The Role and Genetic Mechanism of Epigenetic Plasticity in Age-Related Disease

描述（由申请人提供）： 糖尿病相关的疾病易感性是发病、死亡和生活质量下降的最常见原因。虽然可能与遗传学和表观遗传学有关，但表观遗传学对年龄相关疾病的影响以前没有定义，也没有与遗传变异有关。我们最近提出了一种新的范式，用于理解DNA序列，表观遗传标记和表型之间的关系，认为基因和表观遗传学的作用，不仅影响表型的平均值，而且其可塑性，或方差的变化。我们已经开始通过识别人类基因组中高度甲基化的区域（VMR）来应用我们的方法。我们已经发现，VMR定义了老年人的表观遗传特征，并且它们与重要的健康指标（如BMI）相关。该提案的目的是通过识别与3个领域（身体组成;能量可用性/需求;维持身体稳态）中常见的年龄相关表型相关的VMR，并确定VMR与潜在遗传变异之间的关系，来充分探索这种新的范式。除了基因型直接控制预期（或平均）表型值的传统观点，我们认为，基因型的另一个主要影响是控制随机表观遗传变异，导致在一个特定的基因组位点的甲基化的变异性增加，从而增加表型变异。这是一个全新的概念。我们假设了一种新的SNP，我们称之为vSNP或变异SNP，它与VMR的甲基化变异程度相关，而不是平均甲基化水平，因此也与群体中表型的传播或变异性相关，而不是平均值。这样的vSNP会增加处于高和低疾病风险的个体的比例，因此在传统的关联分析中是不可检测的。为了支持我们的方法，我们显示了初步数据，识别与VMR相关的vSNP，与表型方差增加相关的vSNP，以及与表型相关的VMR。我们的目标是：1 -使用巴尔的摩老龄化纵向研究（BLSA）中的2000名参与者，以及全基因组SNP和甲基化方法，在我们的平均模型和可塑性模型下研究DNA序列、DNA甲基化和定量衰老表型之间的关系。2 -进行聚焦DNA测序和捕获亚硫酸氢盐测序，以鉴定导致目标1中发现的特定序列和表观遗传变体。这项工作将有助于阐明遗传变异如何与甲基化变异相关，以及两者如何影响增加疾病易感性的年龄相关表型。DNA甲基化可能是风险评估和干预的新目标，可以减少疾病和残疾的负担，减缓衰老的有害影响。 公共卫生相关性： 我们计划研究基因、DNA的表观遗传修饰和增加疾病易感性的年龄相关表型之间的关系。我们将重点讨论两个假设：（1）基因控制DNA甲基化的平均值和表型的平均值;（2）基因控制群体中DNA甲基化和表型的变异或扩散。如果我们的假设是正确的，即DNA和DNA甲基化的特定变化对与年龄相关的疾病易感性增加很重要，那么DNA甲基化可能是风险评估和干预的新目标，可以减少与衰老相关的疾病和残疾的负担。

DESCRIPTION (provided by applicant): Age-related susceptibility to disease is the most common cause of morbidity, mortality, and diminished quality of life. Although likely related to both genetics and epigenetics, the epigenetic influences on age- related disease have not been defined previously or related to genetic variation. We have recently proposed a novel paradigm for understanding the relationship between variation in DNA sequence, epigenetic marks, and phenotype that considers the role of genes and epigenetics in affecting not only the mean of a phenotype but also its plasticity, or variance. We have begun to apply our approach by identifying highly variably methylated regions (VMRs) in the human genome. We have discovered that VMRs define an epigenetic signature in aged individuals, and that they are associated with important health indicators such as BMI. The purpose of this proposal is to fully explore this new paradigm by identifying VMRs associated with common age-related phenotypes across 3 domains (body composition; energy availability/demand; maintenance of body homeostasis) and determine the relationship between VMRs and underlying genetic variation. In addition to the traditional view that genotypes directly control expected (or mean) phenotype values, we argue that another major effect of genotype is to control stochastic epigenetic variation leading to increased variability of methylation at a particular genomic site and to a consequent increased phenotypic variation. This is a dramatically new concept. We postulate a new kind of SNP, which we call a vSNP, or variation-SNP, that is associated with the degree of methylation variability at VMRs, rather than mean methylation level, and thus also associates with the spread, or variability, of a phenotype in a population rather than the mean value. Such a vSNP would increase the proportion of individuals at both high and low risk of disease, and thus would not be detectible in traditional association analyses. To support our approach, we show preliminary data identifying vSNPs related to VMRs, vSNPs related to increased phenotypic variance, and VMRs related to phenotype. Our aims are: 1 - To investigate the relationship between DNA sequence, DNA methylation, and quantitative aging phenotypes under both our mean and plasticity models, using 2000 participants in the Baltimore Longitudinal Study of Aging (BLSA), and genome-wide SNP and methylation approaches. 2 - To perform focused DNA sequencing and capture bisulfite sequencing to identify the specific sequence and epigenetic variants responsible for findings in Aim 1. This work will help elucidate how genetic variation relates to methylation variation and how both impact age-associated phenotypes that increase disease susceptibility. DNA methylation could be a new target for risk assessment and intervention that can reduce the burden of disease and disability and slow down the deleterious effects of aging. PUBLIC HEALTH RELEVANCE: Narrative We plan to study the relationship between genes, epigenetic modifications of DNA, and age- related phenotypes that increase susceptibility to disease. We will focus on two hypotheses: (1) that genes control the mean values of DNA methylation and the mean values of phenotypes and (2) that genes control the variability, or spread, of DNA methylation and phenotypes in a population. If our hypothesis is correct that specific changes in DNA and DNA methylation are important for the age-associated increase in disease susceptibility, DNA methlyation could be a new target for risk assessment and intervention that can reduce the burden of disease and disability associated with aging.