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

描述(申请人提供)：吸烟是一种行为，是遗传和环境过程的复杂发育相互作用的结果。吸烟反过来又会导致许多不利的健康后果。通过使用其他组织制剂，我们和其他人已经证明，吸烟的一些不利影响可能是通过改变DNA甲基化来调节的。然而，吸烟是否导致淋巴细胞差异DNA甲基化仍然存在很大争议，以及观察到的任何差异甲基化是否在功能上相关仍是完全未知的。在R21的应用中，我们建议明确地确定吸烟是否与淋巴细胞DNA甲基化的变化有关，并为我们和其他人未来的研究奠定基础。为了实现这一目标，我们将利用两个庞大、信息丰富、种族多样的人口的生物资源。第一个人群，爱荷华州收养研究(IAS)是美国最大的病例和对照收养研究。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生和维持中的重要性方面发挥了关键作用。第二个群体，家庭和社区健康研究(FACHS)，是一项大型纵向研究，旨在研究种族主义和贫困等社会心理因素对900个农村非裔美国家庭抑郁和健康行为的影响。我们研究小组的总体假设是，物质使用与表观遗传变化有关，其中一些变化可能在缓和物质使用的持续和吸烟相关并发症的易感性方面发挥重要作用。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，我们将测试吸烟与DNA甲基化变化相关的假设。为了做到这一点，我们将使用我们建立的方法，使用来自女性IAS和800名FACHS受试者的初级淋巴细胞DNA来识别在吸烟时其甲基化改变的基因组区域。由于我们的人群具有良好的行为和身体结果特征，我们拥有一整套用于未来研究的生物材料和数据，并嵌入了跨学科合作，我们已经做好了迅速利用任何积极发现的准备。这一应用具有创新性，因为吸烟对淋巴细胞DNA甲基化的影响是有很大争议的，而且还没有得到明确的证明。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替代品，成功地证明吸烟对DNA甲基化的影响将对医疗保健产生影响，因为这些对这一关键细胞类型的研究可能导致针对吸烟和吸烟相关并存的新的干预策略。它是高度可行的，因为它建立在现有的种群和存储库之上。最后，调查小组做好了充分的准备，其中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。 公共卫生相关性：这项应用的目的是确定吸烟是否与淋巴细胞DNA甲基化的变化有关。由于淋巴细胞是许多吸烟相关疾病的关键参与者，这可能会导致对吸烟相关疾病的新干预和治疗，包括癌症、关节炎、肺部和心血管疾病。

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.