Circulating levels of T-cell traits and the risk of amyotrophic lateral sclerosis: a Mendelian randomization study

Abstract

Abstract Background：Amyotrophic lateral sclerosis (ALS) is a rare fatal neurodegenerative disorder. Evidence from observational studies indicates that different T-cell subsets may have opposite effects on the development of ALS. However, further studies that can yield higher-level evidence are required to confirm these findings. Thus, we conducted a two-sample Mendelian randomization (MR) analysis to determine the association between T-cell traits and the risk of ALS. Methods：Genetic instrumental variables were chosen from a commonly used genome-wide association study (GWAS) involving 3757 European subjects to analyze 244 T-cell subsets. ALS summary statistics were extracted from a GWAS encompassing 20,806 ALS cases and 59,804 controls of European descent. Comprehensive sensitivity tests were conducted to validate the robustness of the results. We also performed a reverse MR analysis to determine the effect of ALS on T-cell traits. This study was conducted using the STROBE-MR checklist for reporting MR studies. Results：After Bonferroni correction, 24 T-cell traits out of the 244 subsets showed potential associations with the risk of ALS. Notably, 75% (n = 18) of the associations involved CD3 expression on various T-cell subtypes (for example, CD3 expression on terminally differentiated CD8+ T cells), indicating a highly consistent negative correlation with the risk of ALS. The proportion of T regulatory cells (Tregs) in CD4+ T cells (odds ratio [OR] = 0.84, 95% confidence interval [CI] = 0.72–0.99, p = 0.032), the proportion of secreting Tregs in CD4+ T cells (OR = 0.90, 95% CI = 0.81–1.00, p = 0.044), CCR7 expression on naive CD4+ T cells (OR = 1.12, 95% CI = 1.01–1.20, p = 0.025), and CCR7 expression on naive CD8+ T cells (OR = 1.16, 95% CI = 1.02–1.33, p = 0.025) were associated with the risk of ALS. The results of the sensitivity analyses were consistent. The reverse MR analysis did not reveal any significant causal effect of ALS on T-cell traits. Conclusion： ALS risk is associated with 24 T-cell subsets, including those characterized by CD3 expression on terminally differentiated CD8+ T cells, Treg, and CCR7 levels. These results align with and build upon the findings of previous observational studies on the involvement of T lymphocyte subset-induced immunological processes in ALS.