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

摘要 药物遗传学测试有望通过以下方式提高药物的安全性和有效性，同时改善临床结果 为个人量身定做治疗方案。最大限度地发挥此方法的优势的关键是 调节药物吸收、分布、代谢的遗传变异的综合特征 以及跨人群的排泄、药物靶点相互作用和药理反应。重大进展 在编目世界主要人群的药物基因组图谱方面，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土著(AIAN)。这些人口继续是 在基因组研究中代表性不足的原因有多种：缺乏社区参与，历史 不信任和地理上的偏僻。美国西北阿拉斯加药物遗传学公司的最新遗传学研究 拥有多个机构和部落伙伴的研究网络(NWA-PGRN)表明， AIAN人携带新的和常见的药理基因变异，等位基因频率为 不同于其他民族或种族群体的已知变异，并表现出高度的部落间变异性，如 井。为了扩大这项研究的范围，我们建议利用吸取的经验教训，并在 NWA-PGRN以了解药物反应的个体间差异，并提供新的指标和 在AIAN社区实施个性化医疗的指导方针。我们的总体目标是填补这一空白 通过描述AIAN大范围内药物产生菌的基因组变异而产生的知识差距 使用注重发展和深化的道德和社区参与框架的人口 与AIAN社区的研究伙伴关系。我们还试图调查两者之间的关系 用于计算机预测和体内功能分析的新变异体的基因-表型。这项工作将 创建基因组研究的一般模型，使社区参与整个研究计划 研究项目(从开始到完成以及以后)，将成为转变 基因组学研究框架。

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.