Identification of molecular mediators of renal sarcopenia risk: a mendelian randomization analysis

Observational studies have shown an association between reduced renal function and the risk of sarcopenia. However, the causal relationship and the underlying biological mechanisms remain uncertain. Using a Mendelian randomization (MR) framework, we investigated the causal role of 27 hypothetical risk mediators, including metabolites, hormones, inflammation, and stress traits, on the risk of sarcopenia.

Instrumental variables (IVs) to proxy renal function were identified by selecting single nucleotide polymorphisms (SNPs) reliably associated with creatinine and cystatin C-based glomerular filtration rate (GFR) in CKDGen summary data. IVs for putative risk traits and sarcopenia traits were constructed from relevant genome-wide association studies (GWAS). MR estimated effects were obtained using an inverse-variance weighted effects model, and various sensitivity analyses were performed. The mediating role of hypothetical risk factors in the relationship between GFR and sarcopenia was assessed through multivariate MR.

Genetically predicted reduced GFRcrea was associated with higher odds of appendicular lean mass (ALM) (odds ratio (OR): 0.64, 95% confidence interval (CI) 0.37 to 0.68) and grip strength (OR: 0.67; 95% CI 0.58 to 0.78). Likewise, GFRcys highlighted a causal relationship with ALM (OR: 0.52; 95% CI 0.42 to 0.65) and grip strength (OR: 0.66; 95% CI 0.59 to 0.74). Both estimated GFR (eGFR) were negatively associated with IGF-1, IL-16, 25(OH)D, triglycerides (range of effect size per standard deviation: -0.81 to -0.30), and positively correlated with HDL cholesterol (0.62, 0.31). There was a positive correlation between IGF-1, fasting insulin and ALM as well as grip strength (OR range: 1.04-1.67) and a negative correlation between serum CRP and ALM (OR: 0.95) as well as grip strength (OR: 0.98). Additionally, genetically predicted IL-1β (OR: 0.95) and total cholesterol (OR: 0.96) were negatively associated with ALM. We found evidence that IGF-1 mediates the relationship between eGFR and risk for muscle mass and strength.

This MR study provides insight into the potential causal mechanisms between renal function and the risk of sarcopenia and proposes IGF-1 as a potential target for the prevention of renal sarcopenia.