Genetically Predicted Levels of Serum Metabolites and Risk of Sarcopenia: A Mendelian Randomization Study.

Sha T ，Wang N ，Wei J ，He H ，Wang Y ，Zeng C ，Lei G ... -  《Nutrients》

Causality between sarcopenia and diabetic nephropathy: a bidirectional Mendelian randomization study.

Observational studies have shown that sarcopenia and diabetic nephropathy (DN), are closely related; however, the causal relationship is unclear. This study aims to address this issue using a bidirectional Mendelian randomization (MR) study. We data from genome-wide association studies including appendicular lean mass (n = 244,730), grip strength (right: n = 461,089, left: n = 461026), walking speed (n = 459,915), and DN (3283 cases and 181,704 controls) to conduct a bidirectional MR study. First, we conducted a Forward MR analysis to evaluate the causality of sarcopenia on the risk of DN from the genetic perspective with appendicular lean mass, grip strength, and walking speed as exposure and DN as the outcome. Then, DN as the exposure, we performed a Reverse MR analysis to determine whether DN impacted the appendicular lean mass, grip strength, and walking speed of the appendices. Finally, a series of sensitivity studies, such as heterogeneity tests, pleiotropy evaluations, and Leave-one-out analyses, were conducted to assess the MR analysis's accuracy further. According to a forward MR analysis, a genetically predicted decrease in appendicular lean mass is associated with an increased risk of developing DN risk (inverse variance weighting[IVW]: odd ratio [OR] = 0.863, 95% confidence interval [CI] 0.767-0.971; P = 0.014). According to reverse MR results, grip strength decreased as DN progressed (IVW: right β = 0.003, 95% CI: - 0.021 to - 0.009, P = 5.116e-06; left β = 0.003, 95% CI: - 0.024 to - 0.012, P = 7.035e-09). However, the results of the other MR analyses were not statistically different. Notably, our findings suggest that the causal relationship between sarcopenia and DN cannot be generalized. According to analysis of the individual characteristic factors of sarcopenia, reducing in appendicular lean mass increases the risk of developing DN and DN is linked to reduced grip strength. But overall, there is no causal relationship between sarcopenia and DN, because the diagnosis of sarcopenia cannot be determined by one of these factors alone.

Ren L ，Wang Y ，Ju F ，Sun M ，Gang X ，Wang G ... -  《Frontiers in Endocrinology》

Causality between urate levels with sarcopenia-related traits: a bi-directional Mendelian randomization study.

Observational studies have suggested associations between serum urate levels and sarcopenia, but the causality underlying this correlation remains uncertain. The principal objective of this study is to investigate a causal relationship of serum urate levels with sarcopenia-related traits (hand grip strength, lean mass, walking pace) using bidirectional two-sample Mendelian randomization (MR) approach. The utilization of MR methodology serves to minimize bias caused by reverse causality and confounding factors from observational studies. The summary statistics of serum urate levels were derived from a cohort consisting of 288,659 individuals participating in CKDGen study. The parameters of right-hand grip strength (N=461,089), left-hand grip strength (N=461,026), appendicular lean mass (ALM) (N=450,243), whole-body lean mass(N=454,850),right-leg fat-free mass(FFM;N=454,835),left-leg FFM(N=454,805), right-arm FFM(N=454,753),left-arm FFM(N=454,672) and walking pace (N=459,915)were sourced from the UK Biobank. MR analysis was conducted utilizing inverse variance weighted (IVW), weighted median, and MR-Egger to evaluate causality. Sensitivity analysis was performed using Cochran's Q test, MR-Egger intercept test, leave-one-out analysis and the funnel plot. IVW estimates demonstrated that serum urate levels exhibited no causal association with sarcopenia-related traits. In the inverse MR investigation, we had exclusively discerned an inverse correlation between walking pace and serum urate levels. No compelling evidence had surfaced to substantiate any association of other sarcopenia-related traits with serum urate. Supplemental MR methods consistently validated the findings obtained from the primary analysis. Sensitivity analysis demonstrated the robustness of findings. Our MR study revealed the absence of the bidirectional causal relationship between serum urate levels and sarcopenia. It is imperative to acknowledge that advanced age and an individual's health status are pivotal determinants influencing urate level and the initiation and advancement of sarcopenia. However, it is worth underscoring that these aspects remain unexamined within the purview of this study. Thus, future investigations should delve deeper into these intricate facets.

Lin Y ，Wang X ，Yao W ，Sun Y ，Zhou J ，Feng F ... -  《Frontiers in Endocrinology》

Exploring the causal link between circulating cytokines and sarcopenia traits: A Mendelian randomization analysis.

Previous observational studies have linked circulating cytokines to sarcopenia, but their causal relationship remains unclear. This study employed Mendelian Randomization (MR) to investigate the causal links between circulating cytokines and sarcopenia-related traits using genetic data. A two-sample bidirectional MR analysis was conducted using data from individuals of European ancestry, utilizing genome-wide association studies (GWAS) statistics. The study selected instrumental single nucleotide polymorphisms (SNPs) significantly associated with circulating cytokines and applied multiple MR methods, including inverse variance weighted (IVW), Weighted Median, MR-Egger, Weighted Mode, Simple Mode, and MR-PRESSO. The traits analyzed were appendicular lean mass (ALM) and grip strength. Heterogeneity, robustness, and consistency of results were assessed using Cochran's Q statistic, MR-Egger regression, and "leave-one-out" sensitivity analyses. The IVM-MR analysis showed a casual association between genetically predicted circulating levels of interleukin-16 and both ALM and grip strength (ALM: OR = 0.990, 95% CI: 0.980-1.000, p = .049; grip strength: OR = 0.971, 95% CI: 0.948-0.995, p = .020). Additionally, interferon-gamma-induced protein 10 (IP-10), interleukin-1-beta (IL-1β), and hepatocyte growth factor (HGF) were correlated with ALM and vascular endothelial growth factor (VEGF), interleukin-12 (IL-12), and interleukin-5 (IL-5) with grip strength. Comparable results were confirmed via the MR-Egger, Weighted Median, Weighted Mode, and Simple Mode methods. Sensitivity analysis showed no horizontal pleiotropy to bias the causal estimates. The results suggest a significant causal effect of inflammatory cytokines on sarcopenia, offering new avenues for therapeutic target development. However, the study's focus on a European ancestry cohort limits its generalizability to other populations. Future research should aim to include diverse ethnic groups to validate and broaden these findings, thereby enhancing our understanding of sarcopenia's mechanisms in a global context.

Di W ，Luyao Y ，Chengwei Y ，Valtonen AM ，Juha-Pekka K ，Ying G ... -  《-》

Bidirectional two-sample mendelian randomization analysis identifies causal associations between age at menarche and sarcopenia-related traits.

Observational studies have shown that the age of menarche is associated with sarcopenia, but confounding factors make the causal relationship difficult to infer. Therefore, we conducted a bidirectional two-sample Mendelian randomized (MR) analysis to evaluate the potential causal relationship between age at menarche and sarcopenia-related traits (hand grip strength, lean mass, walking pace). We obtained the latest aggregate statistics from the Genome-wide association studies (GWAS) database on the age of menarche of 182,416 participants from ReproGen, the appendicular lean mass of 244,730 participants from EMBL's European Bioinformatics Institute, the left-hand grip strength of 401,026 participants, the right-hand grip strength of 461,089 participants and the usual walking pace of 459,915 participants from the UK Biobank. The inverse variance weighting (IVW) method and other MR methods were used to evaluate the bidirectional causal relationship between the age of menarche and sarcopenia. The forward MR results showed that the age of menarche predicted by the gene was positively correlated with left-hand grip strength (IVWβ=0.041, P = 2.00 × 10-10), right-hand grip strength (IVWβ=0.053, P = 1.97 × 10-18), appendicular lean mass (IVWβ=0.012, P = 4.38 × 10-13) and usual walking pace (IVWβ=0.033, P = 1.62 × 10-8).In the reverse MR analysis, we also found that the usual walking pace was positively correlated with the age of menarche predicted by genes (IVWβ=0.532, P = 1.65 × 10-4). Still, there was no causal relationship between grip strength and appendicular lean mass and the age at menarche. Our results show that earlier menarche will increase the risk of sarcopenia. In addition, people with higher muscle function tend to have menarche later. These findings may provide a reference for prevention strategies and interventions for menarche in advance and sarcopenia.

Fan W ，Gu P ，Pu B ，Yue D ，Xin Q ，Zheng X ，Zeng Z ，Fan S ... -  《-》