Abstract: BACKGROUND: Sarcopenia is a degenerative illness in the elderly, and there is currently a dearth of particular therapeutic medications. Abnormalities in immune cells are risk factors for sarcopenia. CD4+ T lymphocytes play a vital role in skeletal muscle repair and regeneration. Previous research generally used expression quantitative trait loci data from whole tissues or blood to identify pharmacological targets, making it difficult to uncover the regulatory effects of gene expression on distinct cell subpopulations and their dynamic activation states. This study integrates dynamic expression quantitative trait locus data of CD4+ T cells to evaluate the immune cell specificity and activation time-dependent impacts of gene expression on sarcopenia, providing a platform for the development of precise immune intervention techniques.
OBJECTIVE: To reveal the specific causal relationship between gene expression of different activation phases of CD4+ T cell subsets and sarcopenia.
METHODS: Based on the study by Soskic et al. (CD4+ T cell dynamic expression quantitative trait loci data, covering 46 “cell-activation state” expression profiles in European populations), the Database of Immune Cell Expression, eQTLs and Epigenomics platform (led by the National Institutes of Health, providing immune cell expression quantitative trait loci data), the eQTLGen platform (jointly constructed by 37 institutions, providing a resource library of blood-specific expression quantitative trait loci in European populations), the Genotype-Tissue Expression platform (led by the National Institutes of Health, integrating data from 49 human tissues in European populations, providing skeletal muscle expression quantitative trait loci data), and the GWAS Catalog platform (developed by the European Bioinformatics Institute, providing genome-wide association study data globally), a two-sample Mendelian randomization analysis was systematically conducted. First, Mendelian randomization analysis will be undertaken utilizing dynamic expression quantitative trait loci of CD4+ T cells as exposure and sarcopenia phenotype as outcome to screen for candidate genes. Subsequently, Mendelian randomization analysis was undertaken using expression quantitative trait loci data from immune cells, whole blood, and skeletal muscle tissue to validate gene specificity. Simultaneously, the reproducibility of the results was tested by combining Mendelian randomization analysis based on summary data, heterogeneity testing, colocalization analysis, and differential gene expression analysis (using the dataset # GSE111016 from the Gene Expression Omnibus database). All data are publicly aggregated statistics data and conform to ethical norms. All analyses properly screened instrumental variables and followed the STROBE standards for observational research.
RESULTS AND CONCLUSION: (1) After Mendelian randomization analysis and heterogeneity tests based on summary data, the results showed that RAB29, member RAS oncogene family (RAB29), NADH:ubiquinone oxidoreductase core subunit S3 (NDUFS3), and matrix metallopeptidase 24 antisense RNA (MMP24OS) had specific causal associations with sarcopenia. The expression level of RAB29 at 5 days post-activation of CD4+ naive T cells and the expression level of MMP24OS at 5 days post-activation of CD4+ memory T cells were positively causally associated with the risk of sarcopenia; the expression levels of NDUFS3 at 16 and 40 hours post-activation of naive T cells were negatively causally associated with the risk of sarcopenia. (2) Colocalization analysis further indicated that the expression quantitative trait loci of RAB29, NDUFS3, and MMP24OS had possible causative variations with the genome-wide association study signals for sarcopenia. (3) The results of differential gene expression analysis demonstrated that compared with the healthy control group, the expression level of NDUFS3 in the sarcopenia group was dramatically downregulated, but there was no significant change in the expression levels of RAB29 and MMP24OS between the two groups. It is confirmed that NDUFS3 is a possible gene therapy target for sarcopenia with temporal regulatory properties in CD4+ T cells. This analysis is based on data from the European population. In the future, a Mendelian randomization analysis framework for dynamic expression quantitative trait loci can be introduced to create and formulate precise intervention methods for the temporal control of T cell activity based on the Chinese population.

Key words: ">">font-size:12px, ">sarcopenia, CD4+ T cells, expression quantitative trait loci, genome-wide association study, Mendelian randomization, therapeutic targets, Mendelian randomization analysis based on pooled data, co-localization analysis