Pharmacogenomic approaches to drug metabolism in American Indian/Alaska Native People

总结 药物遗传学测试有望通过以下方式提高药物安全性和有效性，同时改善临床结局： 为个人定制治疗方案。最大化这种方法的好处的关键是 调节药物吸收、分布、代谢的遗传变异的综合表征 和排泄、药物靶点相互作用和人群间的药理学反应。重大进展 对世界主要人群的药物基因组学图谱进行编目有助于临床应用 但在很大程度上排除了历史上被边缘化的人口和地理上孤立的小人口， 包括美国印第安人和阿拉斯加原住民（AIAN）。这些人口仍然是 由于各种原因，在基因组研究中代表性不足：缺乏社区参与，历史 不信任和地理偏远。西北阿拉斯加药物遗传学研究所（Northwest Alaska Pharmacogenetic） 研究网络（NWA-PGRN）-一个拥有多个机构和部落合作伙伴的中心-已经表明， AIAN人携带药物基因的变异，这些变异既新颖又常见， 已知的变体不同于其他民族或种族群体，并显示出较高的部落间变异性， 好.为了扩大这一研究，我们建议利用吸取的教训，并建立在研究的基础上， NWA-PGRN了解药物反应的个体间差异，并提供新的指标， 在AIAN社区实施个性化医疗的指导方针。我们的总体目标是 通过表征各种AIAN中药物基因组变异的知识差距 使用一个道德和社区参与的框架，重点是发展和深化 与AIAN社区的研究伙伴关系。我们还试图研究 使用计算机模拟预测和体内功能测定的新变体的基因型-表型。这项工作将 创建一个通用的基因组研究模型，使社区参与整个研究计划， 研究项目（从开始到完成及以后），并将作为改变 基因组学的研究框架。

Summary Pharmacogenetic testing is expected to enhance drug safety and efficacy while improving clinical outcomes by tailoring treatment regimens to the individual. Key to maximizing benefits of this approach will be comprehensive characterization of genetic variation that modulates drug absorption, distribution, metabolism and excretion, drug target interaction and pharmacological response across populations. Significant advances in cataloguing pharmacogenomic profiles from major populations of the world have aided clinical applications but have largely excluded historically marginalized populations and small, geographically isolated populations, including American Indian and Alaska Native (AIAN) people. These populations continue to be underrepresented in genomic research for a variety of reasons: lack of community engagement, historical mistrust, and geographical remoteness. Recent genetic studies by the Northwest Alaska Pharmacogenetic Research Network (NWA-PGRN)—a center with multiple institutional and tribal partners—have shown that AIAN people carry variants in pharmacogenes that are both novel and common, have allele frequencies of known variants that are different than other ethnic or racial groups, and display high inter-tribal variability as well. To broaden this research, we propose to leverage the lessons learned and build on research from the NWA-PGRN to understand inter-individual variation in drug responses and provide novel indicators and guidelines for implementing personalized medicine in AIAN communities. Our overall goal is to fill this knowledge gap through characterizing genomic variation of pharmacogenes in a wide range of AIAN populations using an ethical and community-engaged framework that focuses on developing and deepening research partnerships with AIAN communities. We also seek to investigate the relationships between genotype-phenotype of novel variants using in silico prediction and in vivo functional assays. This work will create a general model for genomic research that engages communities in the research plan throughout the research project (from start to completion and beyond) and will serve as a foundational way to shift the research framework in genomics.