Warfarin Pharmacogenomics in the rat (Rattus norvegicus)

大鼠（褐家鼠）的华法林药物基因组学

• 批准号: 7904087
• 负责人: Hans Michael Kohn
• 金额: $ 22.63万
• 依托单位: RICE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7904087
• 关键词: Address; Adverse effects; Affect; Animals; Anticoagulants; Arts; Binding; Biochemical; Biochemical Pathway; Bioinformatics; Biological Models; Biological Process; Blood Clot; Blood coagulation; Candidate Disease Gene; Complement; Computer Simulation; Data; Dose; Drug Interactions; Extrahepatic; Foundations; Funding; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genome; Genome Scan; Genomics; German population; Health; Hepatic Tissue; Human; Human Genome; Investments; Ischemic Stroke; Link; Linkage Disequilibrium; Liver; Mediating; Medical; Minor; Modeling; Myocardial Infarction; Orthologous Gene; Pathway interactions; Pharmaceutical Preparations; Pharmacogenomics; Population Genetics; Proteins; Pulmonary Embolism; Rat Strains; Rattus; Rattus norvegicus; Regulatory Pathway; Resistance; Risk; Role; Surveys; System; Therapeutic Uses; Tissues; United States National Institutes of Health; Vitamin K; Warfarin; Work; Xenobiotics; base; gene induction; genetic association; genetic regulatory protein; genome sequencing; novel; promoter; rat genome; response; sex; sulfotransferase; vitamin K epoxide reductase

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.

描述（由申请人提供）：大鼠基因组序列已经发布，以进一步提高这种广泛使用的实验室动物的价值。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）。迄今为止，尚未尝试用于华法林。Warcantine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，以减轻由血凝块引起的健康风险，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体中的安全有效应用。在这里，我们注释了大鼠基因组中与华法林相互作用的基因，并推断其人类直系同源物。首先，使用Affyridine微阵列检测肝脏（肝组织）中响应华法林的基因表达的诱导或抑制。第二，生物信息学将被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，研究德国品系大鼠华法林抗性的遗传学。所有这三项调查都将得到遗传变异和候选基因关联研究的帮助。最后，结果将在最先进的生物信息学分析中收敛，该分析推断基因、途径、调控网络以及蛋白质和调控序列基序与华法林在计算机上相互作用，从而可能将结果扩展到其他肝外组织。初步结果显示，在众多其他人中，一种新的途径，涉及磺基转移酶，有合理的生化连接到维生素K循环和启动子多态性显着相关的华法林反应。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Cyp 2c 9和Vkorc 1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。该研究首次确定了与大鼠华法林相互作用的基因，途径和调控网络的互补性，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，目前由大约38个NIH提案资助，可能不足以完全描述华法林的作用。