Genes Contributing to Opioid Abuse in Humans

导致人类阿片类药物滥用的基因

• 批准号: 7193006
• 负责人: Kari Stefansson
• 金额: $ 47.05万
• 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/7193006
• 关键词: clinical research; genes; genome; genotype; human; pain

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）：阿片类药物代表了可用于大多数形式疼痛的最有效的治疗方法之一。然而，诸如中毒和身体依赖性等负面健康后果是一个日益严重的问题，并可能导致阿片类药物滥用和成瘾。阿片类药物在疼痛情况下的患病率以及如何预防、减少和治疗这些负面健康后果尚不清楚。此外，疼痛患者对鸦片滥用和成瘾的恐惧导致慢性疼痛患者用药不足。发现可能标记对阿片类药物成瘾风险增加的疼痛患者的 DNA 标记，可以通过对易受影响的人更谨慎地使用阿片类药物以及对真正需要阿片类药物的人更积极地使用阿片类药物来显着改善临床实践。我们建议识别在最初用于控制疼痛时给予阿片类药物成瘾的显着风险的基因变异。我们将使用超高通量 SNP 标记基因分型平台直接在全基因组范围内搜索易感性变异。在第一阶段，我们建议使用具有 317,000 个标记的 Tag-SNP 阵列对 800 名阿片类药物成瘾者进行基因分型，并在全基因组范围内搜索与阿片类药物成瘾的关联。与此同时，我们将在至少有 2 名阿片类药物成瘾患者的大家庭中开展关联研究。将选择至少表现出名义意义的前 1% SNP（3000 个 SNP）进行后续基因分型。连锁峰下标记标准的严格性将低于连锁峰外标记的标准严格性，这样所选的 SNP 中最多一半将在连锁峰内，其余则在连锁峰外。在第二阶段，这些选定的 SNP 将在来自美国、欧洲和澳大利亚的鸦片成瘾队列收集的其他白人样本上进行基因分型，该队列收集已由 NIDA 资助，总共至少有 800 个病例和 800 个对照。将对两个队列中这 3000 个 SNP 的基因型进行联合分析，寻找与阿片类药物成瘾的关联。将对 317,000 项测试的 P 值进行校正，校正后满足全基因组显着性的 SNP 将用于对冰岛前瞻性队列中接受处方阿片类药物治疗疼痛的个体中的成瘾患者与非成瘾患者进行基因分型，以确认其在定义风险方面的效用的成瘾。阿片成瘾基因的分离有助于研究它们对使用处方阿片类药物后成瘾风险的贡献，因为阿片成瘾基因的危险或保护性变体的存在可用于预测成瘾的风险处方阿片类药物。该项目中鉴定的基因可能会揭示与成瘾有关的生化途径，并可能为诊断和药物治疗的开发提供新的靶点。