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Dissecting Immune Mechanisms Underlying Sarcopenia Using Multi-omics Approaches.

Kaixi Ding1,2, Wei Jiang3, Ming Lei4

  • 1School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China. jerryding21@stu.cdutcm.edu.cn.

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Summary

This study reveals immune cell gene regulation

Keywords:
Immune cellsMediation analysisMendelian randomizationSarcopeniaSingle-cell expression quantitative trait loci

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Area of Science:

  • Genetics
  • Immunology
  • Gerontology

Background:

  • Sarcopenia is an age-related muscle disease with poorly understood gene regulation in immune cells.
  • Investigating immune cell gene expression is crucial for understanding sarcopenia pathogenesis.

Purpose of the Study:

  • To systematically explore the causal roles of immune cell-specific gene expression in sarcopenia.
  • To identify potential therapeutic targets and mechanistic insights for sarcopenia.

Main Methods:

  • Integrated immune cell-specific expression quantitative trait loci (sc-eQTLs), genome-wide association studies (GWAS), and multi-omics data.
  • Employed Mendelian randomization (MR), Bayesian colocalization, and genetic structural equation modeling (GSEM) across 14 immune cell types, whole blood, and skeletal muscle.
  • Utilized two-step MR to investigate mediation pathways through common diseases and carnitine metabolites.

Main Results:

  • Identified 14 genes, including HLA-DRB1, HLA-C, and SLC22A5, with significant causal effects on sarcopenia phenotypes in immune cells.
  • Discovered mediation of causal effects by heart failure, rheumatoid arthritis, and chronic kidney disease for specific genes.
  • Found that isovalerylcarnitine (C5) mediates the causal effect of SLC22A5 in skeletal muscle on sarcopenia, with a substantial mediation proportion.

Conclusions:

  • Immune cell-specific gene expression of HLA-DRB1, HLA-C, SLC22A5, and FNBP4 contributes to sarcopenia development.
  • These genes represent potential therapeutic targets for combating age-related muscle loss.
  • The study provides novel mechanistic insights into sarcopenia pathogenesis involving immune and metabolic pathways.