Integrative multi-omics analysis reveals novel idiopathic pulmonary fibrosis endotypes associated with disease progression.
Integrative multi-omics analysis reveals novel idiopathic pulmonary fibrosis endotypes associated with disease progression.
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综合多组学分析揭示了与疾病进展相关的新型特发性肺纤维化内源性类型
DOI：
10.1186/s12931-023-02435-0
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发表时间：
2023-05-31
影响因子：
5.8
通讯作者：
中科院分区：
文献类型：
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作者：
特发性肺纤维化（IPF）的特点是肺间质细胞外基质积聚和进行性功能下降。我们假设多组学数据的整合将识别具有临床意义的 IPF 分子内型。 IPF-PRO 登记处是 IPF 患者的前瞻性登记处。使用入组时收集的血液进行蛋白质组学和转录组学（包括总 RNA [toRNA] 和 microRNA [miRNA]）分析。使用相似网络融合整合分子数据，然后进行无监督光谱聚类来识别分子亚型。 Cox 比例风险模型测试了这些亚型与无进展和无移植生存之间的关系。根据先前描述的 52 基因（toRNA 表达）特征将分子亚型与风险组进行比较。通过线性回归差异表达和典型途径（独创性途径分析[IPA]）过度代表性分析来评估分子亚型的生物学特征。在 232 名受试者中，确定了两种分子亚型。亚型 1 (n = 105, 45.3%) 和亚型 2 (n = 127, 54.7%) 具有相似的年龄分布（70.1 +/- 8.1 vs. 69.3 +/- 7.6 岁；p = 0.31）和性别（79.1% vs. 70.1% 男性， p = 0.16）。根据综合生理指数 (CPI)，亚型 1 的疾病更为严重（55.8 vs. 51.2；p = 0.002）。在入组时调整 CPI 和抗纤维化治疗后，亚型 1 的无进展生存期较短（HR 1.79，95% CI 1.28,2.56；p = 0.0008），并且与亚型 2 相似的无移植生存期（HR 1.30，95% CI 0.87,1.96；p = 0.20）。根据 52 基因特征将受试者分配至分子亚型和风险组（kappa = 0.04，95% CI= -0.08，0.17），并且 52 基因特征风险组与无移植生存率差异相关，但与无进展生存率差异无关。根据热图和差异表达分析，蛋白质和 miRNA（但不是 RNA）有助于将受试者分类为分子亚型。 IPA 显示肺纤维化相关通路的富集，包括 mTOR、VEGF、PDGF 和 B 细胞受体信号传导。整合血液中的转录组和蛋白质组数据能够识别具有临床意义的 IPF 分子内型。如果得到验证，这些内型可以促进识别可能经历疾病进展的个体并丰富临床试验。 NCT01915511 在线版本包含可在 10.1186/s12931-023-02435-0 获取的补充材料。
Idiopathic pulmonary fibrosis (IPF) is characterized by the accumulation of extracellular matrix in the pulmonary interstitium and progressive functional decline. We hypothesized that integration of multi-omics data would identify clinically meaningful molecular endotypes of IPF. The IPF-PRO Registry is a prospective registry of patients with IPF. Proteomic and transcriptomic (including total RNA [toRNA] and microRNA [miRNA]) analyses were performed using blood collected at enrollment. Molecular data were integrated using Similarity Network Fusion, followed by unsupervised spectral clustering to identify molecular subtypes. Cox proportional hazards models tested the relationship between these subtypes and progression-free and transplant-free survival. The molecular subtypes were compared to risk groups based on a previously described 52-gene (toRNA expression) signature. Biological characteristics of the molecular subtypes were evaluated via linear regression differential expression and canonical pathways (Ingenuity Pathway Analysis [IPA]) over-representation analyses. Among 232 subjects, two molecular subtypes were identified. Subtype 1 (n = 105, 45.3%) and Subtype 2 (n = 127, 54.7%) had similar distributions of age (70.1 +/- 8.1 vs. 69.3 +/- 7.6 years; p = 0.31) and sex (79.1% vs. 70.1% males, p = 0.16). Subtype 1 had more severe disease based on composite physiologic index (CPI) (55.8 vs. 51.2; p = 0.002). After adjusting for CPI and antifibrotic treatment at enrollment, subtype 1 experienced shorter progression-free survival (HR 1.79, 95% CI 1.28,2.56; p = 0.0008) and similar transplant-free survival (HR 1.30, 95% CI 0.87,1.96; p = 0.20) as subtype 2. There was little agreement in the distribution of subjects to the molecular subtypes and the risk groups based on 52-gene signature (kappa = 0.04, 95% CI= -0.08, 0.17), and the 52-gene signature risk groups were associated with differences in transplant-free but not progression-free survival. Based on heatmaps and differential expression analyses, proteins and miRNAs (but not toRNA) contributed to classification of subjects to the molecular subtypes. The IPA showed enrichment in pulmonary fibrosis-relevant pathways, including mTOR, VEGF, PDGF, and B-cell receptor signaling. Integration of transcriptomic and proteomic data from blood enabled identification of clinically meaningful molecular endotypes of IPF. If validated, these endotypes could facilitate identification of individuals likely to experience disease progression and enrichment of clinical trials. NCT01915511 The online version contains supplementary material available at 10.1186/s12931-023-02435-0.
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影响因子：
30.8
作者：
Fingerlin, Tasha E.;Murphy, Elissa;Zhang, Weiming;Peljto, Anna L.;Brown, Kevin K.;Steele, Mark P.;Loyd, James E.;Cosgrove, Gregory P.;Lynch, David;Groshong, Steve;Collard, Harold R.;Wolters, Paul J.;Bradford, Williamson Z.;Kossen, Karl;Seiwert, Scott D.;du Bois, Roland M.;Garcia, Christine Kim;Devine, Megan S.;Gudmundsson, Gunnar;Isaksson, Helgi J.;Kaminski, Naftali;Zhang, Yingze;Gibson, Kevin F.;Lancaster, Lisa H.;Cogan, Joy D.;Mason, Wendi R.;Maher, Toby M.;Molyneaux, Philip L.;Wells, Athol U.;Moffatt, Miriam F.;Selman, Moises;Pardo, Annie;Kim, Dong Soon;Crapo, James D.;Make, Barry J.;Regan, Elizabeth A.;Walek, Dinesha S.;Daniel, Jerry J.;Kamatani, Yoichiro;Zelenika, Diana;Smith, Keith;McKean, David;Pedersen, Brent S.;Talbert, Janet;Kidd, Raven N.;Markin, Cheryl R.;Beckman, Kenneth B.;Lathrop, Mark;Schwarz, Marvin I.;Schwartz, David A.
通讯作者：
Schwartz, David A.
影响因子：
64.8
作者：
Baek, Daehyun;Villen, Judit;Shin, Chanseok;Camargo, Fernando D.;Gygi, Steven P.;Bartel, David P.
通讯作者：
Bartel, David P.
DOI：
10.1016/s2213-2600(17)30349-1
发表时间：
2017-11
期刊：
The Lancet. Respiratory medicine
影响因子：
--
作者：
Herazo-Maya JD;Sun J;Molyneaux PL;Li Q;Villalba JA;Tzouvelekis A;Lynn H;Juan-Guardela BM;Risquez C;Osorio JC;Yan X;Michel G;Aurelien N;Lindell KO;Klesen MJ;Moffatt MF;Cookson WO;Zhang Y;Garcia JGN;Noth I;Prasse A;Bar-Joseph Z;Gibson KF;Zhao H;Herzog EL;Rosas IO;Maher TM;Kaminski N
通讯作者：
Kaminski N
影响因子：
8.1
作者：
Amano H;Matsui Y;Hatanaka K;Hosono K;Ito Y
通讯作者：
Ito Y
影响因子：
10
作者：
通讯作者：
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