ALS blood expression profiling identifies new biomarkers, patient subgroups, and evidence for neutrophilia and hypoxia

Journal of Translational Medicine

Colin P. S. Kruse¹  John J. Kopchick²  Edward O. List²  Darlene E. Berryman²  William R. Swindell³ 

[1] 0000 0001 0668 7841, grid.20627.31, Department of Environmental and Plant Biology, Ohio University, 45701, Athens, OH, USA;0000 0001 0668 7841, grid.20627.31, Edison Biotechnology Institute, Ohio University, 45701, Athens, OH, USA;0000 0001 0668 7841, grid.20627.31, Heritage College of Osteopathic Medicine, Ohio University, 45701, Athens, OH, USA;0000 0001 0668 7841, grid.20627.31, Edison Biotechnology Institute, Ohio University, 45701, Athens, OH, USA;0000 0001 0668 7841, grid.20627.31, The Diabetes Institute, Ohio University, 45701, Athens, OH, USA;0000 0001 0668 7841, grid.20627.31, Heritage College of Osteopathic Medicine, Ohio University, 45701, Athens, OH, USA;0000 0004 0447 0798, grid.414987.7, Department of Internal Medicine, The Jewish Hospital, 45236, Cincinnati, OH, USA;

关键词: Amyotrophic lateral sclerosis;    Biomarker;    GWAS;    Hypoxia;    Machine learning;    Microarray;    Neutrophil;    Ribosome;    Translation;   

DOI  :  10.1186/s12967-019-1909-0

来源: publisher

【 摘 要 】

BackgroundAmyotrophic lateral sclerosis (ALS) is a debilitating disease with few treatment options. Progress towards new therapies requires validated disease biomarkers, but there is no consensus on which fluid-based measures are most informative.MethodsThis study analyzed microarray data derived from blood samples of patients with ALS (n = 396), ALS mimic diseases (n = 75), and healthy controls (n = 645). Goals were to provide in-depth analysis of differentially expressed genes (DEGs), characterize patient-to-patient heterogeneity, and identify candidate biomarkers.ResultsWe identified 752 ALS-increased and 764 ALS-decreased DEGs (FDR < 0.10 with > 10% expression change). Gene expression shifts in ALS blood broadly resembled acute high altitude stress responses. ALS-increased DEGs had high exosome expression, were neutrophil-specific, associated with translation, and overlapped significantly with genes near ALS susceptibility loci (e.g., IFRD1, TBK1, CREB5). ALS-decreased DEGs, in contrast, had low exosome expression, were erythroid lineage-specific, and associated with anemia and blood disorders. Genes encoding neurofilament proteins (NEFH, NEFL) had poor diagnostic accuracy (50–53%). However, support vector machines distinguished ALS patients from ALS mimics and controls with 87% accuracy (sensitivity: 86%, specificity: 87%). Expression profiles were heterogeneous among patients and we identified two subgroups: (i) patients with higher expression of IL6R and myeloid lineage-specific genes and (ii) patients with higher expression of IL23A and lymphoid-specific genes. The gene encoding copper chaperone for superoxide dismutase (CCS) was most strongly associated with survival (HR = 0.77; P = 1.84e−05) and other survival-associated genes were linked to mitochondrial respiration. We identify a 61 gene signature that significantly improves survival prediction when added to Cox proportional hazard models with baseline clinical data (i.e., age at onset, site of onset and sex). Predicted median survival differed 2-fold between patients with favorable and risk-associated gene expression signatures.ConclusionsPeripheral blood analysis informs our understanding of ALS disease mechanisms and genetic association signals. Our findings are consistent with low-grade neutrophilia and hypoxia as ALS phenotypes, with heterogeneity among patients partly driven by differences in myeloid and lymphoid cell abundance. Biomarkers identified in this study require further validation but may provide new tools for research and clinical practice.

【 授权许可】

CC BY