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.

抽象的 尽管研究了数十年来研究肝素诱导的血小板减少症的免疫病理学（HIT） 对肝素治疗的不良，威胁生命，免疫介导的不良反应，这是一种基本 关于命中原因的知识差距。无法预测命中是相当大的责任 与肝素给药有关。因为命中的确切细胞和分子机制 尚未确定，包括抗体产生和关键免疫细胞角色的动力，有一个 采用替代方法来了解命中的生物学基础并在临床上识别的基本需求 可实施的生物标志物。该提案的研究目标是确定基因组和 命中发病机理中的转录组变异。 PI的中心假设是基因组和 转录组途径会影响发病机理，可用于识别可实施的命中 生物标志物。基于构成首个全基因组关联研究（GWAS）的强大初步数据 和N-OF-1途径研究的HIT，工作假设是T细胞激活的上调 途径导致PF4/肝素抗体产生和组织血管基因基因abo o等位基因 随后导致通过血小板激活打击。我们将追求两个具体目标（SAS）来测试中央 假设：（1）确定基因组变异对命中的影响，（2）识别转录途径 使用N-OF-1策略参与命中发病机理。在SA＃1中，GWAS和基因重新陈述方法将 被用来鉴定与HIT和血小板因子4（PF4）/肝素抗体产生的遗传关联。在 将收集SA＃2，外周血单核细胞（PBMC），并将进行RNA-Seq。然后- OF-1途径方法将用于确定涉及的上调和下调的转录途径 在PF4/PF4/肝素抗体的开发中。拟议的研究有可能获得 对HIT发病机理的重要见解，并为HIT生物标志物的临床翻译提供框架 进入早期诊断和预防策略。拟议的研究在技术上是创新的 大规模生物学数据的新型策略，包括N-1-1途径方法，因为 建立以区分预先击中的患者的工具可能会改变当前的临床 练习范式。 PI的职业发展目标是获得生物信息学方面的专业知识和 解决他的长期研究目标所必需的研究工具，包括大数据，基因组和 转录组途径和创新的临床研究方法。在期间获得的知识和技能 该奖项将为未来的药物基因组学工作提供基础培训和资源，促进 最终提交R01提案，并促进向独立研究人员的过渡 对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