Warfarin Pharmacogenomics in the rat (Rattus norvegicus)

描述(由申请人提供)：大鼠基因组序列已经公布，以进一步提高这种广泛使用的实验动物的价值。它的基因组现在可以根据医学上重要的功能方面进行系统的注释，包括对药物的反应(药物基因组学)。到目前为止，还没有人尝试使用华法林。华法林抑制维生素K循环，因此起到了“血液稀释剂”的作用。它是使用最广泛的治疗药物之一，用于缓解肺血栓、心脏病发作和缺血性中风等血栓带来的健康风险。然而，基因与药物的相互作用威胁着华法林在人体内的安全有效应用。在这里，我们根据与华法林相互作用的基因来注释大鼠基因组，并推断它们的人类同源基因。首先，利用Affymetrix微阵列检测华法林对肝脏(肝组织)基因表达的诱导或抑制。其次，生物信息学将被用来识别大鼠基因组中可能与华法林相互作用的基因。第三，研究了一种德国品系大鼠对华法林抗药性的遗传学。所有这三项调查都将得到候选基因的遗传变异和关联研究的帮助。最后，结果将汇聚在最先进的生物信息学分析中，该分析推断基因、通路、调控网络以及蛋白质和调控序列基序与华法林在计算机中相互作用，从而潜在地将结果扩展到其他肝外组织。初步结果显示，在众多途径中，一种涉及磺基转移酶的新途径与维生素K循环具有可信的生化联系，其启动子多态性与华法林反应显著相关。此外，数据表明，大鼠是人类状况的有效模型，因为高度公开的华法林相互作用基因CYP2C9和VKORC1是从初步分析中出现的。然而，观察到了新的性别特异性效应。这项研究首次确定了与华法林相互作用的基因、途径和调控网络的互补，并推断了它们在人类中的对应关系。结果可能有助于预测华法林剂量、副作用和基因-药物相互作用。此外，虽然华法林的作用通常被归因于血液凝结，但其他途径值得考虑。被认为与华法林剂量有关的基因，目前由NIH提出的38项建议资助，可能不足以完全描述华法林的作用。

DESCRIPTION (provided by applicant): The rat genome sequence has been released to further the value of this widely used lab animal. Its genome can now be annotated systematically with respect to medically important functional aspects, including response to drugs (pharmacogenomics). To date, this has not been attempted for warfarin. Warfarin inhibits the vitamin K cycle and, thus, acts as a 'blood thinning' drug. It is one if the most widely used therapeutic drugs to alleviate health risks posed by blood clots, such as pulmonary embolisms, heart attacks and ischemic strokes. However, gene-drug interactions threaten the safe and effective application of warfarin in humans. Here, we annotate the rat genome with respect to genes that interact with warfarin and infer their human orthologs. First, Affymetrix microarrays are employed to detect induction or suppression of gene expression in response to warfarin in the liver (hepatic tissue). Second, bioinformatics will be used to identify genes in the rat genome that might interact with warfarin in silico. Third, the genetics of warfarin resistance in a German strain of rats is examined. All these three surveys will be assisted by genetic variation and association studies of candidate genes. Finally, results shall converge in a state-of-the-art bioinformatics analysis that infers genes, pathways, regulatory networks, and protein and regulatory sequence motifs interacting with warfarin in silico, thereby potentially extending results to other, extrahepatic tissues. Preliminary results reveal, among numerous others, a novel pathway involving a sulfotransferase that has plausible biochemical connections to the vitamin K cycle and for which a promoter polymorphism is significantly associated with warfarin response. Moreover, data show that the rat is a valid model for the human condition because the highly publicized warfarin-interacting genes Cyp2c9 and Vkorc1 emerged from preliminary analyses. However, novel sex-specific effects were observed. The study is first to identify the complement of genes, pathways, and regulatory networks that interact with warfarin in rat and infers their human counterparts. Results could assist predicting warfarin doses, side effects, and gene-drug interactions. Moreover, while the effects of warfarin usually are attributed to blood clotting, other pathways deserve consideration. The genes considered as relevant to warfarin dosing, currently funded by ~38 NIH proposals, likely are insufficient to describe warfarin action fully.