Bleeding on Direct Oral Anticoagulants: Identification of Genetic Risk Factors and a Polygenic Predictive Score in Patients with Atrial Fibrillation

项目总结/摘要 心房颤动（AF）是最常见的心律失常，也是缺血性卒中的主要原因。 抗凝剂可将房颤患者的卒中风险降低约三分之二，但其主要安全性问题 长期口服治疗有致命或危及生命的出血风险。沃克尔曾经是领先的口头 在AF患者中，它是一种抗凝剂，但正在被直接口服抗凝剂（DOAC）取代。虽然AF 使用DOAC的患者出血量比使用华法林的患者少，但出血仍然是一个主要问题，比例从~2%到~ 40%不等。 诱发出血的临床因素是众所周知的，但它们不能完全解释出血风险。最好的 临床预测模型仍然无法解释DOAC中32%的出血事件。不像华法林， 通过国际标准化比值（INR）进行监测，没有常规使用的临床监测指标， DOACs。因此，迫切需要更好地了解DOAC出血的风险因素。以来 药物反应是高度遗传的，这项研究的中心假设是，遗传学可以帮助解释 接受DOAC治疗的AF患者的出血风险。因此，这项研究的总体目标是识别遗传变异 与DOAC的出血风险相关。先前的候选基因研究将遗传变异与 DOAC的血浆浓度变化，可能增加AF患者的出血风险。但 只有少数候选基因研究以非常小的样本量（通常 n <400）和不确定的结果。因此，目标1的目标是通过执行 出血结局的大型临床和基因组数据集的候选基因关联分析（n= 2，470 AF 密歇根基因组学倡议[MGI]中的DOAC患者）。先前研究的另一个局限性是， 依赖于候选基因的方法，这可能会错过未知的基因。全基因组关联研究 （GWAS）可以发现与DOAC出血风险相关的新变异，并能够推导出 预测这种风险的第一个多基因评分，这是目标2的目标。这两种方法将 以弥补每种方法的局限性。总体方法是分析现有的 临床和基因组数据集（MGI），整合了全基因组阵列数据（质量控制和插补后） 并完全访问电子病历（EMR）。主要结局是主要和 临床相关非大出血（CRNM）。次要结局是主要的和临床相关的非- 大出血这项研究是可行的，利用现有的数据集，所有赞助商的专业知识， 密歇根大学的资源，并建立了方法。此外，这项研究是高度相关的，因为 它通过确定遗传变异与出血的关联， DOAC的风险，这可能导致精准医疗方法。此外，我将学习批判性研究 在药物基因组学的技能，这将使我准备成为我自己的实验室的首席研究员（PI）在 美国

PROJECT SUMMARY/ABSTRACT Atrial fibrillation (AF) is the most common cardiac arrhythmia and the leading cause of ischemic stroke. Anticoagulants reduce the risk of stroke in AF patients by about two-thirds, but the main safety concern of this long-term oral therapy is the risk of fatal or life-threatening bleeding. Warfarin was once the leading oral anticoagulant in patients with AF, but it is being replaced by Direct Oral Anticoagulants (DOACs). Although AF patients bleed less with DOACs than warfarin, bleeding is still a major problem varying from ~2% to ~40%. Clinical factors predisposing to bleeding are well-known, but they do not fully explain bleeding risk. The best clinical prediction model still does not explain 32% of bleeding events on DOACs. Unlike warfarin, which is monitored by international normalized ratio (INR), there is no routinely used measure for clinical monitoring of DOACs. Therefore, there is a critical need to better understand the risk factors for bleeding from DOACs. Since drug responses are highly heritable, the central hypothesis of this research is that genetics can help explain bleeding risk in AF patients on DOACs. Therefore, the overall goal of this research is to identify genetic variants associated with bleeding risk from DOACs. Previous candidate gene studies associated genetic variants with changes in plasma concentration of DOACs, which may increase bleeding risk in AF patients. However, there are only a few candidate gene studies assessing bleeding as an outcome with very small sample sizes (typically n <400) and inconclusive results. Therefore, the objective of Aim 1 is to overcome those limitations by performing candidate gene association analysis of a large clinical & genomic dataset with bleeding outcomes (n=2,470 AF patients on DOACs in the Michigan Genomics Initiative [MGI]). Another limitation of the previous studies was the reliance on the candidate gene approach, which can miss unsuspected genes. A genome-wide association study (GWAS) could discover novel variants associated with the risk of bleeding from DOACs and enable the derivation of the first polygenic score for predicting this risk, which are the objective of Aim 2. Both approaches will be carried out to compensate for the limitations of each method. The overall approach is to analyze an existing clinical & genomic dataset (MGI), which integrates whole genome array data (post quality control & imputation) and complete access to electronic medical records (EMR). The primary outcome is a composite of major and clinically relevant non-major (CRNM) bleeding. The secondary outcomes are major and clinically relevant non- major bleeding. This research is feasible by leveraging an existing dataset, the expertise of all sponsors, resources at the University of Michigan, and established methods. Also, this research is highly relevant because it addresses an important clinical knowledge gap by determining the association of genetic variants with bleeding risk from DOACs, which could lead to Precision Medicine approaches. Moreover, I will learn critical research skills in pharmacogenomics that will prepare me to become the Principal Investigator (PI) of my own lab in the U.S.