Effect of Genetic, Individual & Neighborhood Factors on Telomere Length

描述(由申请者提供)：这是一名正在攻读流行病学学位论文阶段的博士生申请的培训补助金。这位候选人立志成为衰老研究领域的领先独立科学家。在她的博士学位期间，她将100%的时间投入到这项研究中。她在论文阶段的实践训练，加上精心挑选的课程，旨在使她成为使用先进的统计学方法来定义个人和邻居因素、基因变异和端粒长度之间的联系的专家。这种双重训练方法将为她未来的研究做好准备，研究与衰老相关的分子标记，以及邻里环境和遗传学在健康差距和老龄化中所起的作用。在整个奖项过程中，她将得到行为、地理空间分析、老龄化结果、遗传学、分子标记和生物统计学方面的资深专家的指导。以端粒长度衡量的细胞衰老过程可能是通过多种因素在生命周期内的复杂相互作用而发生的。这里提出的研究的目标是使用替代生物标记物端粒长度更好地解释细胞衰老的复杂的、多因素的性质。我们将采用多水平统计方法，包括在现有的多种族老年男性纵向队列中，识别影响端粒长度的个人水平(目标1)和邻域水平因素(目标2)，以及端粒遗传变异和端粒长度之间的关系(目标3)。据报道，端粒长度与遗传变异、个人危险行为(吸烟、体重指数)和社会人口变量(个人的种族、性别、社会地位)之间存在关联。然而，社区层面的因素(社会孤立、结构衰退、暴力等)代表着老龄化研究的一个重要考虑因素，因为它们与年龄相关的疾病有关，尤其与老年人有关，他们可能长期生活在不利的社区。这是第一次研究多种因素对端粒长度的共同影响。使用线性回归和反向回归，申请人将基线端粒长度(由T/S比率定义)建模为连续变量，具有单独的水平测量，并选择单独输入的邻域因素作为自变量，使用p值0.20作为纳入的阈值。分析将按种族进行重复分层。在评估邻域变量对端粒长度的影响时，将考虑聚类和多重共线性。为了测试遗传单倍型在邻域环境中的影响，我们将使用多变量分析来模拟目标1和2中确定的端粒长度和协变量向量。如果基因或个体风险因素在某些邻域环境中更深刻地影响端粒长度，那么这种性质的研究是至关重要的。这项研究将建立一个概念模型的基础，该模型可以用作未来老龄化研究的基础。

DESCRIPTION (provided by applicant): This training grant is being sought by a PhD student entering the dissertation phase of her degree in Epidemiology. The candidate aspires to become a leading independent scientist in the field of aging research. She will devote 100% of her time to this research for the duration of her PhD. Her hands-on training during her dissertation phase, coupled with carefully selected courses, are designed to make her expert in the use of advanced statistical methods to define associations between individual and neighborhood factors, genetic variants, and telomere length. This dual training approach will prepare her for future studies investigating molecular markers associated with aging and the role neighborhood environment and genetics play in health disparities and aging. Throughout this award, she will be mentored by senior experts in behavior, geospatial analyses, aging outcomes, genetics, molecular markers and biostatistics. The process of cellular aging, as measured by telomere length, likely occurs through the complex interactions of multiple factors over the lifespan. The goal of the research proposed here is to better explain the complex, multifactorial nature of cellular aging using a surrogate biomarker, telomere length. We will undertake a multilevel statistical approach that includes identifying individual-level (Aim 1) and neighborhood- level factors (Aim 2) that affect telomere length and the relationship between telomere genetic variants and telomere length (Aim 3), in an existing multi-ethnic longitudinal cohort of older men. Associations have been reported between telomere length and genetic variants, individual risk behaviors (smoking, body mass index) and sociodemographic variables (an individual's race, sex, social status). However, neighborhood level factors (social isolation, structural decline, violence, etc) represent an important consideration for aging studies since they have been associated with age-related disease and are particularly relevant for older adults, who may live in unfavorable neighborhoods for long time periods. This is the first study to account for the collective effects of multiple factors on telomere length. Using linear regression and backward regression, the applicant will model baseline telomere length (defined by T/S ratio) as a continuous variable, with individual level measures, and select neighborhood factors entered separately as independent variables, using a p-value of 0.20 as the threshold for inclusion. Analyses will be repeated stratifying by race. Clustering and multicollinearity will be considered when assessing the effect of neighborhood variables on telomere length. In order to test the effects of genetic haplotypes in the neighborhood context, we will use multivariable analysis to model telomere length and a vector of covariates identified in Aims 1 and 2. Studies of this nature are critical if genes or individual risk factors affect telomere length more profoundly in certain neighborhood settings. This study will build the foundations of a conceptual model that can be used as the basis for future studies on aging.