Precision Medicine Description of Novel Asthma Endotype

新型哮喘内型的精准医学描述

• 批准号: 10580870
• 负责人: Scott Michael Matson
• 金额: $ 12.49万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-18 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10580870
• 关键词: Affect; Antibodies; Antigens; Asthma; Autoantibodies; Autoimmune Diseases; Biological; Biological Assay; Clinical; Data; Development; Disease; Future; Generations; Genetic; Goals; Helper-Inducer T-Lymphocyte; Institutes; Intervention Studies; Kansas; Measures; Methods; Morbidity - disease rate; Peptides; Phenotype; Population; Quality of life; Questionnaires; Refractory; Research Design; Rheumatoid Arthritis; Risk; Serum; Specificity; Sputum; Techniques; Therapeutic; United States; asthmatic patient; cell type; clinically relevant; cohort; conventional therapy; improved outcome; insight; mortality; novel; precision medicine; pulmonary function; rho; targeted treatment; therapeutic target; therapy outcome

Asthma affects 8.4% of the United States population and 4.3% of the worldwide population and leads to significant morbidity and mortality. Identification of clinically relevant endotypes, such as high T2 (T helper cell, type) asthma, led to the development of targeted therapeutics and improved outcome. However, despite these advances, there remains 5-10% of asthma patients who are refractory to conventional treatment and have limited therapeutic options. We propose to meet this need by utilizing precision medicine techniques to define a unique asthma phenotype that we have described which are likely influenced by the generation of autoimmune antibodies. My preliminary data identified a population of asthma patients at risk for the development of autoimmune disease through the generation of autoantibodies specific for rheumatoid arthritis (RA). In our preliminary data I found that 15% of asthma subjects had clinically positive levels of RA specific autoantibodies (antibodies to citrullinated peptide antigens (ACPA)) in serum and 92% in sputum (n=42) compared to 5.6% in a normal population (p=<0.01 for both). In our preliminary data, higher ACPA levels were correlated (via Spearman's method) with lower Asthma Quality of Life Questionnaire scores (rho=-0.42, p=0.02) and worse pulmonary function as measured by forces expiratory volume in 1 second (rho=-.32, p=0.03). My preliminary data describes a cohort of asthma patients who develop clinically positive serum ACPA, which is associated with increased risk for the development of RA (specificity of positive ACPA assay is 90.4% for the development of RA) and associated with worse asthma-specific disease metrics. The central hypothesis for this study is that asthma patients who generate ACPA represent a specific clinical endotype which can be further characterized using precision medicine techniques. Our long-term goal is to develop biologic and genetic insights into the mechanism of ACPA development in asthma to generate future therapeutic targets for interventional study designs.

哮喘影响着 8.4% 的美国人口和 4.3% 的全球人口，并导致显着的发病率和死亡率。临床相关内型的鉴定，例如高 T2（辅助性 T 细胞型）哮喘，导致了靶向治疗的开发和改善的结果。然而，尽管取得了这些进展，仍有 5-10% 的哮喘患者对常规治疗耐药且治疗选择有限。我们建议通过利用精准医学技术来定义我们所描述的独特的哮喘表型来满足这一需求，该表型可能受到自身免疫抗体产生的影响。 我的初步数据确定了一群哮喘患者因产生类风湿性关节炎 (RA) 特异性自身抗体而面临患自身免疫性疾病的风险。在我们的初步数据中，我发现 15% 的哮喘受试者血清中 RA 特异性自身抗体（瓜氨酸肽抗原 (ACPA) 抗体）呈临床阳性水平，92% 的痰液 (n=42) 呈临床阳性水平，而正常人群中这一比例为 5.6% （两者的 p=<0.01）。在我们的初步数据中，较高的 ACPA 水平（通过 Spearman 方法）与较低的哮喘生活质量问卷评分（rho=-0.42，p=0.02）以及较差的肺功能（通过 1 秒呼气量测量）相关（rho=- .32，p=0.03）。我的初步数据描述了一组出现临床阳性血清 ACPA 的哮喘患者，这与发展 RA 的风险增加相关（阳性 ACPA 检测对于发展 RA 的特异性为 90.4%），并且与更严重的哮喘特异性疾病相关指标。 这项研究的中心假设是，产生 ACPA 的哮喘患者代表了一种特定的临床内型，可以使用精准医学技术进一步表征。我们的长期目标是从生物学和遗传学角度深入了解 ACPA 在哮喘中的发展机制，从而为介入研究设计制定未来的治疗目标。