Gene-environment interactions in COCCaINE Use Disorder: Collaborative Case-Control Initiative in Coccaine Addiction

摘要 我们建议对可卡因使用障碍进行基于人群的遗传流行病学研究。 (CUD)在巴西里奥格兰德地区确定环境应激源的作用，包括创伤 暴露和HIV感染对慢性阻塞性肺疾病患者表观遗传特征和基因-环境相互作用的影响 丘德。使用1000名CUD受试者和1000名对照的已有DNA，我们将检查基因组- 广泛的关联和基因环境交互作用(目标1)，创伤应激之间的关系 和DNA甲基化(目标2)，以及作为生物应激源的艾滋病毒感染对DNA的相加效应 甲基化(目标3)。所有的分子评估都将与行为和生理相关 所有个人都可以进行的评估，以确定CUD的潜在风险标记。这些 研究将检验以下假设：1)参与压力调节的基因将与 患有CUD和CUD严重程度2)暴露于生活压力和逆境(即创伤)中的遗传易感性 个体是罹患慢性阻塞性肺疾病的危险因素，3)艾滋病病毒感染将是一个附加因素。 对CUD受试者应激调节相关基因表观遗传修饰的影响。 该应用程序的PI具有已建立的合作和研究能力历史 大楼。年发起了吸毒成瘾病例控制协作倡议(COCCaINE) 2014年是Grassi-Oliveira博士和Walss-Bass博士进行需求评估讨论的结果。这 该项目构成了目前申请福格蒂国际中心的基础。作为这项工作的一部分 应用我们将通过实施培训来加强研究能力和基础设施(目标4) 分子流行病学、生物信息学和物质使用障碍管理课程 巴西里奥格兰德地区的调查人员遭受了创伤。在第一年，我们将组织为期一周的 休斯敦UTHealth的专家讲授理论和实践研讨会。在第二个阶段， 获奖第三年、第四年和第五年，我们建议为巴西人创建迷你奖学金计划 调查人员将前往美国接受培训。这些培训活动将对 在巴西进行研究能力建设和开发合格的人力资源，并取得成功 落实研究目标。 拟议的研究将有助于更好地理解DNA甲基化的变化，如 受基因构成的调节，与环境侮辱相结合，影响CUD 严重程度，并可作为开发更有针对性和针对性的治疗方法的生物标志物 慢性和全球性的公共卫生问题。

ABSTRACT We propose to perform a population-based genetic epidemiological study of cocaine use disorder (CUD) in the region of Rio Grande Brazil to characterize the role of environmental stressors, both trauma exposure and HIV infection, on epigenetic signatures and gene-environment interactions in patients with CUD. Using already available DNA from 1000 CUD subjects and 1000 controls we will examine genome- wide associations and gene environment interactions (Aim 1), the relationship between traumatic stress and DNA methylation (Aim 2), and the additive effect of HIV infection as a biological stressor on DNA methylation (Aim 3). All molecular assessments will be correlated with behavioral and physiologic evaluations which are available from all individuals, to identify potential risk markers for CUD. These studies will examine the following hypotheses: 1) Genes involved in stress regulation will be associated with CUD, and CUD severity 2) Exposure to life stress and adversity (i.e., trauma) in genetically susceptible individuals represents a risk factor for development of CUD, and 3) HIV infection will have an additive effect on epigenetic modifications in genes related to stress regulation in subjects with CUD. The PI’s of this application have an established collaboration and history of research capacity building. The COllaborative Case-Control INitiativE in crack addiction (COCCaINE) project was initiated in 2014 as the result of needs assessment discussions between Drs. Grassi-Oliveira and Walss-Bass. This project forms the basis for the current application to the Fogarty International Center. As part of this application we will enhance research capacity and infrastructure (Aim 4) by implementing training programs in molecular epidemiology, bioinformatics, and management of substance use disorders and trauma for investigators in the area of Rio Grande Brazil. During the first year we will organize week-long theoretical and practical workshops taught by experts from UTHealth in Houston. During the second, third, fourth, and fifth years of the award we propose to create mini-fellowship programs for Brazilian investigators to travel to the United States for training. These training activities will be of great value for the research capacity building and development of qualified human resources in Brazil, and for successful implementation of the research goals. The proposed studies will lead to a better understanding of how changes in DNA methylation, as modulated by genetic make-up and in combination with exposure to environmental insults, impacts CUD severity and may serve as a biomarker for development of more tailored and targeted treatments for this chronic and global public health problem.