Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
Clin Pharmacol Ther. 2011 Apr;89(4):571-8. doi: 10.1038/clpt.2010.353. Epub 2011 Mar 2.
Little is known about how genetic variations in enhancers influence drug response. In this study, we investigated whether nucleotide variations in enhancers that regulate drug transporters can alter their expression levels. Using comparative genomics and liver-specific transcription factor binding site (TFBS) analyses, we identified evolutionary conserved regions (ECRs) surrounding nine liver membrane transporters that interact with commonly used pharmaceuticals. The top 50 ECRs were screened for enhancer activity in vivo, of which five--located around ABCB11, SLC10A1, SLCO1B1, SLCO1A2, and SLC47A1--exhibited significant enhancer activity. Common variants identified in a large ethnically diverse cohort (n = 272) were assayed for differential enhancer activity, and three variants were found to have significant effects on reporter activity as compared with the reference allele. In addition, one variant was associated with reduced SLCO1A2 mRNA expression levels in human liver tissues, and another was associated with increased methotrexate (MTX) clearance in patients. This work provides a general model for the rapid characterization of liver enhancers and identifies associations between enhancer variants and drug response.
关于增强子中的遗传变异如何影响药物反应，目前知之甚少。在这项研究中，我们研究了调节药物转运体的增强子中的核苷酸变异是否可以改变它们的表达水平。通过比较基因组学和肝脏特异性转录因子结合位点（TFBS）分析，我们确定了与常用药物相互作用的九个肝脏膜转运体周围的进化保守区域（ECR）。对体内的 50 个 ECR 进行了增强子活性筛选，其中 5 个——位于 ABCB11、SLC10A1、SLCO1B1、SLCO1A2 和 SLC47A1 周围——表现出显著的增强子活性。在一个大型种族多样化队列（n=272）中鉴定出的常见变体进行了差异增强子活性检测，发现三个变体与报告基因活性与参考等位基因相比具有显著影响。此外，一个变体与人类肝组织中 SLCO1A2 mRNA 表达水平降低有关，另一个变体与患者中甲氨蝶呤（MTX）清除率增加有关。这项工作为快速表征肝脏增强子提供了一个通用模型，并确定了增强子变体与药物反应之间的关联。
