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Insight into telomere regulation: road to discovery and intervention in plasma drug-protein targets

Kaixi Ding1, Juejue Zhangwang1,2, Ming Lei3

  • 1School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China.

BMC Genomics
|March 2, 2024
PubMed
Abstract

Insights

This study identified four key proteins—RPN1, GDI2, NT5C, and TYRO3—that causally influence telomere length. These proteins represent potential new drug targets for precision therapies related to aging and disease.

Area of Science:

  • Genetics and genomics
  • Biochemistry
  • Pharmacology

Background:

  • Telomere length is a crucial biomarker for aging, health, and disease.
  • Current drug target discovery for telomere length is limited, hindering therapeutic development.
  • Integrating large-scale genetic data offers new avenues for identifying relevant drug targets.

Purpose of the Study:

  • To identify novel drug target proteins associated with telomere length using genetic data.
  • To provide insights for precision therapy and targeted drug development.
  • To explore the causal relationships between plasma proteins and telomere length.

Main Methods:

  • Utilized Mendelian randomization (MR) with plasma cis-pQTLs and telomere length GWAS data (UK Biobank, n=472,174).
  • Performed external validation, reverse causality testing, and co-localization analysis.
  • Conducted phenome-wide association studies, enrichment analysis, and protein-protein interaction network construction.

Main Results:

  • Identified significant causal associations between RPN1, GDI2, NT5C, and TYRO3 with telomere length.
  • RPN1, GDI2, and NT5C showed a negative causal effect, while TYRO3 showed a positive causal effect.
  • GDI2 demonstrated shared genetic variants with telomere length, confirmed by co-localization analysis.

Conclusions:

  • Plasma proteins RPN1, GDI2, NT5C, and TYRO3 are genetically determined to have significant causal effects on telomere length.
  • These proteins represent promising candidates for future drug targets.
  • Further research is warranted to elucidate the mechanisms by which these proteins regulate telomere length.
Keywords:
Causal associationsMendelian randomizationProtein expression regulatory lociTarget proteinsTelomere length

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