Discovery of Pharmacogenomic Biomarkers for OATP1B1 and OATP1B3

OATP1B1和OATP1B3药物基因组生物标志物的发现 与众多关注人类疾病的全基因组关联研究形成鲜明对比的是， 关注药物基因组学特征的GWA一直很少，例如药物反应的变异和 毒性。此外，许多药物基因组GWA的动力不足，因此很少有基因 已经发现了具有全基因组意义的变异。世界上最广泛的 处方药，磺脲类药物的反应有很大的个体间差异，约35% 2型糖尿病患者5年后治疗失败，经常需要胰岛素治疗才能实现 可接受的血糖控制。在关注磺脲类药物反应的激动人心的初步GWA中，我们 发现磺脲类药物糖化血红蛋白水平(HbA1c)的变化与 SLCO1B1/1B3基因座在全基因组水平上编码转运蛋白OATP1B1和OATP1B3的SNP P=4.8×10-8，N=5,479。这一竞争续订申请的主要目标是 确定OATP1B1和OATP1B3与反应相关的药理学机制 发现和验证转运蛋白的选择性生物标志物，以及发现其他 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是一个大型多种族国际财团，在本授权期内成立 以及Suge-MGH，这是一个由健康志愿者组成的丰富且表型深刻的联盟，可以用来探索 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中使用全基因组方法来识别SLCO1B1/1B3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，我们将确定 SLCO1B1/1B3基因座与药物反应相关，采用多层次方法，从靶向开始 SLCO1B3/1b1基因座的重新测序及其在细胞中的详细功能基因组研究 从健康志愿者那里获得的样本中也有。最后，在目标3中，我们将发现和 验证可用作预测OATP1B3活性的工具的SLCO1B3代谢生物标志物，包括 OATP1B3介导的多种作为底物、抑制剂的处方药的药物相互作用 或传送器的诱导者。我们提出的方法包括全基因组关联和下一代 对大量患者进行高通量功能基因组和基因组测序研究和分析 细胞代谢组学研究与健康志愿者的临床药代动力学研究。我们假设 这种综合的基因组、代谢和功能方法，包括深入的临床表型 将作为对其他药物进行系统评估的蓝图，为精确治疗铺平道路。

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.