Identifying Genetic Variants Associated with Opioid Overdose Mortality

识别与阿片类药物过量死亡率相关的遗传变异

• 批准号: 10597418
• 负责人: ARPANA AGRAWAL
• 金额: $ 15.75万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10597418
• 关键词: African American; African American population; Age; Area; Biological; Black Populations; Brain region; Candidate Disease Gene; Cell Nucleus; Centers for Disease Control and Prevention (U.S.); Cessation of life; Childhood; Clinical; DNA; Data; Epidemic; European; Female; Fentanyl; Foundations; Functional disorder; Gene Expression; General Population; Genes; Genetic; Genetic Research; Genotype; Heroin; Human; Individual; Investigation; Matched Group; Not Hispanic or Latino; Operative Surgical Procedures; Opiate Addiction; Opioid; Outcome; Outcome Measure; Patients; Pharmaceutical Preparations; Pontine structure; Prescription opioid overdose; Process; Public Health; Reporting; Research; Research Design; Risk; Sampling; Tissue-Specific Gene Expression; Toxicology; United States; Variant; Ventilatory Depression; age group; analog; comparison group; differential expression; experience; genetic variant; genome wide association study; heroin overdose; illicit opioid; improved; insight; male; member; mortality; novel; opioid mortality; opioid overdose; opioid use disorder; overdose death; preBotzinger complex; raphe nuclei; risk sharing; trend

The CDC has documented the worsening “opioid overdose epidemic” in the U.S. Opioid overdose deaths have increased among males and females, non-Hispanic whites and blacks, and all age groups over age 25.24 Interrelated trends contributing to the epidemic include an increase in prescription opioid overdose deaths spanning more than 15 years and more recent surges in overdose deaths due to illicit opioids (i.e., heroin and fentanyl-related drugs). Overdose deaths involving heroin rose nearly five-fold in the U.S. from 2010 to 2016 while those involving fentanyl and its analogues more than doubled from 2015 to 2016.24,26 Research to improve understanding of the pathophysiology of opioid-induced respiratory depression is thus a public health imperative. Prior genetic research in this area has been limited to candidate gene studies that genotyped a handful of SNPs in samples of very modest size that consisted primarily of European ancestry (EA) individuals. We are proposing to conduct the first GWAS of death due to opioid-induced respiratory depression. Our large EA and African American (AA) sub-samples will each exceed that of the largest prior study by well over an order of magnitude. We will utilize two distinct comparison groups, large previously-genotyped EA and AA samples of opioid dependent individuals and general population members that are well-suited, respectively, to identify effects contingent upon repeated use and those shared with liability of opioid use disorder. Our study design focuses on a definitive outcome measure, death due to opioid-induced respiratory depression, which is expected to provide additional power for our investigation. Many prior studies have examined less clearly demarcated outcomes (clinically observed respiratory depression) in convenience samples (e.g. pediatric surgical patients). This revised proposal is very well-powered to identify common genetic variants in EAs and AAs associated with liability for opioid-induced respiratory depression. We are also proposing to conduct the first examination performed in human opioid overdose decedents of gene expression changes in brain regions involved in opioid-induced respiratory depression including the preBötzinger complex, parabrachial/Kölliker-Fuse nuclei (PB/KF), and raphe nucleus. This complementary investigation will provide additional insight into the pathophysiology underlying this process and enable examination of alterations in gene expression associated with common variants implicated in the GWAS. The specific aims are: 1) To obtain DNA from 15,000 accidental opioid overdose decedents (N’s EA ~10,000; AA ~5000). 2) To conduct a GWAS of opioid-induced respiratory depression including risk shared across opioids, and drug-specific effects, comparing these individuals to two large previously GWAS-genotyped groups of AA and EA individuals: 1) those with opioid use disorder; and 2) those ascertained in general population samples. 3) To examine differential gene expression in the medullary preBötzinger complex and raphe nucleus, and pontine PB/KF nuclei in those who died from accidental opioid overdose (N=50) compared with a matched group of decedents who died from other causes and had negative toxicology screens (N=50) and to relate differential expression in these regions to GWAS data for Aim 2, providing a biological foundation for novel GWAS discoveries.

疾病预防控制中心已经记录了美国日益恶化的“阿片类药物过量流行病”。 男性和女性、非西班牙裔白人和黑人以及所有年龄段的死亡人数都有所增加 25.24造成这一流行病的相互关联的趋势包括： 处方阿片类药物过量死亡超过15年，最近激增， 由于非法阿片类药物导致的过量死亡（即，海洛因和芬太尼相关药物）。过量死亡 从2010年到2016年，美国涉及海洛因的人数增加了近五倍， 芬太尼及其类似物从2015年到2016年增加了一倍多。 因此，了解阿片类药物引起的呼吸抑制的病理生理学是一个公共卫生问题。 势在必行在这一领域的先前遗传学研究仅限于候选基因研究， 少数SNP在非常适度的大小的样品，主要包括欧洲血统（EA）的个人。 我们建议进行第一次因阿片类药物引起的呼吸抑制而死亡的GWAS。我们的大型 EA和非裔美国人（AA）子样本将分别超过先前最大研究的样本量， 数量级。我们将利用两个不同的对照组，大型先前基因型EA和AA 阿片类药物依赖个体和一般人群成员的样本，分别非常适合于 确定重复使用的影响和阿片类药物使用障碍的责任。我们的研究 设计重点是一个明确的结果衡量，死亡由于阿片类药物诱导的呼吸抑制， 有望为我们的调查提供额外的力量许多先前的研究都没有清楚地检查 方便样本（例如，儿科）中的分界结果（临床观察到的呼吸抑制） 手术患者）。这项修订后的建议是非常有力的，以确定共同的遗传变异的EA和 与阿片类药物诱导的呼吸抑制易感性相关的AA此外，我们亦建议举办 在人类阿片类药物过量死亡者中进行的第一次检查大脑中基因表达的变化 参与阿片类药物诱导的呼吸抑制的区域，包括前Bötzinger复合体， 臂旁核/Köliker-Keller-Keller-Kellernucleus（PB/KF）和中缝核。这项补充调查将提供 对这一过程的病理生理学的进一步了解，并使检查的变化， 与GWAS中涉及的常见变异相关的基因表达。具体目标是：（1） 从15，000例意外阿片类药物过量死亡者中获得DNA（N的EA约为10，000; AA约为5000）。2)进行 阿片类药物诱导的呼吸抑制的GWAS，包括阿片类药物之间的风险共享和药物特异性效应， 将这些个体与两个大的先前GWAS基因分型的AA和EA个体组进行比较：1） 阿片类药物使用障碍; 2）在一般人群样本中确定的。3)审查 延髓前Bötzinger复合体和中缝核以及脑桥PB/KF中的差异基因表达 与匹配的死亡组相比，死于意外阿片类药物过量的患者（N=50）的细胞核 因其他原因死亡且毒理学筛查结果为阴性的患者（N=50）， 这些地区的目标2 GWAS数据，提供了新的GWAS发现的生物学基础。