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引起的行为。反过来，吸烟会导致一些不利的健康后果。使用其他组织制备物，我们和其他人已经表明，吸烟的一些不利影响可能是由改变的DNA甲基化介导的。然而，吸烟是否会诱导淋巴细胞中的差异DNA甲基化仍然存在很大争议，并且任何观察到的差异甲基化是否与功能相关完全未知。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甲基化的变化相关，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的、信息丰富的、种族多样的种群的生物资源。第一个人口，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）相互作用在常见行为疾病（包括重度抑郁症和尼古丁依赖）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），是一个大型的纵向研究的社会心理因素，如种族主义和贫困对抑郁症和健康行为的影响，在900个农村非洲裔美国人家庭。我们研究小组的过度假设是，物质使用与表观遗传变化有关，其中一些变化可能在调节物质使用的持续性和吸烟相关合并症的脆弱性方面都很重要。不幸的是，迄今为止，该领域的许多人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，以确定其甲基化在吸烟中改变的基因组区域，使用来自女性IAS和800 FACHS受试者的初级淋巴细胞DNA。由于我们的人群具有良好的行为和身体结果特征，我们拥有完整的生物材料和数据用于未来的研究，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。这种应用是创新的，因为吸烟对淋巴细胞DNA甲基化的影响是非常有争议的，并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CNS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，因为对这种关键细胞类型的这些研究可能导致针对吸烟和吸烟相关合并症的新干预策略。它是高度可行的，因为它建立在现有的人口和储存库。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。 公共卫生相关性：本申请的目的是确定吸烟是否与淋巴细胞DNA甲基化的变化相关。由于淋巴细胞是许多吸烟相关疾病的关键参与者，这可能会导致新的干预措施和治疗吸烟相关疾病，包括癌症，关节炎，肺和心血管疾病。

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.