Polygenic and transcriptional risk scores identify chronic obstructive pulmonary disease subtypes in the COPDGene and ECLIPSE cohort studies.

IF 9.7 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

EBioMedicine Pub Date : 2024-11-06 DOI:10.1016/j.ebiom.2024.105429

Matthew Moll, Julian Hecker, John Platig, Jingzhou Zhang, Auyon J Ghosh, Katherine A Pratte, Rui-Sheng Wang, Davin Hill, Iain R Konigsberg, Joe W Chiles, Craig P Hersh, Peter J Castaldi, Kimberly Glass, Jennifer G Dy, Don D Sin, Ruth Tal-Singer, Majd Mouded, Stephen I Rennard, Gary P Anderson, Gregory L Kinney, Russell P Bowler, Jeffrey L Curtis, Merry-Lynn McDonald, Edwin K Silverman, Brian D Hobbs, Michael H Cho

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引用次数: 0

Abstract

Background: Genetic variants and gene expression predict risk of chronic obstructive pulmonary disease (COPD), but their effect on COPD heterogeneity is unclear. We aimed to define high-risk COPD subtypes using genetics (polygenic risk score, PRS) and blood gene expression (transcriptional risk score, TRS) and assess differences in clinical and molecular characteristics.

Methods: We defined high-risk groups based on PRS and TRS quantiles by maximising differences in protein biomarkers in a COPDGene training set and identified these groups in COPDGene and ECLIPSE test sets. We tested multivariable associations of subgroups with clinical outcomes and compared protein-protein interaction networks and drug repurposing analyses between high-risk groups.

Findings: We examined two high-risk omics-defined groups in non-overlapping test sets (n = 1133 NHW COPDGene, n = 299 African American (AA) COPDGene, n = 468 ECLIPSE). We defined "high activity" (low PRS, high TRS) and "severe risk" (high PRS, high TRS) subgroups. Participants in both subgroups had lower body-mass index (BMI), lower lung function, and alterations in metabolic, growth, and immune signalling processes compared to a low-risk (low PRS, low TRS) subgroup. "High activity" but not "severe risk" participants had greater prospective FEV₁ decline (COPDGene: -51 mL/year; ECLIPSE: -40 mL/year) and proteomic profiles were enriched in gene sets perturbed by treatment with 5-lipoxygenase inhibitors and angiotensin-converting enzyme (ACE) inhibitors.

Interpretation: Concomitant use of polygenic and transcriptional risk scores identified clinical and molecular heterogeneity amongst high-risk individuals. Proteomic and drug repurposing analysis identified subtype-specific enrichment for therapies and suggest prior drug repurposing failures may be explained by patient selection.

Funding: National Institutes of Health.

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在 COPDGene 和 ECLIPSE 队列研究中，多基因和转录风险评分可识别慢性阻塞性肺病亚型。

背景：基因变异和基因表达可预测慢性阻塞性肺病（COPD）的风险，但它们对慢性阻塞性肺病异质性的影响尚不清楚。我们旨在利用遗传学（多基因风险评分，PRS）和血液基因表达（转录风险评分，TRS）定义高风险 COPD 亚型，并评估临床和分子特征的差异：我们通过最大限度地扩大 COPDGene 训练集中蛋白质生物标志物的差异，根据 PRS 和 TRS 量值定义了高风险组，并在 COPDGene 和 ECLIPSE 测试集中确定了这些组。我们测试了亚组与临床结果的多变量关联，并比较了高风险组之间的蛋白质-蛋白质相互作用网络和药物再利用分析：我们在不重叠的测试集（n = 1133 NHW COPDGene、n = 299 African American (AA) COPDGene、n = 468 ECLIPSE）中研究了两个由omics定义的高风险组。我们定义了 "高活动"（低 PRS、高 TRS）和 "严重风险"（高 PRS、高 TRS）亚组。与低风险（低 PRS、低 TRS）亚组相比，这两个亚组的参与者体重指数（BMI）较低，肺功能较差，代谢、生长和免疫信号过程发生了改变。"高活性 "而非 "严重风险 "参与者的前瞻性 FEV1 下降幅度更大（COPDGene：-51 mL/年；ECLIPSE：-40 mL/年），蛋白质组图谱中的基因集因使用 5-脂氧合酶抑制剂和血管紧张素转换酶（ACE）抑制剂而受到干扰：同时使用多基因和转录风险评分可确定高危人群的临床和分子异质性。蛋白质组学和药物再利用分析确定了亚型特异性富集疗法，并表明之前的药物再利用失败可能是由于患者选择所致：美国国立卫生研究院。

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来源期刊

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.