Sex- and Smoking- Specific DNA Methylation Signatures of Central Adiposity Change

 描述(由申请人提供)：摘要候选人：这是一份NHLBI K99/R00拨款提案，旨在促进我作为北卡罗来纳大学博士后研究员的职业生涯，成为一名专注于肥胖症表观遗传学的遗传流行病学家。我是一名训练有素的人类学遗传学家，在遗传流行病学方面拥有丰富的经验，在创新和信息丰富的研究方面有着良好的记录。研究和职业目标：我的总体研究目标是整合我作为人类学家、人口遗传学家和流行病学家的技能，使用生物文化和公共卫生的视角来确定在整个生命过程中影响肥胖和下游心脏代谢疾病(CMD)的遗传、表观遗传和环境因素。与此相关，我的长期职业目标包括在一所研究型大学获得一个教员职位，在那里我将作为一名独立研究员和教育工作者继续研究影响CMD风险的遗传和环境因素。职业发展：我将发展：1)肥胖发病机制的专业知识，2)纵向数据分析的坚实基础，3)表观遗传学研究的理论和分析技能。我的培训和拟议的研究将由一群才华横溢的导师监督，其中包括我的主要导师Kari North，她是一位著名的遗传流行病学家，将提供整合遗传学和表观遗传学分析和方法的专业知识；我的共同导师，Penny Gordon-Larsen，营养学家和国际公认的肥胖症专家；李云，生物统计学家和遗传学家，擅长开发和应用遗传学和表观遗传学的分析方法；Annie Green Howard，专门从事纵向数据分析的生物统计学家；Ellen Dmerath，顾问，终身课程CMD流行病学家，具有甲基化研究经验；Eric Whitsel，合作者，CVD流行病学家和医生，具有药物基因组方面的经验。研究项目：拟议的项目旨在确定与中心性肥胖增加有关的甲基化变异(MeQTL)，其影响可能受到环境暴露(性别、肥胖药物、吸烟)的影响，参与社区动脉粥样硬化风险(ARIC)研究的非裔美国人。在K99阶段，我将使用单个时间点的甲基化数据，同时考虑环境暴露，对中心性肥胖进行表观基因组广泛关联分析(Ewas)。在R00阶段，我将使用访问五号存储的生物样本收集从头开始的甲基化数据，以实施纵向、多水平和混合模型，以检查年龄和时间对中心性肥胖的不同表观遗传效应，并检查中心性肥胖变化、甲基化和环境暴露之间的因果关系。像这里提出的项目，使我们能够识别影响中心性肥胖的表观遗传变异，并对全面了解肥胖的发病机制至关重要。这项研究的结果和持续的保护训练时间将最终推出 我在肥胖表观遗传学领域的职业生涯。

 DESCRIPTION (provided by applicant): ABSTRACT Candidate: This is a NHLBI K99/R00 grant proposal, intended to promote my career as a post-doctoral fellow at the University of North Carolina, into independence as a genetic epidemiologist with a focus in obesity epigenetics. I am a trained anthropological geneticist with extensive experience in genetic epidemiology and a strong track record of innovative and informative research. Research and Career Goals: My over-arching research goal is to integrate my skills as an anthropologist, population geneticist, and epidemiologist, using the bio-cultural and public health perspectives to identify genetic, epigenetic and environmental factors that influence obesity and downstream cardiometabolic disease (CMD) across the lifecourse. Related to this, my long-term career goals include securing a faculty position at a research university where I will continue my research on the genetic and environmental factors that influence risk of CMD as an independent researcher and educator. Career Development: I will develop: 1) expertise in the pathogenesis of obesity, 2) a strong foundation in longitudinal data analysis, and 3) the theoretical and analytical skills specific for epigenetics research. My training and proposed research will be overseen by a talented group of mentors, including my primary mentor, Kari North, a renowned genetic epidemiologist that will provide expertise in integrating genetics and epigenetic analysis and methods; and my co-mentors, Penny Gordon-Larsen, a nutritionist and internationally recognized obesity expert; Yun Li, a biostatistician and geneticist with expertise in the development and application of analytical methods for genetics and epigenetics; Annie Green Howard, a biostatistician that specializes in longitudinal data analysis; Ellen Demerath, consultant, a lifecourse CMD epidemiologist with experience in methylation research; and Eric Whitsel, collaborator, a CVD epidemiologist and physician with experience in pharmacogenomics. Research Project: The proposed project aims to identify methylation variants (meQTLs) associated with increased central adiposity and for which the effects may be influenced by environmental exposures (sex, obesogenic medications, smoking) in the African American participants of the Atherosclerosis Risk in Communities (ARIC) study. In the K99 phase, I will conduct an epigenome wide association analysis (EWAS) with central adiposity using methylation data from a single time point and while accounting for environmental exposures. During the R00 phase, I will collect de novo methylation data using stored biospecimens from visit five to implement longitudinal, multilevel, and mixed models to examine differential epigenetic effects on central adiposity by age and time, and to examine the causal relationships between central adiposity change, methylation, and environmental exposures. Projects, like that proposed herein, allow us to identify epigenetic variation that influences central adiposity, and are critical to gain a comprehensive understanding of the pathogenesis of obesity. The results of this study and the continued protected training time will ultimately launch my career in lifecourse obesity epigenetics.