Systemic interindividual epigenetic variants in African Americans: Identification, characterization, and prospective associations with obesity

项目摘要(摘要) 除了遗传和环境外，表观遗传调控中的个体间差异可能决定了 肥胖。在各种表观遗传机制中，DNA甲基化是最稳定的；一旦在 在发育过程中，DNA甲基化模式是有丝分裂可遗传的，并可在人类中持续多年。 然而，与遗传流行病学相比，研究肥胖的表观遗传决定因素要多得多。 这很复杂，主要有两个原因。首先，表观遗传机制在很大程度上是细胞类型特有的，所以研究 容易接触到的组织(如外周血)中的DNA甲基化通常不能提供信息 关于对能量平衡很重要的器官(如大脑)的表观遗传调节。其次，肥胖本身可能 影响DNA甲基化模式，所以“反向因果关系”是一个问题。在过去的十年中，我们开创了一个 通过识别表现系统性疾病的人类基因组区域来绕过这些障碍的方法 DNA甲基化的个体间变异(系统个体间变异的相关区域- CoRSIV)。去年，我们报告确认了近10,000例人类CoRSIV。这些地区是稳定的 以及系统性表观遗传变异--本质上是表观遗传多态--使大规模表观遗传成为可能 使用外周血DNA进行流行病学研究。我们最初的筛查是用高加索人进行的，我们的 数据显示，还有更多的人类CoRSIV需要识别。鉴于非洲裔美国人既是 在基因组和表观基因组分析中被严重低估，并不成比例地负担过重 对于肥胖，现在迫切需要通过直接研究非裔美国人来扩大我们的CoRSIV筛查并使其多样化。 因此，我们在这个项目中的目标是：1)对非裔美国人进行无偏见的CoRSIV筛查 NIH基因-组织表达计划(GTEx)中的捐赠者，2)验证系统个体间表观遗传学 非裔美国人大样本中基因表达的变异和跨组织预测，以及3)测试 出生时CoRSIV甲基化是否预测再生障碍性贫血儿童的儿童肥胖风险。我们预料到 我们项目的完成将改变人类肥胖症的表观遗传学和表观遗传学流行病学的研究 总体而言。这一项目对非裔美国人的关注在科学上和从以下两个方面都是合理的 社会正义。

PROJECT SUMMARY (Abstract) In addition to genetics and environment, interindividual variation in epigenetic regulation may determine risk of obesity. Of various epigenetic mechanisms, DNA methylation is this most stable; once established during development, DNA methylation patterns are mitotically heritable and can persist for many years in humans. Compared to genetic epidemiology, however, studying epigenetic determinants of obesity is much more complicated, for two main reasons. First, epigenetic mechanisms are largely cell type-specific, so studying DNA methylation in easily accessible tissues (like peripheral blood) does not generally provide information about epigenetic regulation in organs important to energy balance (like the brain). Second, obesity itself can affect DNA methylation patterns, so `reverse causality' is a problem. Over the last decade we pioneered an approach to circumvent these obstacles by identifying human genomic regions that exhibit systemic interindividual variation in DNA methylation (correlated regions of systemic interindividual variation – CoRSIVs). Last year we reported the identification of nearly 10,000 human CoRSIVs. These regions are stable and systemic epigenetic variants – essentially epigenetic polymorphisms - enabling large-scale epigenetic epidemiologic studies using peripheral blood DNA. Our initial screen was conducted in Caucasians, and our data show that there are many more human CoRSIVs to identify. Given that African Americans are both grossly underrepresented in genomic and epigenomic analyses, and disproportionately overburdened by obesity, it is now urgent to scale up and diversify our CoRSIV screen by studying African Americans directly. Accordingly, our Aims in this project are to 1) Perform an unbiased screen for CoRSIVs in African American donors in the NIH Gene-Tissue Expression program (GTEx), 2) Validate systemic interindividual epigenetic variation and cross-tissue prediction of gene expression in a large sample of African Americans, and 3) Test whether CoRSIV methylation at birth predicts risk of childhood obesity in AA children. We anticipate that completion of our project will transform the study of epigenetics in human obesity, and epigenetic epidemiology in general. The focus of this project on African Americans is justified both scientifically and from the basis of social justice.