The Effects of Smoking on DNA Methylation in Primary Human Lymphocytes.

描述（由申请人提供）：吸烟是一种由遗传和环境过程复杂的发育相互作用导致的行为。吸烟反过来又会造成一些不利的健康后果。使用其他组织制剂，我们和其他人已经表明，吸烟的一些不良影响可能是由DNA甲基化改变介导的。然而，吸烟是否会诱导淋巴细胞的差异DNA甲基化仍然存在很大争议，是否观察到任何差异甲基化与功能相关也完全未知。在这项R21申请中，我们建议明确确定吸烟是否与淋巴细胞DNA甲基化的变化有关，并为我们和其他人的未来研究奠定基础。为了实现这一目标，我们将利用两个庞大、信息丰富、种族多样的种群的生物资源。第一个人口，爱荷华收养研究（IAS）是美国最大的案例和对照收养研究。IAS在证明遗传(G)，环境(E)因素和基因-环境（GxE）相互作用在包括重度抑郁症和尼古丁依赖在内的常见行为疾病的发展和维持中的重要性方面发挥了关键作用。第二个人口，家庭和社区健康研究（FACHS），是一项大型纵向研究，研究了900个农村非洲裔美国家庭中种族主义和贫困等社会心理因素对抑郁和健康行为的影响。我们研究小组的首要假设是，物质使用与表观遗传变化有关，其中一些变化可能在减缓物质使用的持续和吸烟相关合并症的脆弱性方面都很重要。不幸的是，到目前为止，该领域的许多人都不相信吸烟或任何其他形式的物质使用会导致外周淋巴细胞甲基化的改变。为了为表观遗传因素在吸烟中的作用的综合研究奠定基础，我们将检验吸烟与DNA甲基化变化有关的假设。为此，我们将使用已有的方法，利用女性IAS和800名FACHS受试者的原代淋巴细胞DNA，鉴定吸烟中甲基化发生改变的基因组区域。由于我们的人群在行为和身体结果方面具有良好的特征，我们为未来的研究提供了完整的生物材料和数据，并且嵌入了跨学科合作，我们已经做好了充分的准备，可以迅速利用任何积极的发现。这一应用具有创新性，因为吸烟对淋巴细胞DNA甲基化的影响是极具争议的，尚未得到明确证明。由于淋巴细胞是吸烟相关自身免疫性疾病的关键参与者，并且可能是中枢神经系统表观遗传过程的有效代理，因此成功证明吸烟对DNA甲基化的影响将对医疗保健产生影响，因为这些关键细胞类型的研究可能会导致吸烟和吸烟相关合共病的新介入策略。它是高度可行的，因为它建立在现有种群和存储库的基础上。最后，调查小组准备充分，包括一名在甲基化研究方面具有丰富经验的分子生物学家/精神病学家和一名训练有素的生物信息学家。

DESCRIPTION (provided by applicant): Smoking is a behavior that results from a complex developmental interplay of genetic and environmental processes. Smoking, in turn, causes a number of adverse health outcomes. Using other tissue preparations, we and others have shown that some of these adverse effects of smoking may be mediated by altered DNA methylation. However, whether smoking induces differential DNA methylation in lymphocytes is still highly controversial and whether any observed differential methylation is functionally relevant is completely unknown. In this R21 application, we propose to unequivocally determine whether smoking is associated with changes in lymphocyte DNA methylation and set the stage for future investigations by ourselves and others. To accomplish this goal, we will use the bioresources of two large, informative, ethnically diverse populations. The first population, the Iowa Adoption Studies (IAS) is the largest case and control adoption study in the United States. The IAS has been pivotal in the demonstration of the importance of genetic (G), environmental (E) factors and gene-environment (GxE) interactions in the development and maintenance of common behavioral illnesses including major depression and nicotine dependence. The second population, the Family and Community Health Studies (FACHS), is a large longitudinal study of the impact of sociopsychological factors such as racism and poverty on depression and health behaviors in 900 rural African-American families. The over-arching hypotheses of our research group are that substance use is associated with epigenetic changes and that some of these changes may be important in both moderating the continuation of substance use and the vulnerability to smoking related comorbidities. Unfortunately, to date, many in the field do not believe that smoking, or any other form of substance use, leads to alterations in peripheral lymphocyte methylation. To set the groundwork for integrated studies of the role of epigenetic factors in smoking, we will test the hypothesis that smoking is associated with changes in DNA methylation. To do this, we will use our established approaches to identify genomic regions whose methylation is altered in smoking using primary lymphocyte DNA from female IAS and 800 FACHS subjects. Because our populations are well characterized for behavioral and physical outcomes, we have complete sets of biomaterials and data for future studies and are embedded transdisciplinary collaboration, we are well poised to rapidly exploit any positive findings. This application is innovative because the effect of smoking on lymphocyte DNA methylation is highly controversial and has not been unequivocally demonstrated. Since lymphocytes are key players in smoking associated autoimmune illnesses and may be effective proxies for CNS epigenetic processes, the successful demonstration of effects of smoking on DNA methylation will have an impact on health care because these investigations of this critical cell type may lead to new interventional strategies for smoking and smoking related comorbidities. It is highly feasible because it builds off existing populations and repositories. Finally, the investigative team is well prepared and includes a molecular biologist/psychiatrist with extensive experience in methylation studies and a well-trained bioinformatician. PUBLIC HEALTH RELEVANCE: The purpose of this application is to determine whether cigarette smoking is associated with changes in lymphocyte DNA methylation. Because lymphocytes our key players in many smoking associated illnesses, this may lead to new interventions and treatments for smoking-related illnesses including cancer, arthritis, lung and cardiovascular disease.