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

直接口服抗凝剂导致的出血：房颤患者遗传风险因素的鉴定和多基因预测评分

• 批准号: 10536789
• 负责人: Alessandra Menezes Campos-Staffico
• 金额: $ 7.86万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10536789
• 关键词: Academic Medical Centers; Address; Adverse reactions; Affect; American; Anticoagulants; Arrhythmia; Atrial Fibrillation; Candidate Disease Gene; Cardiac; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Clinical; Computerized Medical Record; Data; Data Set; Derivation procedure; Drug Kinetics; Emergency department visit; Event; Faculty; Fellowship; Funding; Gene Expression; Genes; Genetic; Genomics; Goals; Guidelines; Hemorrhage; Heritability; Individual; International Normalized Ratio; Intracranial Hemorrhages; Ischemic Stroke; Kidney; Knowledge; Lead; Learning; Life; Link; Measures; Medicine; Methods; Michigan; Mission; Modeling; Monitor; Oral; Outcome; Patients; Pharmaceutical Preparations; Pharmacogenetics; Pharmacogenomics; Pharmacology; Plasma; Positioning Attribute; Postdoctoral Fellow; Predisposing Factor; Principal Investigator; Property; Quality Control; Research; Resources; Risk; Risk Factors; Role; Safety; Sample Size; Secure; Stroke prevention; Technology; Testing; Training; United States National Institutes of Health; Universities; Variant; Warfarin; base; career; clinically relevant; cohort; disability; experience; genetic approach; genetic association; genetic risk factor; genetic variant; genome wide association study; genome-wide; genomic data; hazard; improved; large datasets; novel; precision medicine; predictive modeling; primary outcome; response; secondary outcome; skills; stroke risk; stroke therapy; whole genome

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.

项目概要/摘要 心房颤动（AF）是最常见的心律失常，也是缺血性中风的主要原因。 抗凝剂可将 AF 患者中风的风险降低约三分之二，但主要的安全问题 长期口服治疗有致命或危及生命的出血风险。华法林曾经是主要的口服药物 AF 患者的抗凝剂，但它正在被直接口服抗凝剂 (DOAC) 所取代。虽然自动对焦 使用 DOAC 的患者出血量少于华法林，但出血仍然是一个主要问题，范围从约 2% 到约 40%。 导致出血的临床因素是众所周知的，但它们并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 上 32% 的出血事件。与华法林不同的是， 通过国际标准化比值（INR）进行监测，目前尚无常规的临床监测方法 DOAC。因此，迫切需要更好地了解 DOAC 出血的危险因素。自从 药物反应具有高度遗传性，这项研究的中心假设是遗传学可以帮助解释 服用 DOAC 的 AF 患者的出血风险。因此，本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 血浆浓度的变化可能会增加 AF 患者的出血风险。然而，有 只有少数候选基因研究以非常小的样本量评估出血的结果（通常 n <400）和不确定的结果。因此，目标 1 的目标是通过执行来克服这些限制 大型临床和基因组数据集与出血结果的候选基因关联分析（n=2,470 AF 密歇根基因组计划 [MGI] 中使用 DOAC 的患者）。先前研究的另一个局限性是 依赖候选基因方法，这可能会错过未被怀疑的基因。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 用于预测这种风险的第一个多基因评分，这是目标 2 的目标。两种方法都将是 是为了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)，集成了全基因组阵列数据（后期质量控制和插补） 并完全访问电子病历 (EMR)。主要结果是主要结果和 临床相关的非大出血（CRNM）。次要结局是主要的且与临床相关的非 大出血。这项研究通过利用现有数据集、所有赞助商的专业知识是可行的， 密歇根大学的资源和既定方法。此外，这项研究具有高度相关性，因为 它通过确定遗传变异与出血的关联来弥补重要的临床知识空白 DOAC 带来的风险，这可能会导致精准医学方法的出现。此外，我将学习批判性研究 药物基因组学方面的技能将使我做好准备成为我自己实验室的首席研究员 (PI) 我们。

项目成果

The role of SGLT2i in attenuating residual cardiovascular risk through blood pressure-lowering: mechanistic insights and perspectives.

SGLT2i 通过降低血压降低残余心血管风险的作用：机制见解和观点。

• 发表时间: 2023
• 作者: Barreto, Joaquim;Campos;Nadruz, Wilson;Quinaglia, Thiago;Sposito, Andrei C
• 通讯作者: Sposito, Andrei C

Risk scores for major bleeding from direct oral anticoagulants: comparing predictive performance in patients with atrial fibrillation.

直接口服抗凝剂导致大出血的风险评分：比较房颤患者的预测性能。

• 发表时间: 2024-01
• 作者: Campos;Jacoby, Juliet P;Dorsch, Michael P;Limdi, Nita A;Barnes, Geoffrey D;Luzum, Jasmine A
• 通讯作者: Luzum, Jasmine A

Dapagliflozin cardiovascular effects on end-stage kidney disease (DARE-ESKD-2) trial: rationale and design.

达格列净对终末期肾病的心血管影响 (DARE-ESKD-2) 试验：基本原理和设计。

• 发表时间: 2023-10-19
• 作者: Barreto J;Martins M;Pascoa M;Medorima STK;Bonilha I;Jesus DC;Carbonara CEM;Quadros KRS;Assato B;Campos-Staffico AM;Júnior GG;Nadruz W;de Oliveira RB;Sposito AC
• 通讯作者: Sposito AC

Eight pharmacokinetic genetic variants are not associated with the risk of bleeding from direct oral anticoagulants in non-valvular atrial fibrillation patients.

八种药代动力学遗传变异与非瓣膜性房颤患者直接口服抗凝剂的出血风险无关。

• 发表时间: 2022
• 作者: Campos;Dorsch, Michael P;Barnes, Geoffrey D;Zhu, Hao;Limdi, Nita A;Luzum, Jasmine A
• 通讯作者: Luzum, Jasmine A