Elucidating the Genomic Determinants of Outcomes in Idiopathic Pulmonary Fibrosis

阐明特发性肺纤维化结果的基因组决定因素

• 批准号: 10670456
• 负责人: Justin M Oldham
• 金额: $ 10.35万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10670456
• 关键词: Elucidating; Genomic; Determinants; Outcomes; Idiopathic

PROJECT SUMMARY/ABSTRACT Idiopathic pulmonary fibrosis (IPF) is a rare, but devastating interstitial lung disease characterized by a progressive decline in lung function and a median survival of 3-5 years after diagnosis. Despite the poor prognosis, IPF follows a highly variable clinical course, whereby most patients experience gradual disease progression, some demonstrate relative stability and a small group dies from rapidly progressive disease. Anti- fibrotic therapies were recently approved for the treatment of IPF, but it remains unclear which IPF phenotypes derive the most benefit. Recent advances in genomic technology provide an excellent opportunity to improve our understanding of IPF progression and treatment response. In this proposal, I aim to take advantage of these genomic advances to identify single nucleotide polymorphisms (SNPs) linked to relevant IPF outcomes. I will do this using DNA samples collected from patients enrolled in past and current IPF clinical trials, along with two large IPF registries. My central hypothesis is that patients genetically predisposed to death, disease progression and treatment response can be prospectively identified using SNPs linked to these endpoints. I will first conduct a genome-wide survival analysis to identify SNPs linked to early IPF mortality. I will then genotype relevant susceptibility and outcome-associated SNPs in several clinical trial datasets to determine whether they predict relevant trial endpoints, including pulmonary function decline and hospitalization. Finally, I will genotype SNPs at potential pharmacogenetic loci to determine whether such SNPs modulate the response to anti-fibrotic therapy. This work will advance my long-term career goal of incorporating genetics into clinical decision-making in patients with IPF. Concurrently I will pursue a career development plan that will provide outstanding mentorship, hands-on laboratory experience and additional training in genetic epidemiology, statistical genetics, and bioinformatics. This K23 award is vital to successful completion of this proposal and timely execution of my career development plan, as it will provide the time necessary to meet the realistic milestones that have set in conjunction with my advisory committee. Ultimately this award will allow me to successfully compete for R01 funding aimed at advancing my long-term goal above.

项目总结/摘要 特发性肺纤维化（IPF）是一种罕见但破坏性的间质性肺病，其特征是 肺功能进行性下降，诊断后中位生存期为3-5年。尽管穷人 预后方面，特发性肺纤维化遵循高度可变的临床病程，大多数患者都会经历渐进性疾病 一些人表现出相对稳定性，一小部分人死于快速进展的疾病。反 纤维化疗法最近被批准用于治疗IPF，但仍不清楚哪些IPF表型 获得最大的利益。基因组技术的最新进展提供了一个极好的机会， 我们对IPF进展和治疗反应的理解。在这一建议中，我的目的是利用 这些基因组学的进展，以确定单核苷酸多态性（SNP）与相关的IPF的结果。我 将使用从既往和当前IPF临床试验入组的患者中采集的DNA样本以及沿着 两个大型IPF登记研究。我的中心假设是病人的基因倾向于死亡，疾病 可以使用与这些终点相关的SNP前瞻性地鉴定疾病进展和治疗反应。我会 首先进行全基因组生存分析，以确定与早期IPF死亡率相关的SNP。然后我会对 相关的易感性和结果相关的SNP在几个临床试验数据集，以确定是否 他们预测相关的试验终点，包括肺功能下降和住院治疗。最后要 基因型SNP在潜在的药物遗传学基因座，以确定是否这样的SNP调节反应， 抗纤维化治疗这项工作将推进我的长期职业目标，将遗传学纳入临床 IPF患者的决策。同时，我将追求一个职业发展计划， 杰出的指导，实验室实践经验和遗传流行病学方面的额外培训， 统计遗传学和生物信息学。这个K23奖项对于成功完成本提案至关重要， 及时执行我的职业发展计划，因为它将提供必要的时间，以满足现实的 与我的咨询委员会一起设定的里程碑。最终，这个奖项将使我能够 我成功地竞争R 01资金，旨在推进我的长期目标。

项目成果

Association study of human leukocyte antigen (HLA) variants and idiopathic pulmonary fibrosis.

人类白细胞抗原（HLA）变异与特发性肺纤维化的关联研究。

• DOI: 10.1101/2023.07.20.23292940
• 发表时间: 2023
• 期刊: the preprint server for health sciences
• 作者: Guillen-Guio B

Weighing on Our Minds: Baseline BMI and Weight Loss as Predictors of Interstitial Lung Disease Outcome.

掂量我们的心：基线 BMI 和体重减轻作为间质性肺疾病结果的预测因子。

• DOI: 10.1016/j.chest.2021.11.013
• 发表时间: 2022
• 期刊: Chest
• 影响因子: 9.6
• 作者: Pugashetti,JanelleVu;Oldham,JustinM
• 通讯作者: Oldham,JustinM

Rebuttal From Drs Oldham and Danoff.

奥尔德姆博士和丹诺夫博士的反驳。

• DOI: 10.1016/j.chest.2018.08.1071
• 发表时间: 2019
• 期刊: Chest
• 影响因子: 9.6
• 作者: Oldham,JustinM;Danoff,SonyeK
• 通讯作者: Danoff,SonyeK

Clinical Genetics in Interstitial Lung Disease.

间质性肺病的临床遗传学。

• DOI: 10.3389/fmed.2018.00116
• 发表时间: 2018
• 期刊: Frontiers in medicine
• 影响因子: 3.9
• 作者: Newton,ChadA;Molyneaux,PhilipL;Oldham,JustinM
• 通讯作者: Oldham,JustinM

Detection and Early Referral of Patients With Interstitial Lung Abnormalities: An Expert Survey Initiative.

• DOI: 10.1016/j.chest.2021.06.035
• 发表时间: 2022-02
• 期刊: CHEST
• 影响因子: 9.6
• 作者: Hunninghake, Gary M.;Goldin, Jonathan G.;Kadoch, Michael A.;Kropski, Jonathan A.;Rosas, Ivan O.;Wells, Athol U.;Yadav, Ruchi;Lazarus, Howard M.;Abtin, Fereidoun G.;Corte, Tamera J.;de Andrade, Joao A.;Johannson, Kerri A.;Kolb, Martin R.;Lynch, David A.;Oldham, Justin M.;Spagnolo, Paolo;Strek, Mary E.;Tomassetti, Sara;Washko, George R.;White, Eric S.
• 通讯作者: White, Eric S.