权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Epigenetic and Expression Analysis of PCOS

PCOS的表观遗传学和表达分析

基本信息

批准号：
8366639
负责人：
Andrea E Dunaif
金额：
$ 31.25万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-27 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8366639
关键词：
Affect Age Alleles Amenorrhea Androgenization Androgens Animal Model Animals Asses Biological Assay Callithrix Candidate Disease Gene Complex Computer Simulation DNA DNA Methylation DNA Sequence Diabetes Mellitus Disease Environment Environmental Risk Factor Epigenetic Process Event Fatty acid glycerol esters First Degree Relative Gene Expression Genes Genetic Genetic Predisposition to Disease Genetic Variation Genomics Genotype Gonadal Steroid Hormones Health Health Care Costs Heritability Human Instruction Insulin Resistance Laboratories Liver Maps Measures Menstruation Metabolic Methylation Modeling Muscle Non-Insulin-Dependent Diabetes Mellitus Obesity Oligomenorrhea Pathway interactions Pattern Phenocopy Phenotype Polycystic Ovary Syndrome Predisposition RNA Splicing Reproductive Health Resistance Risk Role Sampling Signal Transduction Site Syndrome Testing Testosterone Tissues Variant Visceral Woman case control epigenetic variation follow-up genetic variant genome-wide improved in utero innovation insight mRNA Expression male novel prenatal reproductive subcutaneous trait

项目摘要

Polycystic Ovary Syndrome (PCOS) is a complex phenotype that is defined by elevated testosterone levels and amenorrhea/oligomenorrhea. It occurs in ~7% of reproductive age women and is also strongly associated with obesity, insulin resistance, and an increased risk of developing Type 2 Diabetes (T2D). While PCOS has a strong familial component and has been shown to be highly heritable (h2=0.8), traditional genetic studies conducted by our laboratory and others have identified only a limited number of reproducible PCOS susceptibility genetic loci. It is clear from current genetic studies of PCOS and other complex genetic phenotypes that common genetic variation does not explain the bulk of the observed heritability. One possible explanation for this observed deficit is that the observed heritability in complex phenotypes is due to epigenetic rather than genomic variation. Epigenetic changes are heritable changes in gene expression or cellular phenotype that occur in the absence of changes to the DNA sequence. Variation in DNA methylation patterns is one major form of epigenetic variation and can be captured on a genomic level using methylation specific DNA arrays that test >450,000 DNA methylation sites. We hypothesize that: 1) a significant component of the heritability of PCOS is due to epigenetic changes including variation in niethylation pattern, 2) these changes in methylation patterns correlate with changes in expression patterns, and 3) these changes in methylation are due to either specific changes in the DNA or environmental factors including the in utero environment. We propose to test these hypotheses by assessing the differential DNA methylation status in target tissues (muscle, visceral fat, subcutaneous fat, and liver) of obese women with and without PCOS, the impact of differential methylation on gene expression, and whether the differential methylation status is due to genomic or epigenetic event. PCOS is common syndrome which severely impacts the health of affected women and their first degree relatives and contributes greater than $4 billion annually to our health care costs. The proposed studies will increase our understanding to the underlying pathways that are affected in PCOS and with the potential of improved treatment for this pervasive syndrome. RELEVANCE (See instructions); PCOS is a common disorder defined by elvated male sex hormones and irregular menses and is strongly associated with obesity and diabetes. Current genetic approaches have failed to identify the bulk of the hertitable factors contributing to PCOS susceptibility. We propose to asses the role of epigenetic variation, heritable changes in gene expression that occur in the absence of DNA changes, in the cause of PCOS

多囊卵巢综合征（PCOS）是一种复杂的表型，其特征是睾酮水平升高和闭经/月经过少。它发生在约7%的育龄妇女中，与肥胖、胰岛素抵抗和发展2型糖尿病（T2D）的风险增加相关。虽然PCOS具有很强的家族性，并且已被证明具有高度遗传性（h2 = 0.8），但传统的我们的实验室和其他人进行的遗传研究只确定了有限数量的可重复的 PCOS易感基因位点。从目前对PCOS和其他复杂遗传因素的遗传研究中可以清楚地看出，表型表明，常见的遗传变异不能解释观察到的遗传力的大部分。一对这种观察到的缺陷的可能解释是，在复杂表型中观察到的遗传力是由于表观遗传而不是基因组变异。表观遗传变化是基因表达的可遗传变化，在DNA序列没有变化的情况下发生的细胞表型。DNA甲基化的变异模式是表观遗传变异的一种主要形式，可以使用甲基化在基因组水平上捕获特异性DNA阵列可检测超过45万个DNA甲基化位点。我们假设：1）一个重要的 PCOS遗传力的组成部分是由于表观遗传变化，包括甲基化模式的变化， 2)这些甲基化模式的变化与表达模式的变化相关，3）这些甲基化模式的变化与表达模式的变化相关。甲基化的变化是由于DNA中的特定变化或环境因素，在子宫环境中。我们建议通过评估差异DNA甲基化来验证这些假设，肥胖妇女靶组织（肌肉、内脏脂肪、皮下脂肪和肝脏）的状态，多囊卵巢综合征，差异甲基化对基因表达的影响，以及差异甲基化是否状态是由于基因组或表观遗传事件。多囊卵巢综合征是一种常见的综合征，受影响的妇女及其一级亲属的健康，每年贡献超过40亿美元，我们的医疗费用。拟议的研究将增加我们对潜在途径的理解，受PCOS影响，并有可能改善这种普遍综合征的治疗。相关性（参见说明）; 多囊卵巢综合征是一种常见的男性性激素升高和月经不规则的疾病，与肥胖和糖尿病有关。目前的遗传学方法未能确定大部分的导致PCOS易感性的遗传因素。我们建议评估表观遗传变异的作用，在没有DNA变化的情况下发生的基因表达的遗传性变化，导致PCOS