Genomic and Transcriptomic Influences on Heparin-Induced Thrombocytopenia

基因组和转录组对肝素诱导的血小板减少症的影响

• 批准号: 10379303
• 负责人: Jason Hansen Karnes
• 金额: $ 15.38万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10379303
• 关键词: Address; Adverse drug effect; Adverse reactions; Alleles; Antibodies; Antibody Formation; Anticoagulants; Award; Big Data; Bioinformatics; Biological; Biological Assay; Biological Markers; Blood Platelets; Cardiovascular Agents; Cardiovascular Diseases; Cells; Clinical; Clinical Research; Clinical Treatment; Complement; DNA Resequencing; Data; Development; Diagnostic; Exposure to; Fostering; Foundations; Future; Genes; Genomics; Goals; Heparin; Immune; Incidence; Individual; Investigation; Knowledge; Life; Mediating; Mission; Molecular; PF4 Gene; Pathogenesis; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmacogenomics; Pharmacy facility; Platelet Activation; Prevention; Prevention strategy; Preventive; Production; Public Health; Reaction; Research; Research Personnel; Resources; Role; T-Cell Activation; T-Cell Activation Pathway; Techniques; Testing; Thromboembolism; Training; Translating; United States National Institutes of Health; Up-Regulation; Variant; Work; adverse drug reaction; base; blood group; career; career development; clinical practice; clinical predictors; clinical translation; cohort; diagnostic strategy; direct application; experience; genetic association; genome wide association study; genomic variation; heparin-induced thrombocytopenia; immunopathology; innovation; insight; mortality; novel; novel strategies; precision medicine; skills; tool; transcriptome sequencing; transcriptomics

ABSTRACT Despite decades of research into the immunopathology of heparin-induced thrombocytopenia (HIT), an unpredictable, life-threatening, immune-mediated adverse reaction to heparin treatment, a fundamental knowledge gap regarding the cause of HIT remains. The inability to predict HIT represents a considerable liability associated with heparin administration. Because the exact cellular and molecular mechanisms underlying HIT have yet to be identified, including the impetus for antibody production and critical immune cell roles, there is an essential need to apply alternative approaches to understand the biological basis for HIT and to identify clinically implementable biomarkers. The research objective of this proposal is to determine the role of genomic and transcriptomic variation in HIT pathogenesis. The PI's central hypothesis is that variation in genomic and transcriptomic pathways impacts HIT pathogenesis and can be used to identify clinically implementable HIT biomarkers. Based on strong preliminary data that constitute the first genome-wide association study (GWAS) and N-of-1 pathways studies for HIT, the working hypothesis is that the upregulation of T cell activation pathways results in PF4/heparin antibody production and that histo-blood group gene ABO O alleles subsequently result in HIT through platelet activation. We will pursue two Specific Aims (SAs) to test the central hypothesis: (1) determine the influence of genomic variation on HIT and (2) identify transcriptomic pathways involved in HIT pathogenesis using an N-of-1 strategy. In SA #1, a GWAS and gene resequencing approach will be utilized to identify genetic associations with HIT and platelet factor 4 (PF4)/heparin antibody production. In SA #2, peripheral blood mononuclear cells (PBMCs) will be collected and RNA-Seq will be performed. The N- of-1 pathways approach will be utilized to determine up- and down-regulated transcriptomic pathways involved in HIT and in the development of PF4/heparin antibodies. The proposed research has the potential to garner significant insights into HIT pathogenesis and to provide a framework for the clinical translation of HIT biomarkers into early diagnostic and preventive strategies. The proposed studies are technically innovative as they leverage novel strategies for large-scale biological data, including the N-of-1 pathways approach, and because establishing tools to distinguish patients that are pre-disposed to HIT could potentially shift current clinical practice paradigms. The PI's career development objective is to acquire expertise in bioinformatics and the research tools necessary to address his long-term research goal, including experience in big data, genomic and transcriptomic pathways, and innovative clinical study approaches. The knowledge and skills garnered during this award will provide foundational training and resources for future work in pharmacogenomics, facilitate eventual submission of an R01 proposal, and foster the transition to an independent researcher investigating adverse reactions to cardiovascular drugs.

摘要 尽管对肝素诱导的血小板减少症（HIT）的免疫病理学进行了数十年的研究， 不可预测的，危及生命的，免疫介导的肝素治疗不良反应，一个基本的 关于HIT原因的知识差距仍然存在。无法预测命中率是一个相当大的负担 与肝素给药相关。因为HIT的细胞和分子机制 还没有被确定，包括抗体产生的动力和关键的免疫细胞作用，有一个 基本需要应用替代方法来了解HIT的生物学基础，并在临床上识别 可实施的生物标志物。这项研究的目的是确定基因组的作用， HIT发病机制中的转录组变异。PI的中心假设是，基因组和 转录组学途径影响HIT发病机制，可用于鉴定临床上可实施的HIT 生物标志物。基于构成第一个全基因组关联研究（GWAS）的强大初步数据， 和N-of-1途径的研究，工作假设是T细胞活化的上调 途径导致PF 4/肝素抗体产生，组织血型基因ABO O等位基因 随后通过血小板活化导致HIT。我们将追求两个特定目标（SA），以测试中央 假设：（1）确定基因组变异对HIT的影响，（2）确定转录组通路 使用N-of-1策略参与HIT发病机制。在SA #1中，GWAS和基因重测序方法将 用于鉴定与HIT和血小板因子4（PF 4）/肝素抗体产生的遗传关联。在 SA #2，将采集外周血单核细胞（PBMC）并进行RNA-Seq。N- 将使用1种途径的方法来确定涉及的上调和下调转录组学途径 在HIT和PF 4/肝素抗体的开发中。拟议的研究有可能获得 对HIT发病机制的重要见解，并为HIT生物标志物的临床翻译提供框架 早期诊断和预防策略。拟议的研究在技术上是创新的，因为它们利用了 大规模生物数据的新策略，包括N-of-1途径方法， 建立区分易患HIT的患者的工具可能会改变当前的临床 实践范式PI的职业发展目标是获得生物信息学方面的专业知识， 研究工具，以解决他的长期研究目标，包括在大数据，基因组和 转录组学途径和创新的临床研究方法。在此期间获得的知识和技能 该奖项将为药物基因组学的未来工作提供基础培训和资源， 最终提交R 01提案，并促进向独立研究员调查的过渡 心血管药物的不良反应。

项目成果

Psychological and Genetic Predictors of Pain Tolerance.

疼痛耐受性的心理和遗传预测因子。

• DOI: 10.1111/cts.12605
• 发表时间: 2019
• 期刊: Clinical and translational science
• 作者: Patanwala,AsadE;Norwood,Charles;Steiner,Heidi;Morrison,Daniel;Li,May;Walsh,Keith;Martinez,Marina;Baker,SarahE;Snyder,EricM;Karnes,JasonH
• 通讯作者: Karnes,JasonH

Efficacy of personal pharmacogenomic testing as an educational tool in the pharmacy curriculum: A nonblinded, randomized controlled trial.

• DOI: 10.1111/cts.13121
• 发表时间: 2021-11
• 期刊: Clinical and translational science
• 作者: Grace C;Larriva MM;Steiner HE;Marupuru S;Campbell PJ;Patterson H;Cropp CD;Quinn D;Klimecki W;Nix DE;Warholak T;Karnes JH
• 通讯作者: Karnes JH