The FSHD muscle-blood biomarker: a circulating transcriptomic biomarker for clinical severity in facioscapulohumeral muscular dystrophy.
The FSHD muscle-blood biomarker: a circulating transcriptomic biomarker for clinical severity in facioscapulohumeral muscular dystrophy.
复制标题
DOI：
10.1093/braincomms/fcad221
复制
发表时间：
2023
影响因子：
4.8
通讯作者：
中科院分区：
文献类型：
--
作者：
面肩肱骨肌营养不良症（FSHD）是一种常见的，无法治愈的骨骼肌病。FSHD的临床试验受到与临床严重程度相关性较差的异质生物标志物的阻碍，需要侵入性肌肉活检。从宏观上看，FSHD表现为缓慢的脂肪替代肌肉，炎症迅速加速。转录因子DUX4的错误表达目前被认为是发病机制的基础，并且已经提出了包括PAX7靶基因抑制在内的机制。在这里，我们对来自相同临床特征的FSHD患者（n = 24）的mri引导下的炎症和等基因非炎症肌肉活检进行了rna测序，同时对来自一部分患者（n = 13）和未受影响的对照组（n = 11）的等基因外周血单核细胞进行了测序。采用多变量模型评估五种已发表的FSHD转录组生物标志物的临床相关性。我们证明PAX7靶基因抑制可以独立于年龄和性别区分对照组、炎症和非炎症的FSHD肌肉（P < 0.013），而DUX4靶基因的区分能力仅限于区分FSHD肌肉和对照组。重要的是，非炎症肌肉中PAX7靶基因的抑制水平与FSHD严重程度的临床评估相关（P = 0.04）。FSHD肌肉中的DUX4靶基因生物标志物与下肢脂肪分数和D4Z4阵列长度相关，但与临床评估无关。最后，FSHD肌肉中PAX7靶基因的抑制与等基因外周血单核细胞的水平相关（P = 0.002）。一种精炼的PAX7靶基因生物标志物，包括外周血中计算的143/601个PAX7靶基因（FSHD肌肉-血液生物标志物）与FSHD患者的临床严重程度相关（P < 0.036）。我们的新循环生物标志物在54例FSHD患者和29例匹配对照血液样本的独立数据集中被验证为临床严重程度的分类器，在老年患者中效果更好（P = 0.03）。总之，我们提出了一种微创FSHD肌肉-血液生物标志物，可用于患者肌肉和血液中FSHD临床严重程度，在常规疾病监测和临床试验中具有潜在的应用价值。Lima-Filho、Benedet等人报道，携带FNDC5等位基因rs1746661(T)的认知功能正常的老年人出现脑糖代谢低下和淀粉样蛋白沉积增加。这些发现表明FNDC5可能参与人脑区域葡萄糖代谢。请参阅Kyba和Bosnakovski （https://doi.org/10.1093/braincomms/fcad235）对本文的科学评论。
Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent, incurable skeletal myopathy. Clinical trials for FSHD are hindered by heterogeneous biomarkers poorly associated with clinical severity, requiring invasive muscle biopsy. Macroscopically, FSHD presents with slow fatty replacement of muscle, rapidly accelerated by inflammation. Mis-expression of the transcription factor DUX4 is currently accepted to underlie pathogenesis, and mechanisms including PAX7 target gene repression have been proposed. Here, we performed RNA-sequencing on MRI-guided inflamed and isogenic non-inflamed muscle biopsies from the same clinically characterized FSHD patients (n = 24), alongside isogenic peripheral blood mononucleated cells from a subset of patients (n = 13) and unaffected controls (n = 11). Multivariate models were employed to evaluate the clinical associations of five published FSHD transcriptomic biomarkers. We demonstrated that PAX7 target gene repression can discriminate control, inflamed and non-inflamed FSHD muscle independently of age and sex (P < 0.013), while the discriminatory power of DUX4 target genes was limited to distinguishing FSHD muscle from control. Importantly, the level of PAX7 target gene repression in non-inflamed muscle associated with clinical assessments of FSHD severity (P = 0.04). DUX4 target gene biomarkers in FSHD muscle showed associations with lower limb fat fraction and D4Z4 array length but not clinical assessment. Lastly, PAX7 target gene repression in FSHD muscle correlated with the level in isogenic peripheral blood mononucleated cells (P = 0.002). A refined PAX7 target gene biomarker comprising 143/601 PAX7 target genes computed in peripheral blood (the FSHD muscle–blood biomarker) associated with clinical severity in FSHD patients (P < 0.036). Our new circulating biomarker validates as a classifier of clinical severity in an independent data set of 54 FSHD patient and 29 matched control blood samples, with improved power in older patients (P = 0.03). In summary, we present the minimally invasive FSHD muscle–blood biomarker of FSHD clinical severity valid in patient muscle and blood, of potential use in routine disease monitoring and clinical trials. Lima-Filho, Benedet et al. reported that cognitively unimpaired elders carrying the FNDC5 allele rs1746661(T) develop brain low glucose metabolism and increased amyloid deposition. These findings indicate that FNDC5 may contribute to regional glucose metabolism in the human brain. See Kyba and Bosnakovski (https://doi.org/10.1093/braincomms/fcad235) for a scientific commentary on this article.
登录
查看更多内容
影响因子：
3.7
作者：
Das S;Chadwick BP
通讯作者：
Chadwick BP
影响因子：
16.6
作者：
Banerji CRS;Panamarova M;Hebaishi H;White RB;Relaix F;Severini S;Zammit PS
通讯作者：
Zammit PS
影响因子：
3.9
作者：
Banerji, Christopher R. S.;Knopp, Paul;Zammit, Peter S.
通讯作者：
Zammit, Peter S.
影响因子：
3.3
作者：
Gros M;Nunes AM;Daoudlarian D;Pini J;Martinuzzi E;Barbosa S;Ramirez M;Puma A;Villa L;Cavalli M;Grecu N;Garcia J;Siciliano G;Solé G;Juntas-Morales R;Jones PL;Jones T;Glaichenhaus N;Sacconi S
通讯作者：
Sacconi S
影响因子：
3.5
作者：
Gabriëls, J;Beckers, MC;Belayew, A
通讯作者：
Belayew, A