Genome-wide genotyping in amyotrophic lateral sclerosis and neurologically normal controls: first stage analysis and public release of data
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PROVIDER: PRJNA75709 | ENA |
REPOSITORIES: ENA
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Project description:Importance: Amyotrophic lateral sclerosis demonstrated changes in peripheral immune cells and proteins. However, the relationship between comprehensive immune profiles and clinical progression remained unclear. Objective: To identify the immune cells and proteins related to amyotrophic lateral sclerosis progression rate. Design: This case-control study enrolled healthy volunteers and patients with amyotrophic lateral sclerosis from March 29, 2021, to October 31, 2022. Setting: Tokushima University Hospital and Takeda Pharmaceutical Company Limited in Japan. Participants: This study screened 46 subjects to enroll 30 patients with amyotrophic lateral sclerosis within 2 years from onset and 10 healthy volunteers. Patients with rapid and non-rapid amyotrophic lateral sclerosis were those with Revised Amyotrophic Lateral Sclerosis Functional Rating Scale decreases of ≥1.0/month and <1.0/month, respectively. Exposure(s): Peripheral blood samples were collected. Main Outcome(s) and Measure(s): The progression rate as assessed with the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale decrease/month and the immune cell and protein profiles via single-cell RNA sequencing and immunoproteomics. Results: Samples of 7 (mean [standard deviation] age: 69.8 [14.4] years; male, 3) and 23 (60.7 [10.8] years; male, 17) patients with rapid and non-rapid amyotrophic lateral sclerosis, respectively, and 10 healthy volunteers (63.6 [10.2] years; male, 7) were analyzed. The ratios of T helper 17/regulatory T cells, mature/naïve CD8 T cells, and mature/naïve natural killer cells were significantly higher in rapid than in non-rapid amyotrophic lateral sclerosis. The ratio of T helper 17/regulatory T cells was significantly correlated with the progression rate. The immunoproteomics identified killer cell lectin-like receptor D1, trefoil factor 2, keratin 19, interleukin-17A, YTH N6-methyladenosine RNA binding protein F3, and neutrophil cytosolic factor 2 as significantly elevated in rapid amyotrophic lateral sclerosis. Cell type frequency and protein expression, such as T helper 17 cell–interleukin-17A and mature CD8 T cell–killer cell lectin-like receptor D1, were significantly correlated. Conclusions and Relevance: The progression rate was related to the increase of T helper 17 cells versus regulatory T cells and titers of T helper 17 cell- and CD8 T cell-related immunoproteins in patients with amyotrophic lateral sclerosis. These results provide promising biomarkers and targets for amyotrophic lateral sclerosis disease-modifying therapies.
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