The implementation of a pharmacogenomics-based algorithm for warfarin dosing

描述（由申请人提供）：佩雷拉博士的长期职业目标是实施临床药物遗传学测试作为临床护理不可或缺的一部分。随着药物遗传学研究的爆炸式增长，将药物遗传学应用于临床护理的机会变得显而易见。长期以来，由于其治疗指标狭窄和严重的毒副作用，华法林一直是研究的目标。目前，已开发出使用CYP 2C 9和VKORC 1遗传变异的算法来预测高加索人和亚洲人的华法林维持剂量。然而，影响非裔美国人剂量的变化程度和指导剂量的算法尚未得到研究。为了实现这一目标，Perera博士将首先确定非裔美国人CYP 2C 9和VKORC 1的遗传单倍型结构。通过使用比较基因组学和识别推定功能区域的软件，重测序可以缩小到最有可能产生信息SNP的区域。接下来，单体型标记SNP沿着非遗传因素将用于开发该人群维持剂量的预测算法。佩雷拉博士，沿着与合作医生，将招募非洲裔美国抗凝患者和收集基因型数据和非遗传信息。回归分析将用于推导预测维持剂量的给药算法。将招募第二组患者以测试该算法的预测能力。患者将根据经验给药，这是标准治疗;但是，将确定预测和观察到的维持剂量之间的相关性。最后，她将通过在非洲裔美国骨科患者中进行的试点研究评估临床结果。这项研究将确定可行性的各个方面。将确定诸如至治疗性INR的时间和不良事件等结局，以帮助开发具有良好功效的临床试验。将进行额外的成本效益分析，以确定该算法在临床护理中的效用。拟议的研究是及时和必要的，以填补目前的知识空白，并影响真实的翻译药物遗传学到临床实践。这些研究有可能改变医学的实践方式。相关性（见说明）：华法林的准确剂量对临床医生和机构都至关重要。因此，开发一种预测非裔美国人（目前研究不足的人群）华法林剂量的算法，将大大改善许多医学领域的临床实践。这样的研究将有助于引导药物遗传学研究成果转化为临床实践。

DESCRIPTION (provided by applicant): Dr. Perera's long-term career goal is to implement clinical pharmacogenetic testing as an indispensable part of clinical care. With the explosion of pharmacogenetic research, the opportunity to advance the use of pharmacogenetics into clinical care has become apparent. Warfarin has been a long-standing target of research because of its narrow therapeutic index and serious side effect profile. Currently, algorithms using genetic variants in CYP2C9 and VKORC1 have been developed to predict maintenance dose of warfarin in Caucasians and Asians. However, the extent of variation that affects dose in African Americans and an algorithm to guide dosing have yet to be investigated. In pursuit of this goal, Dr. Perera will first determine the genetic haplotype structure of CYP2C9 and VKORC1 in African Americans. By using comparative genomics and software that identifies putative functional regions, resequencing can be narrowed to areas most likely to yield informative SNPs. Next, haplotype-tagging SNPs along with non-genetic factors will be used to develop a predictive algorithm for maintenance dose in this population. Dr. Perera, along with collaborating physicians, will recruit African American anticoagulation patients and collect genotype data and non-genetic information. Regression analysis will be used to derive a dosing algorithm to predict maintenance dose. A second cohort of patients will be recruited to test the predictive power of this algorithm. Patient will be dosed empirically, as is standard of care; however, the correlation between predicted and observed maintenance dose will be determined. Lastly, she will evaluate the clinical outcomes through a pilot study in African American orthopedic patients. This study will be conducted to determine aspects of feasibility. Outcomes such as time to therapeutic INR and adverse events will be determined to assist in the development of a well-power clinical trial. Additional cost-effective analysis will be conducted to determine the utility of this algorithm in clinical care. The proposed research is both timely and necessary to fill gaps in the current knowledge and to affect real translation of pharmacogenetics into clinical practice. Such studies have the potential to change the way medicine is practiced. RELEVANCE (See instructions): The accurate dosing of warfarin is critical to both clinicians and institutions. Therefore the development of an algorithm that would predict warfarin dose in African Americans, a currently under-studied population, would greatly improve clinical practice in numerous medical fields. Such research will help lead the way to the translation of pharmacogenetic findings into clinical practice.