Moll Matthew, Hecker Julian, Platig John, Zhang Jingzhou, Ghosh Auyon J, Pratte Katherine A, Wang Rui-Sheng, Hill Davin, Konigsberg Iain R, Chiles Joe W, Hersh Craig P, Castaldi Peter J, Glass Kimberly, Dy Jennifer G, Sin Don D, Tal-Singer Ruth, Mouded Majd, Rennard Stephen I, Anderson Gary P, Kinney Gregory L, Bowler Russell P, Curtis Jeffrey L, McDonald Merry-Lynn, Silverman Edwin K, Hobbs Brian D, Cho Michael H
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA; Division of Pulmonary, Critical Care, Sleep and Allergy, Veterans Affairs Boston Healthcare System, West Roxbury, MA, 02123, USA; Harvard Medical School, Boston, MA, 02115, USA.
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA; Harvard Medical School, Boston, MA, 02115, USA.
EBioMedicine. 2024 Dec;110:105429. doi: 10.1016/j.ebiom.2024.105429. Epub 2024 Nov 6.
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.
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.
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 FEV 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.
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.
National Institutes of Health.
基因变异和基因表达可预测慢性阻塞性肺疾病（COPD）的风险，但其对COPD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）来定义高危COPD亚型，并评估临床和分子特征的差异。
我们通过最大化COPDGene训练集中蛋白质生物标志物的差异，基于PRS和TRS分位数定义高危组，并在COPDGene和ECLIPSE测试集中识别这些组。我们测试了亚组与临床结局的多变量关联，并比较了高危组之间的蛋白质-蛋白质相互作用网络和药物再利用分析。
我们在非重叠测试集中检查了两个由组学定义的高危组（n = 1133名非西班牙裔白人COPDGene患者，n = 299名非裔美国人（AA）COPDGene患者，n = 468名ECLIPSE患者）。我们定义了“高活性”（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，两个亚组的参与者体重指数（BMI）较低、肺功能较差，且代谢、生长和免疫信号传导过程存在改变。“高活性”而非“严重风险”参与者的FEV预期下降幅度更大（COPDGene：-51 mL/年；ECLIPSE：-40 mL/年），蛋白质组学图谱在受5-脂氧合酶抑制剂和血管紧张素转换酶（ACE）抑制剂治疗干扰的基因集中富集。
多基因和转录风险评分的联合使用确定了高危个体中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治疗的亚型特异性富集，并表明先前药物再利用失败可能可以通过患者选择来解释。
美国国立卫生研究院。
