DNA methylation differences between identical twins

描述(由申请人提供)： 大多数复杂的疾病都有遗传原因，但来自家庭，特别是来自双胞胎的观察表明，其他因素几乎总是对疾病的实际出现是必要的。一个这样的因素似乎是带有甲基的DNA单位的比例，或者更准确地说，是重要特定基因座的甲基化状态。众所周知，甲基化水平因个体而异，并与几种慢性病有关。这一水平已被证明会随着年龄的增长而变化，即使是在同卵双胞胎成员中也是如此。其中一些变化可能是内生力量的结果，因此很可能是随机出现的。然而，其他疾病很可能是由导致疾病的环境暴露或其出现之前的风险因素造成的。这项研究试图评估DNA甲基化状态和已知的预测疾病发生的环境因素之间的联系。甲基化将使用更准确的焦磷酸测序方法进行分析，并在血细胞和口腔鳞状上皮细胞中进行研究，血细胞和口腔鳞状上皮细胞可能更严重地暴露在高水平的环境介质中。有相关环境暴露史的双胞胎的甲基化水平将与相对未暴露的同卵双胞胎的甲基化水平进行比较。这类接触的清单包括吸烟、饮酒、肥胖、食用已知含有叶酸的食物和已知含有致癌物质的食物，以及职业性和住宅性接触各种环境化学品和毒素。该计划还将根据居住地、职业暴露和饮食选择那些最不可能接触环境毒素的同卵双胞胎，以测量特定年龄的DNA甲基化水平，以及这些水平与性别和双胞胎的差异程度。这些差异水平和指数将与根据性别、教育状况和母亲教育状况(衡量儿童社会阶层的一种衡量标准)选择的配对中的相同结果进行比较。最后，将调查任何可遗传倾向改变甲基化状态的证据，这些证据基于同卵同性异卵双胞胎累积接触有毒物质的证据最少。

DESCRIPTION (provided by applicant): Most complex diseases have genetic causes, but observations from families and especially from twins indicate that other factors are almost always necessary for the actual appearance of disease. One such factor appears to be the proportion of DNA units that have methyl groups attached to them, or more accurately the methylation status at important specific loci. The level of methylation is known to vary between individuals and has been linked to several chronic diseases. The level has been shown to change with increasing age, even within the members of identical twin pairs. Some of these changes are probably the result of endogenous forces and therefore are likely to have appeared at random. Others, however, are likely to be the result of the environmental exposures that cause disease or the risk factors that precede its appearance. This study seeks to evaluate the linkage between the DNA methylation status and environmental factors known to predict disease occurrence. Methylation will be assayed using the more accurate pyrosequencing method, and studied both in blood cells, upon which much of the current understanding is based, and squamous epithelial cells from the mouth, likely to be more heavily exposed to high levels of environmental agents. The level of methylation will be compared in twins who give a history of pertinent environmental exposure, to that in their relatively unexposed identical co-twins. The list of such exposures includes smoking, alcohol usage, obesity, consumption of foods known to contain folic acid and food known to contain carcinogens, and occupational and residential exposure to various environmental chemicals and toxins. The plan is to also select those sets of identical twins least likely to have been exposed to environmental toxins, based on residence, occupational exposure, and diet, in order to measure the age-specific levels of DNA methylation, and the degree to which those levels vary in relation to sex and twin pair. These levels and indices of variation will be compared to the same findings from pairs selected on the basis of sex, educational status, and maternal educational status (a measure of childhood social class). Finally, any evidence of a heritable propensity to change methylation status, based on identical and like sex fraternal twins having the least evidence of cumulative toxic exposure, will be investigated.