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系统地注释医学上重要的功能方面，包括对药物的反应（药物基因组学）。到目前为止，还没有对华法林进行这样的尝试。华法林抑制维生素K循环，因此，作为一种“血液稀释”药物。它是最广泛使用的治疗药物之一，用于减轻由血栓造成的健康风险，如肺栓塞、心脏病发作和缺血性中风。然而，基因-药物相互作用威胁着华法林在人类中的安全有效应用。在这里，我们对大鼠基因组中与华法林相互作用的基因进行了注释，并推断出它们在人类中的同源基因。首先，Affymetrix微阵列被用来检测肝（肝组织）中华法林对基因表达的诱导或抑制。其次，生物信息学将用于识别大鼠基因组中可能与华法林相互作用的基因。第三，对一种德国大鼠的华法林抗性基因进行了研究。所有这三个调查都将由候选基因的遗传变异和关联研究来辅助。最后，结果将集中在最先进的生物信息学分析中，推断基因、途径、调控网络、蛋白质和调控序列基序与华法林相互作用，从而有可能将结果扩展到其他肝外组织。初步结果显示，在众多其他途径中，涉及硫转移酶的新途径与维生素K周期具有合理的生化联系，并且启动子多态性与华法林反应显着相关。此外，数据显示大鼠是人类状况的有效模型，因为从初步分析中出现了高度宣传的华法林相互作用基因Cyp2c9和Vkorc1。然而，新的性别特异性效应被观察到。该研究首次确定了在大鼠中与华法林相互作用的基因、途径和调控网络的补充，并推断出它们在人类中的对应物。结果可以帮助预测华法林的剂量、副作用和基因-药物相互作用。此外，虽然华法林的作用通常归因于血液凝固，但其他途径值得考虑。被认为与华法林剂量相关的基因，目前由约38个NIH提案资助，可能不足以充分描述华法林的作用。

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.