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

基本信息

批准号：
9901498
负责人：
ARPANA AGRAWAL
金额：
$ 91.8万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
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/9901498
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

项目摘要

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.

疾病预防控制中心已经记录了美国阿片类药物过量的“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增加 25.24岁以上的小组相互关联的趋势有助于流行病处方阿片类药物过量死亡人数超过15年，最近发生的潮流非法阿片类药物（即海洛因和芬太尼相关药物）导致的过量死亡。过量的死亡从2010年到2016年，涉及海洛因的海洛因在美国上升了近五倍芬太尼及其类似物从2015年到2016.24,26增加了一倍以上，以改善因此，了解阿片类药物诱导的呼吸道抑郁的病理生理学是公共卫生至关重要的。该领域的先前遗传研究仅限于候选基因研究，这些研究是基因型的少数SNP的尺寸非常适中的样本中，主要由欧洲血统（EA）个体组成。我们建议由于阿片类药物诱导的呼吸抑郁症引起的第一个GWA死亡。我们的大 EA和非裔美国人（AA）子样本将超过一个井的最大先前研究数量级。我们将利用两个不同的比较组：大型以前的EA和AA 分别非常适合的阿片类药物依赖人和普通人群的样本确定反复使用的效果以及与阿片类药物使用障碍责任共享的效果。我们的研究设计着重于确定的结果度量，阿片类药物诱导的呼吸抑郁症引起的死亡，这预计将为我们的投资提供额外的权力。许多先前的研究都没有清楚地检查方便样本中的划分结局（临床观察到的呼吸抑郁症）（例如儿科手术患者）。这项修订的提案非常有能力确定EA和EA中的常见遗传变异 AAS与阿片类药物诱导的呼吸抑郁症的责任相关。我们还建议进行在人阿片类药物过量的死者中进行基因表达变化的首次检查参与阿片类药物诱导的呼吸道抑郁症的区域，包括Prebötzinger络合物， Parabrachial/Köllliker-Fuse核心（PB/KF）和Raphe Nucus。这项完整的调查将提供对这一过程的基础病理生理学的进一步见解，并能够检查改变与GWA中实现的常见变体相关的基因表达。具体目的是：1）从15,000个意外阿片类药物过量的决定中获得DNA（n's EA约10,000； AA〜5000）。 2）进行阿片类药物诱导的呼吸道抑郁症的GWA，包括各种阿片类药物和药物特异性作用的风险，将这些个体与AA和EA个体的两个大型以前的GWAS生成的组进行比较：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人。 3）检查髓质prebötzinger复合物和raphe核中的差异基因表达，以及pontine pb/kf 与单独的匹配组相比死于其他原因：i）患有阿片类药物使用的记录（n = 50）； ii）决定谁负面毒理学筛查（n = 50），并将这些区域的差异表达与AIM 2的GWAS数据相关联，为新颖的GWAS发现提供了生物基础。