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: 10162576
• 负责人: ARPANA AGRAWAL
• 金额: $ 94.04万
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10162576
• 关键词: ATP-Binding Cassette Transporters; Abstinence; African American; Age; Alfentanil; American; Animals; Area; Attention; Autopsy; Biological; Blood alcohol level measurement; Blood specimen; Brain Stem; Brain region; Breathing; Candidate Disease Gene; Cause of Death; Cell Nucleus; Centers for Disease Control and Prevention (U.S.); Cessation of life; Childhood; Clinic; Clinical; DNA; Data; Data Analyses; Databases; Dissociation; Double-Blind Method; Drug usage; Emergency Situation; Epidemic; Ethnic Origin; European; FOLH1 gene; Family; Female; Fentanyl; Foundations; Functional disorder; Gene Expression; General Population; Genes; Genetic; Genetic Polymorphism; Genetic Research; Genotype; Heritability; Heroin; Human; Illicit Drugs; Inbred Strains Mice; Individual; Ingestion; Investigation; Ischemic Brain Injury; Matched Group; Medical Examiners; Medical History; Morphine; Not Hispanic or Latino; Operative Surgical Procedures; Opiate Addiction; Opioid; Opioid Analgesics; Opioid Receptor; Opioid agonist; Outcome; Outcome Measure; Patients; Pediatric Surgical Procedures; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Pharmacotherapy; Play; Pontine structure; Potassium Channel; Prescription opioid overdose; Process; Public Health; Recording of previous events; Reporting; Research; Research Design; Risk; Role; Saline; Sampling; Site; Social Controls; Source; Testing; Tissue-Specific Gene Expression; Toxicology; Trauma; Twin Multiple Birth; United States; Variant; Ventilatory Depression; age group; analog; comorbidity; comparison group; demographics; differential expression; experience; genetic association; genetic variant; genome wide association study; heroin overdose; illicit opioid; improved; individual variation; insight; male; member; mortality; neighborhood disadvantage; novel; opioid epidemic; opioid mortality; opioid overdose; opioid use; opioid use disorder; opioid user; overdose death; paralogous gene; preBotzinger complex; precision medicine; raphe nuclei; respiratory; risk sharing; sex; trait; transcriptome sequencing; 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 separate matched groups who died from other causes: i) those with documented opioid use (N=50); and ii) decedents who 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均有所增加 25.24 岁以上群体导致这一流行病的相互关联趋势包括 超过 15 年的处方阿片类药物过量死亡案例以及最近的激增 非法阿片类药物（即海洛因和芬太尼相关药物）导致的过量死亡。服药过量死亡 2010 年至 2016 年，美国涉及海洛因的案件增加了近五倍，而涉及海洛因的案件增加了近五倍。 从 2015 年到 2016 年，芬太尼及其类似物增加了一倍多。24,26 研究改进 因此，了解阿片类药物引起的呼吸抑制的病理生理学是一项公共卫生事业 至关重要的。该领域先前的遗传学研究仅限于对候选基因进行基因分型的研究。 在主要由欧洲血统 (EA) 个体组成的规模非常小的样本中发现了少数 SNP。 我们提议对阿片类药物引起的呼吸抑制导致的死亡进行首次 GWAS。我们的大 EA 和非裔美国人 (AA) 子样本将分别超过之前最大研究的样本数 的数量级。我们将利用两个不同的比较组，即大型先前基因分型的 EA 和 AA 阿片类药物依赖个体和普通人群的样本分别非常适合 确定重复使用的影响以及与阿片类药物使用障碍共同承担的影响。我们的研究 设计侧重于明确的结果衡量标准，即阿片类药物引起的呼吸抑制导致的死亡， 预计将为我们的调查提供额外的动力。许多先前的研究都不太清楚地考察了 方便样本（例如儿科）中划分的结果（临床观察到的呼吸抑制） 手术患者）。这个修订后的提案非常有力地识别 EA 和 EA 中的常见遗传变异 AA 与阿片类药物引起的呼吸抑制有关。我们还建议开展 首次对人类阿片类药物过量后裔大脑基因表达变化进行检查 参与阿片类药物引起的呼吸抑制的区域，包括 preBötzinger 复合体， 臂旁核/Kölliker-Fuse 核 (PB/KF) 和中缝核。这项补充调查将提供 对这一过程背后的病理生理学有更多的了解，并能够检查 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 名意外阿片类药物过量死者中获取 DNA（N 的 EA ~10,000；AA ~5000）。 2) 进行 阿片类药物引起的呼吸抑制的 GWAS，包括阿片类药物共享的风险以及药物特异性效应， 将这些个体与先前 GWAS 基因分型的 AA 和 EA 个体的两个大群体进行比较：1) 患有阿片类药物使用障碍的人； 2) 在一般人群样本中确定的那些。 3）检查 髓质 preBötzinger 复合体和中缝核以及脑桥 PB/KF 中的差异基因表达 因意外阿片类药物过量死亡的患者 (N=50) 与单独的匹配组相比，其细胞核 死于其他原因： i) 有记录使用阿片类药物的人 (N=50)； ii) 具有阴性结果的死者 毒理学筛查 (N=50) 并将这些区域的差异表达与目标 2 的 GWAS 数据相关联， 为新的 GWAS 发现提供生物学基础。