Potential therapeutic targets for sarcopenia identified by Mendelian randomisation

Area of Science:

• Genetics
• Biochemistry
• Gerontology

Background:

• Sarcopenia, a geriatric condition, poses significant health challenges.
• Identifying causal plasma proteins is crucial for developing effective therapeutic targets for sarcopenia.

Purpose of the Study:

• To identify plasma proteins causally associated with sarcopenia risk using genetic data.
• To explore the therapeutic potential and clinical relevance of identified proteins.

Main Methods:

• Genome-wide association studies (GWAS) summary data and cis-protein loci genetic instruments were used for screening.
• Cis-Mendelian randomization (MR) and multiverse sensitivity analyses investigated causal effects.
• Druggability and clinical development of identified proteins were assessed.

Main Results:

• Four proteins (HPT, AT1B2, ISLR2, TNFSF12) showed causal associations with sarcopenia in the general population.
• AT1B2 and TNFSF12 were associated with sarcopenia in females; HGF showed a negative association.
• TNFSF12 and HGF were causally associated with appendicular lean mass (ALM) and are druggable, with inhibitors in clinical trials.

Conclusions:

• Five druggable plasma proteins demonstrate causal links to sarcopenia.
• TNFSF12 and HGF represent promising therapeutic targets for sarcopenia, with existing clinical trial data.
• The study provides insights into sarcopenia mechanisms and potential treatment strategies.