It is suggested that genetically predicted increased WP exerts beneficial effects against HF, partially mediated by obesity and sedentary habits, and targeting weight management and anti-sedentary interventions may mitigate HF risk in individuals with sarcopenia-related characteristics.
Abstract
Background
In this two-sample, two-step Mendelian randomization (MR) study, we aimed to elucidate the causal associations between sarcopenia-related characteristics and heart failure (HF) risk, and to identify the factors mediating these associations, with a particular focus on the mediating roles of obesity and sedentary habits.
Methods
Genetic instruments for appendicular lean mass (ALM), hand grip strength (HGS), walking pace (WP) and potential mediators were extracted from genome-wide association studies (GWASs). Inverse-variance weighting (IVW) was used as the primary analytical method, supplemented by MR-Egger regression, weighted median, and weighted mode analyses. Sensitivity analyses including Cochran's Q test and MR-Egger intercept method were performed to assess heterogeneity and pleiotropy. Bidirectional MR was conducted to exclude reverse causation.
Results
IVW revealed that a faster genetically predicted walking pace (WP) was associated with lower HF risk (odds ratio [OR] 0.44, 95% confidence interval [CI] 0.33-0.60, P = 5.806 × 10-7). The mediation analysis indicated that body mass index accounted for 32% of this effect, while time spent watching television accounted for 14%. Elevated appendicular lean mass showed a slight but significant positive association with HF risk (OR 1.06, 95% CI 1.03-1.09, P = 5.437 × 10-4). However, multivariable MR adjusting for BMI completely attenuated this association (P = 0.693), suggesting ALM reflects overall body composition rather than isolated muscle mass. No significant associations were found between HGS and HF. Bidirectional MR showed no robust reverse effects.
Conclusions
These findings suggest that genetically predicted increased WP exerts beneficial effects against HF, partially mediated by obesity and sedentary habits. Targeting weight management and anti-sedentary interventions may mitigate HF risk in individuals with sarcopenia-related characteristics.
Objective This study used two-sample Mendelian Randomization to investigate the causal link between multiple biological aging indicators and vascular disease. Methods Summary genetic data was obtained from genome-wide association studies (GWAS) focusing on aging-related exposures and various vascular disease outcomes. The exposures included granulocyte proportions, PAI-1 (plasminogen activator inhibitor-1), telomere lengths, and the Frailty Index. The primary analysis employed the Inverse Variance Weighted (IVW) method to estimate causal relationships, supported by MR-Egger, weighted median, and weighted mode methods. Sensitivity analyses, including Cochran’s Q test, MR-Egger regression, leave-one-out test, and the MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) test, were conducted to evaluate heterogeneity and pleiotropy. Results The analysis revealed distinct pathways after sensitivity adjustments. A higher genetically predicted Frailty Index was associated with an increased risk of abdominal aortic aneurysm (OR=2.5935, 95% CI: 1.3936–4.8268, P=0.0026, false discovery rate (FDR)=0.0475), atherosclerosis excluding cerebral and coronary sclerosis (OR=2.0262, 95% CI:1.5179–2.705, P=1.66×10-6, FDR=1×10-4), and arterial thromboembolic events (OR = 4.0306, 95% CI: 1.7133–9.4818, P = 0.0014, FDR = 0.0337). Conversely, longer telomere length demonstrated a strong, specific protective effect against abdominal aortic aneurysm (OR=0.5008, 95% CI:0.4111–0.6100, P=6.42×10-12, FDR=9.25×10-10), indicating that shorter telomere length is associated with an increased risk of AAA. Furthermore, a lower granulocyte proportion was causally linked to an increased risk of thoracic aortic aneurysm (OR=0.0181, 95% CI: 0.0014–0.2376, P=0.0023, FDR=0.0465). Conclusion This study identifies three genetic pathways linking biological aging to vascular disease, offering new molecular targets for its prevention and treatment.
Hao Yan, Shang Wei, Hui Hui et al.· Clinical and applied thrombo...· 0 citations
Objective: Genetic factors contribute to physical activity (PA) and sedentary behavior (SB), two complex behavioral traits. They may be associated with musculoskeletal and inflammatory diseases. However, the relationships of domain-specific PA and SB traits with osteoporosis (OS), psoriatic arthritis (PsA), and rheumatoid arthritis (RA) remain unclear. A two-sample Mendelian randomization (MR) analysis assessed potential bidirectional associations between these behavioral traits and the three diseases. Methods: GWAS summary statistics were used to examine five domain-specific PA traits, three SB traits, and OS, RA, and PsA. Primary causal estimates were obtained using the inverse-variance weighted (IVW) method. Complementary analyses used MR-Egger regression, the weighted median method, and the weighted mode method. Sensitivity analyses were performed using Cochran’s Q test, the MR-Egger intercept test, MR-PRESSO, and leave-one-out analysis. Multiple testing was addressed using false discovery rate (FDR) correction. Results: In the forward MR analyses, genetically predicted liability to Light DIY was associated with lower odds of PsA after FDR correction (OR = 0.006, 95% CI = 0.0002–0.236, FDR-adjusted p = 0.018). Genetically predicted longer television viewing was linked to increased odds of PsA (OR = 2.205, 95% CI = 1.089–4.463, FDR-adjusted p = 0.028) and RA (OR = 1.006, 95% CI = 1.002–1.010, FDR-adjusted p = 0.004). Walking for pleasure showed a nominal inverse association with PsA, and computer use showed a nominal inverse association with RA. Neither association remained significant after FDR correction. No evidence of associations with the broad self-reported OS diagnosis was observed. Reverse MR analyses showed lower odds of Walking for pleasure (OR = 0.662, 95% CI = 0.484–0.906, FDR-adjusted p = 0.013) and Other exercises (OR = 0.651, 95% CI = 0.490–0.864, FDR-adjusted p = 0.006) for genetic liability to RA. RA liability was also associated with longer television viewing time (β = 0.708, 95% CI = 0.251–1.165, FDR-adjusted p = 0.006). No reverse associations were observed for PsA. Conclusions: This bidirectional MR study identified several potential genetically predicted associations of domain-specific PA and SB traits with PsA and RA. The findings for television viewing and RA may suggest a potential bidirectional association. However, the results should be considered hypothesis-generating. These findings require independent replication and further validation before causal or clinical conclusions can be drawn.
Tianyu Sun, Fei-Yao Zhang, Chang Liu et al.· Genes· 0 citations
Background Sarcopenia is observationally linked to venous thromboembolism, but the causal architecture and underlying biological pathways remain largely unclear. This study investigated the causal effects of sarcopenia-related traits on lower extremity deep vein thrombosis (DVT) and quantified potential mediating mechanisms. Methods We performed two-sample bidirectional Mendelian randomization (MR) and two-step mediation MR using large-scale GWAS data from UK Biobank, EMBL-EBI, and FinnGen. Exposures included appendicular lean mass (ALM), leg fat-free mass (LFM), hand grip strength, and walking pace. Eighteen candidate mediators were screened for indirect pathways. Results Genetically predicted higher ALM was significantly associated with increased DVT risk (FinnGen: OR = 1.288, 95% CI: 1.215–1.365, P < 0.001). Similar positive associations were observed for LFM (OR = 1.920–1.954, P < 0.001). By contrast, muscle functional traits - grip strength and walking pace - demonstrated no consistent causal effects. Reverse MR confirmed a unidirectional relationship. Body mass index (BMI) emerged as a pivotal mediator, accounting for 7.58% – 10.50% of the ALM–DVT effect and 52.74% – 62.73% of the LFM–DVT effect. Notably, the independent effect of ALM was largely attenuated after adjusting for metabolic confounders in multivariable MR. Conclusion Genetic predisposition to high muscle mass, rather than functional strength, increases DVT risk. This relationship appears to be significantly driven by metabolic adiposity, suggesting that the “muscle–vascular–coagulation” interaction is partly explained by body-size-related metabolic burden. Risk stratification should integrate muscle mass evaluation with comprehensive metabolic health assessments.
Qi-Xiang Sun, Yi-Ming Hu, Zhen-Yong Yang et al.· Clinical and applied thrombo...· 0 citations
Objective This study aimed to investigate the potential causal relationships between chronic pain and three key sarcopenia-related quantitative traits: (a) hand grip strength; (b) usual walking pace; and (c) appendicular lean mass, using bidirectional two-sample Mendelian randomization. Methods We conducted bidirectional two-sample Mendelian randomization using summary-level data from large-scale genome-wide association studies to assess the genetically predicted associations between chronic pain, including multisite chronic pain and chronic widespread musculoskeletal pain, and the aforementioned sarcopenia-related traits. Results Mendelian randomization revealed that multisite chronic pain was significantly associated with an increased risk of low hand grip strength (odds ratio = 1.70; p < 0.001) and decreased usual walking pace (odds ratio = 0.81; p < 0.001); chronic widespread musculoskeletal pain was also significantly associated with decreased usual walking pace (odds ratio = 0.15; p < 0.001). Additionally, higher left hand grip strength was significantly associated with a lower risk of multisite chronic pain (odds ratio = 0.90; p< 0.001) and chronic widespread musculoskeletal pain (odds ratio = 0.99; p = 0.002); higher right hand grip strength was significantly associated with a lower risk of multisite chronic pain (odds ratio = 0.91; p = 0.002); and higher usual walking pace was significantly associated with a lower risk of multisite chronic pain (odds ratio = 0.49; p < 0.001) and chronic widespread musculoskeletal pain (odds ratio = 0.92; p < 0.001). No significant causal associations were detected for appendicular lean mass in either direction (all p > 0.05). Conclusion This study provides genetic evidence supporting potential causal links between chronic pain and key phenotypic components of sarcopenia.
Wei-Jie Wang, Qiankun Zhang, Zhenhua Wu· Journal of International Med...· 0 citations
AIMS/BACKGROUND
Coronary artery disease (CAD) has been epidemiologically linked to idiopathic pulmonary fibrosis (IPF); however, the genetic basis of this association remains unclear. Therefore, this study aims to investigate the potential causal relationships between IPF and CAD using a bidirectional two-sample Mendelian randomization (MR) strategy.
METHODS
Inverse-variance weighted (IVW), MR-Egger, weighted median, and weighted mode approaches were applied to summary statistics obtained from CAD and IPF genome-wide association studies. Heterogeneity among instrumental variables was assessed using Cochran's Q test. Pleiotropy was assessed using MR-Egger regression and MR pleiotropy residual sum and outlier (MR-PRESSO) analyses. Additionally, the robustness and reliability of the findings were validated by applying a leave-one-out analysis.
RESULTS
The forward MR analysis revealed no evidence supporting a genetic causal association between IPF and CAD (odds ratio [OR] = 0.989, 95% confidence interval [CI]: 0.967-1.010, p = 0.305) after excluding an outlier single-nucleotide polymorphism (SNP) (rs7725218). However, reverse MR analysis demonstrated a significant negative genetic causal association between CAD and IPF (OR = 0.832, 95% CI: 0.711-0.975, p = 0.023). Sensitivity analysis revealed heterogeneity in the forward MR analysis, which was resolved after excluding an outlier SNP, with no evidence of horizontal pleiotropy detected.
CONCLUSION
This study demonstrates a potential negative genetic influence of CAD on the risk of IPF, providing valuable insights that may guide the development of more enhanced preventive and therapeutic strategies. Future research should further assess the interactions between CAD and IPF to improve disease management and patient outcomes.
Li-Rui Yang, Xin Zhao, Tingting Feng et al.· British journal of hospital...· 0 citations
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