Genes Contributing to Opioid Abuse in Humans

导致人类阿片类药物滥用的基因

• 批准号: 7292823
• 负责人: Kari Stefansson
• 金额: $ 46.51万
• 依托单位: DECODE GENETICS, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-29 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7292823
• 关键词: Australia; Biochemical Pathway; Caucasians; Caucasoid Race; Clinical; Collection; DNA Markers; Data Analyses; Development; Diagnostic; Disease; Europe; Extended Family; Family; Fright; Funding; Gene Frequency; Genes; Genetic; Genome; Genotype; Goals; Health; Human; Iceland; Individual; Intoxication; Joints; Location; Maps; Microsatellite Repeats; National Institute of Drug Abuse; Opiate Addiction; Opiates; Opioid; Pain; Pain management; Patients; Penetrance; Pharmaceutical Preparations; Pharmacotherapy; Phase; Physical Dependence; Population; Predisposition; Prevalence; Relative Risks; Research Personnel; Resource Sharing; Risk; SNP genotyping; Sampling; Severities; Staging; Testing; Time; Ultrafine; Variant; Withdrawal Symptom; addiction; chronic pain; cohort; cost; design; dosage; follow-up; genetic variant; genome wide association study; genome-wide linkage; improved; novel; opioid abuse; prescription document; prescription procedure; prevent; programs; prospective

DESCRIPTION (provided by applicant): Opioids represent one of the most powerful treatments available for most forms of pain. However, negative health consequences, such as intoxication and physical dependence are a growing problem, and may result in opioid abuse and addiction. The prevalence, and how to prevent, reduce, and treat these negative health consequences of opioid administration in the context of pain are not well understood. Furthermore, the fear of opiate abuse and addiction by patients with pain has led to under- medication of patients with chronic pain. Discovery of DNA markers that may flag pain patients who are at increased risk for addiction to opioids may substantially improve clinical practice by more careful use of opiates in those who are susceptible and more aggressive use of opiates in those who really need them. We propose to identify genetic variants that confer significant risk for addiction to opiates when initially prescribed for pain control. We will use ultra-high throughput SNP marker genotyping platforms in a direct genome-wide search for susceptibility variants. In Phase I we propose to genotype 800 individuals addicted to opiates using Tag-SNP arrays with 317,000 markers and search genome-wide for association to opiate addiction. In parallel, we will carry out a linkage study within extended families that have at least 2 patients addicted to opiates. The top 1% SNPs (3000 SNPs) that show at least nominal significance will be selected for follow-up genotyping. The stringency of criteria for markers under linkage peaks will be less than that for markers outside of linkage peak such that up to half of the SNPs selected will be within linkage peaks and the remaining outside. In phase II these selected SNPs will be genotyped on other Caucasian samples of opiate addiction from the US, Europe and Australia cohort collections already funded by NIDA which total at least 800 cases and 800 controls. A joint analysis of genotypes of these 3000 SNPs in both cohorts will be performed, looking for association to opiate addiction. P-values will be corrected for 317,000 tests and SNPs that meet genome-wide significance after correction will be used to genotype addicted versus non- addicted patients in a prospective Icelandic cohort of individuals treated by prescription opioids for pain to confirm their utility in defining risk of addiction. The isolation of opiate addiction genes facilitates the study of their contribution to the risk of developing addiction following the use of prescription opioids, as the presence of at-risk or protective variants of opiate addiction genes might be used to predict the risk of becoming addicted to prescription opiates. Genes identified in this project may uncover biochemical pathways involved in addiction and possibly provide novel targets for the development of diagnostics and drug therapies.

描述（由申请人提供）：阿片类药物代表了大多数疼痛的最有力治疗方法之一。但是，负面的健康后果（例如中毒和身体依赖性）是一个日益严重的问题，可能导致阿片类药物滥用和成瘾。在疼痛的背景下，患病率以及如何预防，减少和治疗阿片类药物给药的这些负面健康后果。此外，对疼痛患者的鸦片虐待和成瘾的恐惧导致慢性疼痛患者的药物不足。发现可能会增加对阿片类药物成瘾风险增加的疼痛患者的DNA标记可能会通过更仔细地使用阿片类药物来大大改善临床实践，从而在那些真正需要它们的人中对阿片类药片的使用且更具侵略性的使用。我们建议确定遗传变异型，这些变异最初是为了控制疼痛时，会给阿片类药物带来巨大的成瘾风险。我们将在全基因组全基因组搜索易感变体的直接搜索中使用超高的吞吐量SNP标记基因分型平台。在第一阶段，我们建议使用带有317,000个标记的TAG-SNP阵列对阿片类药物的基因型，并在全基因组中进行搜索以使鸦片成瘾的关联。同时，我们将在大家庭内进行至少有2名沉迷于阿片类药物的患者的大家庭中的连锁研究。将选择至少标称意义的最高1％SNP（3000个SNP）进行后续基因分型。连锁峰下标记的标准的严格度将小于链接峰之外的标记，因此，所选的SNP的最多一半将在链接峰和剩余的外部。在第二阶段中，这些选定的SNP将基于来自NIDA资助的美国，欧洲和澳大利亚队列的其他鸦片成瘾样本的基因分型，NIDA总共至少800例和800例对照。将对这两个队列中这3000个SNP的基因型进行联合分析，以寻求鸦片成瘾的关联。在校正后符合全基因组显着性的317,000次测试和SNP的P值将用于基因型上瘾的基因型与非上瘾的患者，而非上瘾的患者则在前瞻性的冰岛群体中，由处方药治疗的个体治疗的个体疼痛，以确认其在定义成瘾风险方面的效用。鸦片成瘾基因的隔离有助于研究其在使用处方阿片类药物后对成瘾风险的贡献，因为存在鸦片成瘾基因的高危或保护性变体的存在可能会用于预测对处方药的上瘾的风险。该项目中鉴定出的基因可能会发现成瘾中涉及的生化途径，并可能为诊断和药物疗法的发展提供新的目标。