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

Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Keywords

• Mendelian randomization
• Renal function
• Sarcopenia
• Grip strength
• Appendicular lean mass
• GFR