in DNA methylation of the IGF2/H19 locus. Moreover, we tested whether this locus was subject to age-related degeneration of epigenetic patterns as was previously suggested for global methylation. We measured methylation of the H19 and IGF2 differentially methylated regions (DMRs) in 196 adolescent and 176 middle-aged twins using a recently developed mass spectrometry-based method. We observed substantial variation in DNA methylation across individuals, underscoring that DNA methylation is a quantitative trait. Analysis of data in monozygotic and dizygotic twins revealed that a significant part of this variation could be attributed to heritable factors. The heritability of methylation of individual CpG sites varied between 20 and 74% for the H19 DMR and was even higher, between 57 and 97%, for the IGF2 DMR. Remarkably, the combined influence of environmental and stochastic factors on DNA methylation was not greater in middle-age than in adolescence, suggesting a limited role for age-related degeneration of methylation patterns at this locus. Single nucleotide polymorphisms in the IGF2/H19 locus were significantly associated with DNA methylation of the IGF2 DMR (P = 0.004). A preliminary analysis suggested an association between H19 DMR methylation and body size (P < 0.05). Our study shows that variation in DNA methylation of the IGF2/H19 locus is mainly determined by heritable factors and single nucleotide polymorphisms (SNPs) in cis, rather than the cumulative effect of environmental and stochastic factors occurring with age.