Discovery of Pharmacogenomic Biomarkers for OATP1B1 and OATP1B3

OATP1B1 和 OATP1B3 药物基因组生物标志物的发现

• 批准号: 10686822
• 负责人: JOSE CARLOS FLOREZ
• 金额: $ 57.9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-25 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10686822
• 关键词: Biological Markers; Blood; Candidate Disease Gene; Cells; Cellular Assay; Clinical; Clinical Research; Diabetes Mellitus; Disease; Dose; Drug Interactions; Drug Kinetics; Drug Prescriptions; Drug usage; Ethnic Origin; Ethnic Population; European; Evaluation; Genes; Genetic; Genetic Polymorphism; Genomic approach; Genomics; Glycosylated Hemoglobin; Glycosylated hemoglobin A; Goals; Grant; Hemoglobin concentration result; In Vitro; Insulin; International; Laboratories; Liver; Mediating; Methodology; Methods; Non-Insulin-Dependent Diabetes Mellitus; Organic Anion Transporters; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Pharmacotherapy; Phenotype; Physiological; Play; Population; Precision therapeutics; Reporting; Research; Resources; Risk; Role; Sample Size; Sampling; Sulfonylurea Compounds; Targeted Resequencing; Toxic effect; Variant; absorption; biomarker selection; causal variant; clinical phenotype; cohort; drug disposition; endophenotype; functional genomics; genetic variant; genome wide association study; genome-wide; glycemic control; healthy volunteer; human disease; improved; in vitro Assay; in vivo; inhibitor; inter-individual variation; metabolomics; multi-ethnic; next generation sequencing; pharmacokinetics and pharmacodynamics; pharmacologic; precision medicine; rare variant; response; tool; trait; validation studies

Discovery of Pharmacogenomic Biomarkers for OATP1B1 and OATP1B3 In marked contrast to the plethora of genome-wide association studies (GWAS) focused on human disease, there has been a dearth of GWAS focused on pharmacogenomic traits such as variation in drug response and toxicity. Further, many of the pharmacogenomic GWAS have been underpowered and therefore few genetic variants at genomewide levels of significance have been discovered. Among the world's most widely prescribed drugs, sulfonylureas are associated with great inter-individual variation in response, with ~35% of patients with type 2 diabetes failing therapy after 5 years and frequently needing insulin therapy to achieve acceptable glycemic control. In exciting preliminary GWAS focused on response to sulfonylureas, we discovered a strong association between change in glycated hemoglobin levels (HbA1c) on sulfonylureas and a SNP in the SLCO1B1/1B3 locus encoding the transporters OATP1B1 and OATP1B3 at genome-wide levels of significance (p=4.8×10-8, N = 5,479). The major goals of this competing renewal application are to determine the pharmacologic mechanisms by which OATP1B1 and OATP1B3 associate with response to sulfonylureas, discover and validate selective biomarkers for the transporters and discover other genes that associate with response to sulfonylureas. To achieve our goals, we will use two large clinical resources: MetGen PLUS, a large multi-ethnic international consortium, established during this granting period and SUGAR-MGH, a rich deeply phenotyped consortium of healthy volunteers, which can be used to probe clinical pharmacokinetic and pharmacodynamic mechanisms. Three specific aims are proposed. In aim 1, we will employ a genome-wide approach in MetGen PLUS to identify common genetic variants in SLCO1B1/1B3 and other genes that impact response to sulfonylureas. In aim 2, we will identify the causal variants in the SLCO1B1/1B3 locus associated with drug response, using a multi-tiered approach, beginning with targeted resequencing of the SLCO1B3/1B1 locus and extending through detailed functional genomic studies in cells and in samples obtained from healthy volunteers in SUGAR-MGH. Finally, in aim 3, we will discover and validate metabolomic biomarkers of SLCO1B3 that can be used as tools to predict OATP1B3 activity including OATP1B3-mediated drug-drug interactions for a wide range of prescription drugs that are substrates, inhibitors or inducers of the transporter. Our proposed methods range from genomewide association and NextGen sequencing studies and analyses in large cohorts of patients to high throughput functional genomic and metabolomic studies in cellular assays to clinical pharmacokinetic studies in healthy volunteers. We postulate that this comprehensive genomic, metabolomic and functional approach including deep clinical phenotyping will serve as a blueprint for systematic evaluations of other drugs, paving the way for precision therapeutics.

OATP 1B 1和OATP 1B 3的药物基因组学生物标志物的发现 与大量关注人类疾病的全基因组关联研究（GWAS）形成鲜明对比， 缺乏关注药物基因组学特征的GWAS，如药物反应的变化， 毒性此外，许多药物基因组学GWAS动力不足，因此很少有遗传学研究。 已经发现了在全基因组水平上具有显著性的变体。世界上最广泛的 在处方药中，磺脲类药物与个体间反应差异很大相关，约35%的 2型糖尿病患者5年后治疗失败，经常需要胰岛素治疗， 血糖控制良好。在令人兴奋的初步GWAS集中在对磺脲类药物的反应，我们 发现磺脲类药物的糖化血红蛋白水平（HbA 1c）变化与 在全基因组水平编码转运蛋白OATP 1B 1和OATP 1B 3的SLCO 1B 1/1B 3基因座中的SNP 显著性（p=4.8×10-8，N = 5，479）。这种竞争性续期申请的主要目标是 确定OATP 1B 1和OATP 1B 3与应答相关的药理学机制 磺脲类药物，发现和验证转运蛋白的选择性生物标志物，并发现其他 与磺脲类药物反应相关的基因。为了实现我们的目标，我们将使用两个大型临床 资源：MetGen PLUS，一个大型的多种族国际财团，在此授权期间成立 和SUGAR-MGH，一个由健康志愿者组成的丰富的深度表型联盟，可用于探测 临床药代动力学和药效学机制。提出了三个具体目标。在目标1中，我们 将在MetGen PLUS中采用全基因组方法来识别SLCO 1B 1/1B 3中的常见遗传变异 以及其他影响对磺脲类药物反应的基因。在目标2中，我们将识别 SLCO 1B 1/1B 3基因座与药物反应相关，使用多层次方法，从靶向 SLCO 1B 3/1B 1基因座的重测序，并通过细胞中详细的功能基因组研究进行扩展 和从SUGAR-MGH中的健康志愿者获得的样品中。最后，在目标3中，我们将发现和 验证可用作预测OATP 1B 3活性的工具的SLCO 1B 3代谢组学生物标志物，包括 OATP 1B 3介导的多种处方药的药物间相互作用，这些处方药是底物、抑制剂 或转运蛋白的诱导物。我们提出的方法包括全基因组关联和NextGen 在大量患者中进行高通量功能性基因组和 从细胞分析中的代谢组学研究到健康志愿者中的临床药代动力学研究。我们推测 这种全面的基因组学、代谢组学和功能方法，包括深度临床表型分析， 将作为其他药物系统评估的蓝图，为精确治疗铺平道路。