logo logo
Causal associations of plasma omega-3 polyunsaturated fatty acids with sarcopenia-related traits: a two-sample Mendelian randomization study. European journal of clinical nutrition OBJECTIVE:To evaluate the causal effect of plasma omega-3 polyunsaturated fatty acids (PUFAs) on sarcopenia-related traits (lean mass, grip strength and walking pace) utilizing two-sample Mendelian randomization (MR) approach. METHODS:Based on genome-wide association study (GWAS) summary statistics, we performed two-sample MR applying the inverse variance weighted (IVW) as the primary method, supplemented with four additional sensitivity analyses. Furthermore, multivariable MR (MVMR) was applied to assess these associations independent of alcohol drinking, type 2 diabetes (T2D), triglycerides (TG), estimated glomerular filtration rate (eGFR) and C-reactive protein (CRP). RESULTS:In univariable MR, the IVW analysis suggested no significant causal effect of genetically determined plasma omega-3 PUFAs on fat-free mass (right leg: β = 0.01, 95% CI = -0.02 to 0.05, P = 0.375; left leg: β = 0.01, 95% CI = -0.02 to 0.04, P = 0.446; right arm: β = 0.01, 95% CI = -0.02 to 0.05, P = 0.376; left arm: β = 0.01, 95% CI = -0.02 to 0.04, P = 0.384; trunk:β = 0.02, 95% CI = -0.02 to 0.06, P = 0.283; whole: β = 0.01, 95% CI = -0.03 to 0.04, P = 0.631), grip strength (right hand: β = -0.01, 95% CI = -0.03 to 0.01, P = 0.387; left hand: β = -0.01, 95% CI = -0.02 to 0.01, P = 0.553) and walking pace (β = 0.00, 95% CI = -0.01 to 0.02, P = 0.575), and sensitive analysis generated similar non-significant results. Furthermore, the MVMR revealed no independent causal association. CONCLUSIONS:Genetically determined plasma omega-3 PUFAs have no causal effect on sarcopenia-related traits. 10.1038/s41430-023-01339-y
The relationship between lifestyles and sarcopenia-related traits: A two-sample Mendelian randomization study. Archives of gerontology and geriatrics OBJECTIVE:To investigate the causal association between lifestyles (smoking, drinking consumption and physical activity) and sarcopenia-related traits by Mendelian randomized analysis. METHODS:Instrumental variables from the genome-wide association study were used for analysis. The exposure factors were lifestyle factors, including smoking, alcohol consumption, moderate physical activity and vigorous physical activity, and the outcome variables were low hand grip strength and appendicular lean mass. The inverse variance weighted (IVW) method and other MR methods were used for analysis. Heterogeneity test, sensitivity analysis and pleiotropy analysis were performed. RESULTS:According to a primary causal effects model with MR analyses by the IVW method, smoking was a decreased risk of low hand grip strength (odds ratio (OR) = 0.899, 95% confidence interval (CI) = 0.829-0.974, P = 0.010), while alcohol consumption was a significant correlation with low hand grip strength (OR = 1.137, 95% CI = 1.020-1.267, P = 0.020). There was no significant relationship between smoking, alcohol, and appendicular lean mass. In addition, moderate or vigorous physical showed no significant correlation with low hand grip strength and appendicular lean mass. CONCLUSION:This study demonstrated that smoking may be causally related to a lower risk of low hand grip strength, while alcohol may increase the risk of low hand grip strength. There was no causal relationship between physical activity and sarcopenia-related traits. 10.1016/j.archger.2023.105169
The causal relationships between iron status and sarcopenia in Europeans: a bidirectional two-sample Mendelian randomization study. European journal of clinical nutrition BACKGROUND:Previous studies have indicated potential associations between metals, lifestyle factors, and sarcopenia. However, the specific causal relationships between iron status, lifestyle factors, and sarcopenia remain unclear. Therefore, we conducted a bidirectional two-sample Mendelian Randomization (MR) approach to investigate these relationships. METHODS:The exposure variables included iron status, living alone, coffee intake, alcohol taken with meals, and moderate physical activity, while the outcome variable was sarcopenia, assessed by grip strength in both hands and usual walking pace. We employed the Weighted Median (WM), the Inverse Variance-Weighted (IVW), and other MR methods to explore these problems for analysis. Simultaneously, we conducted a bidirectional MR analysis to assess whether sarcopenia has a reverse causal relationship with internal iron status. RESULTS:In our present research, we found serum iron (P = 0.033), ferritin (P = 0.001), transferrin saturation (P = 0.029) and coffee intake (P = 0.002) revealed a negative trend for sarcopenia, living alone (P = 0.022) and alcohol taken with meal (P = 0.006) showed a opposite trend for sarcopenia. Whereas sarcopenia showed negative trend for ferritin (P = 0.041) and transferrin saturation (P = 0.043), showed the opposite trend for transferrin (P = 0.021). CONCLUSION:Our study suggested that higher serum iron levels might reduce the risk of sarcopenia. Moreover, living alone and alcohol consumption might increase the sarcopenia risk, while coffee intake and moderate physical activity could reduce the sarcopenia risk. 10.1038/s41430-024-01531-8
Identifying the Shared Metabolite Biomarkers and Potential Intervention Targets for Multiple Sarcopenia-Related Phenotypes. International journal of molecular sciences The relationship between circulating metabolites and sarcopenia-related phenotypes remains unclear. We explored the causality between circulating metabolites and sarcopenia-related phenotypes. Instrumental variables for the human metabolome were derived from the recently published GWAS, which included 690 plasma metabolites. Summary statistics for four sarcopenia phenotypes (whole-body lean mass (WBLM), usual walking pace, appendicular lean mass (ALM), and handgrip strength (HGS)) (both sexes, males and females) were obtained from relevant GWASs. We used MR to evaluate the association between circulating metabolites and sarcopenia-related phenotypes. Colocalization analysis was utilized to determine whether two associated signals were consistent with a shared causal variant rather than the confounding effect of linkage disequilibrium. Subsequently, we explored associations between modifiable risk factors and sarcopenia-related metabolites to explore which metabolites may serve as potential intervention targets through lifestyle modification. Genetically predicted plasma levels of 95 known metabolites were associated with sarcopenia-related phenotypes, and 27 metabolites were supported by robust evidence of colocalization, among which 13 metabolites had a cross-sarcopenia effect. These metabolites primarily included acyl carnitines, amino acids and their derivatives, and phospholipids. Specifically, our analyses supported causal relationships between 23, 6, and 15 metabolites and ALM, HGS, and WBLM, respectively. Seven relevant metabolites might be associated with six modifiable factors. We identified 27 metabolite biomarkers with robust causal evidence for sarcopenia-related phenotypes, highlighting 13 metabolites with a cross-sarcopenia effect, and prioritized several metabolites as the potential interventional targets of lifestyle changes. Our study provided new insight into the etiology and prevention of sarcopenia. 10.3390/ijms252212310
C-Reactive Protein Level as a Novel Serum Biomarker in Sarcopenia. Mediators of inflammation Background:The role of C-reactive protein (CRP), an inflammatory marker, in the development of sarcopenia remains uncertain. Methods:This cross-sectional research involved the enrollment of 207 patients, classified into two groups: 74 patients with sarcopenia and 133 patients without sarcopenia. Clinical data of the participants, including hand grip strength, walking speed, appendicular lean mass (ALM), and calf circumference, were collected and recorded. We evaluated the extent to which CRP levels are associated with the risk of sarcopenia using both univariate and multivariate logistic regression models. Besides, the correlation between CRP levels, hand grip strength, ALM, and walking speed was examined using the Spearman rank correlation test. Moreover, we have employed the Mendelian randomization (MR) analysis technique to explore the causal relationship between CRP levels and the occurrence of sarcopenia. Results:The sarcopenia group showed a higher proportion of older women, with significant differences in anemia prevalence, calf circumference, gait speed, ALM, hand grip strength, and elevated CRP levels compared to the control group. Logistic regression analyses identified CRP as an independent risk factor for sarcopenia (OR: 1.151, 95% CI:1.070-1.238, and < 0.001). Correlation analysis results revealed a noteworthy inverse association with hand grip strength ( = -0.454 and < 0.001), ALM ( = -0.426 and < 0.001), and walking speed ( = -0.431 and < 0.001). MR analysis provided further evidence of a significant detrimental link between genetically predicted CRP levels and essential sarcopenia characteristics, with consistent results across various statistical models. Conclusions:Our study uncovered strong evidence supporting a noteworthy inverse association and causality between CRP concentrations and sarcopenia, indicating that CRP has the potential to serve as a biomarker for sarcopenia. 10.1155/2024/3362336
Causal Relationship Between Circulating Metabolites and Sarcopenia-Related Traits: A Mendelian Randomization and Experimental Study. Food science & nutrition Sarcopenia (SP), an age-associated condition marked by muscle weakness and loss has been strongly connected with metabolic factors according to substantial evidence. Nevertheless, the causal correlation between SP and serum metabolites, and the biological signaling pathways involved, is still not well understood. We performed a bidirectional two-sample Mendelian randomization (MR) analysis to examine the causal relationships between 1091 levels and 309 ratios of metabolites with SP traits, alongside investigating the relevant biological signaling pathways. Additionally, we explored the differential expression of plasma metabolites and potential biological signaling pathways in an animal model of SP. When SP was utilized as the outcome, we identified 11 robust causal associations between seven metabolite levels/ratios and SP-related traits using Bonferroni's correction (threshold:  < 0.05). We verified the stable causal association of glycine levels and SP in the validation. As for the reverse MR analysis, there were 11 strong causal relationships with 11 plasma metabolite levels/ratios remaining after multiple contrast correction. Additionally, biological signaling pathway analysis showed that glycine metabolism, insulin resistance, and cAMP signaling pathways may contribute to the connection between metabolites and SP. Mendelian validation of various datasets and observations in animal serum metabolomics suggests a strong association between glycine metabolism and SP. Our results indicate that the identified metabolites and biosignaling pathways could serve as important circulatory metabolic biomarkers for the screening and prevention of SP in clinical settings. Additionally, they represent potential molecules for future exploration of mechanisms and selection of drug targets. 10.1002/fsn3.4624
Comment on 'Systematic Druggable Genome-Wide Mendelian Randomization Identifies Therapeutic Targets for Sarcopenia' by Yin et al.-The Author's Reply. Journal of cachexia, sarcopenia and muscle 10.1002/jcsm.13652
Comment on 'Causal linkage of tobacco smoking with ageing: Mendelian randomization analysis towards telomere attrition and sarcopenia' by Park et al. Journal of cachexia, sarcopenia and muscle 10.1002/jcsm.13279
Comment on 'Systematic Druggable Genome-Wide Mendelian Randomization Identifies Therapeutic Targets for Sarcopenia' by Yin Et Al. Journal of cachexia, sarcopenia and muscle 10.1002/jcsm.13589
Ischemic stroke and sarcopenia have an asymmetric bidirectional relationship based on a two-sample Mendelian randomization study. Frontiers in neurology Background:We investigated the potential relationship between age-related conditions, particularly sarcopenia and ischemic stroke (IS), through a two-sample Mendelian randomization (MR) study. Methods:We conducted a two-sample bidirectional MR study to investigate the relationship between sarcopenia and stroke. Genetic instruments for sarcopenia were derived from the UK Biobank, while data on IS and its subtypes were obtained from the MEGASTROKE consortium. Inverse variance weighting (IVW) served as the primary analytical method. Additionally, heterogeneity and pleiotropy were assessed to ensure the robustness of the findings. Results:The analysis indicates a negative correlation between appendicular lean mass (ALM) and small vessel stroke (SVS; OR = 0.790, 95% CI: 0.703-0.888,  < 0.001), a positive correlation with cardioembolic stroke (CES; OR = 1.165, 95% CI: 1.058-1.284,  = 0.002), and no causal relationship with any ischemic stroke (AIS) or large artery stroke (LAS). Additionally, SVS is negatively associated with right-hand grip strength (OR = 0.639, 95% CI: 0.437-0.934,  = 0.021), while AIS, LAS, and CES do not exhibit a causal relationship with grip strength. Furthermore, no causal relationship was identified between left-hand grip strength, usual walking pace, and IS or its subtypes. MR analysis reveals only a negative association between CES and usual walking pace (OR = 0.989, 95% CI: 0.980-0.998,  = 0.013), with no associations found between other IS subtypes and sarcopenia-related traits. Conclusion:This study demonstrates that a reduction in ALM and right-hand grip strength is associated with SVS, whereas decreased ALM may serve as a protective factor against CES. Conversely, our analysis suggests that CES can impact walking speed. Overall, these findings provide valuable insights into the prevention and treatment of these conditions. 10.3389/fneur.2024.1427692
Causal roles of circulating cytokines in sarcopenia-related traits: a Mendelian randomization study. Frontiers in endocrinology Background:Epidemiological and experimental evidence suggests that chronic inflammation plays an important role in the onset and progression of sarcopenia. However, there is inconsistent data on the inflammatory cytokines involved in the pathogenesis of sarcopenia. Therefore, we performed a two-sample Mendelian randomization (MR) analysis to explore the causal relationship between circulating cytokines and sarcopenia-related traits. Methods:The MR analysis utilized genetic data from genome-wide association study that included genetic variations in 41 circulating cytokines and genetic variant data for appendicular lean mass (ALM), hand grip strength, and usual walking pace. Causal associations were primarily explored using the inverse variance-weighted (IVW) method, supplemented by MR-Egger, simple mode, weighted median, and weighted mode analyses. Additionally, sensitivity analyses were also performed to ensure the reliability and stability of the results. Results:Three cytokines [hepatocyte growth factor (HGF), interferon gamma-induced protein 10 (IP-10), and macrophage colony-stimulating factor (M-CSF)] were positively associated with ALM (β: 0.0221, 95% confidence interval (CI): 0.0071, 0.0372, = 0.0039 for HGF; β: 0.0096, 95%CI: 4e-04, 0.0189, = 0.0419 for IP-10; and β: 0.0100, 95%CI: 0.0035, 0.0165, = 0.0025 for M-CSF). Conversely, higher levels of interleukin-7 (IL-7), monocyte chemotactic protein 3 (MCP-3), and regulated on activation, normal T cell expressed and secreted (RANTES) were associated with decreased hand grip strength (β: -0.0071, 95%CI: -0.0127, -0.0014, = 0.0140 for IL-7; β: -0.0064, 95%CI: -0.0123, -6e-04, = 0.0313 for MCP-3; and β: -0.0082, 95%CI: -0.0164, -1e-04, = 0.0480 for RANTES). Similarly, interleukin 1 receptor antagonist (IL-1RA) was negatively correlated with usual walking pace (β: -0.0104, 95%CI: -0.0195, -0.0013, = 0.0254). Sensitivity analysis confirmed the robustness of these findings. Conclusions:Our study provides additional insights into the pivotal role of specific inflammatory cytokines in the pathogenesis of sarcopenia. Further research is required to determine whether these cytokines can be used as targets for the prevention and treatment of sarcopenia. 10.3389/fendo.2024.1370985
Comment on "Causal linkage of tobacco smoking with ageing: Mendelian randomization analysis towards telomere attrition and sarcopenia" by Park et al. - The authors reply. Journal of cachexia, sarcopenia and muscle 10.1002/jcsm.13385
The association of appendicular lean mass and grip strength with low-density lipoprotein, very low-density lipoprotein, and high-density lipoprotein particle diameter: a Mendelian randomization study of the UK Biobank cohort. European heart journal open Aims:Reduced muscle mass and reduced strength are frequently associated with both alterations in blood lipids and poorer cardiometabolic outcomes in epidemiological studies; however, a causal association cannot be determined from such observations. Two-sample Mendelian randomization (MR) was applied to assess the association of genetically determined appendicular lean mass (ALM) and handgrip strength (HGS) with serum lipid particle diameter. Methods and results:Mendelian randomization was implemented using summary-level data from the largest genome-wide association studies on ALM ( = 450 243), HGS ( = 223 315), and lipoprotein [low-density lipoprotein (LDL), very LDL (VLDL), and high-density lipoprotein (HDL)] particle diameters ( = 115 078). Inverse variance-weighted (IVW) method was used to calculate the causal estimates. Weighted median-based method, MR-Egger, and leave-one-out method were applied as sensitivity analysis. Greater ALM had a statistically significant positive effect on HDL particle diameter (MR-Egger: = 0.055, SE = 0.031, = 0.081; IVW: = 0.068, SE = 0.014, < 0.001) and a statistically significant negative effect on VLDL particle diameter (MR-Egger: = -0.114, SE = 0.039, = 0.003; IVW: = -0.081, SE = 0.017, < 0.001). Similarly, greater HGS had a statistically significant positive effect on HDL particle diameter (MR-Egger: = 0.433, SE = 0.184, = 0.019; IVW: = 0.121, SE = 0.052, = 0.021) and a statistically significant negative effect on VLDL particle diameter (MR-Egger: = -0.416, SE = 0.163, = 0.011; IVW: = -0.122, SE = 0.046, = 0.009). There was no statistically significant effect of either ALM or HGS on LDL particle diameter. Conclusion:There were potentially causal associations between both increasing ALM and HGS and increasing HDL particle size and decreasing VLDL particle size. These causal associations may offer possibilities for interventions aimed at improving cardiovascular disease risk profile. 10.1093/ehjopen/oeae019
Putative Candidate Drug Targets for Sarcopenia-Related Traits Identified Through Mendelian Randomization Analysis of the Blood Proteome. Frontiers in genetics The increasing prevalence of sarcopenia remains an ongoing challenge to health care systems worldwide. The lack of treatments encouraged the discovery of human proteomes to find potential therapeutic targets. As one of the major components of the human proteome, plasma proteins are functionally connected with various organs of the body to regulate biological processes and mediate overall homeostasis, which makes it crucial in various complex processes such as aging and chronic diseases. By performing a systematic causal analysis of the plasma proteome, we attempt to reveal the etiological mechanism and discover drug targets for sarcopenia. By using data from four genome-wide association studies for blood proteins and the UK Biobank data for sarcopenia-related traits, we applied two-sample Mendelian randomization (MR) analysis to evaluate 310 plasma proteins as possible causal mediators of sarcopenia-related traits: appendicular lean mass (ALM) and handgrip strength (right and left). Then we performed a two-sample bidirectional Mendelian randomization analysis for the identified putatively causal proteins to assess potential reverse causality that the trait values may influence protein levels. Finally, we performed phenome-wide MR analysis of the identified putatively causal proteins for 784 diseases to test the possible side effects of these proteins on other diseases. Five plasma proteins were identified as putatively causal mediators of sarcopenia-related traits. Specifically, leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2), asporin (ASPN), and contactin-2 (CNTN2) had potential causal effects on appendicular lean mass, and ecto-ADP-ribosyltransferase 4 (ART4) and superoxide dismutase 2 (SOD2) had putative causal effects on the handgrip strength, respectively. None of the five putatively causal proteins had a reverse causality relationship with sarcopenia-related traits, and no side effects on other diseases were identified. We identified five plasma proteins that may serve as putatively potential novel drug targets for sarcopenia. Our study attested to the value of two-sample MR analysis in identifying and prioritizing putatively potential therapeutic targets for complex diseases. 10.3389/fgene.2022.923429
Causal relationship between sarcopenia with osteoarthritis and the mediating role of obesity: a univariate, multivariate, two-step Mendelian randomization study. BMC geriatrics BACKGROUND:Recent genetic evidence supports a causal role for sarcopenia in osteoarthritis, which may be mediated by the occurrence of obesity or changes in circulating inflammatory protein levels. Here, we leveraged publicly available genome-wide association study data to investigate the intrinsic causal relationship between sarcopenia, obesity, circulating inflammatory protein levels, and osteoarthritis. METHODS:In this study, we used Mendelian randomization analyses to explore the causal relationship between sarcopenia phenotypes (Appendicular lean mass [ALM], Low hand-grip strength [LHG], and usual walking pace [UWP]) and osteoarthritis (Knee osteoarthritis [KOA], and Hip osteoarthritis [HOA]). Univariable Mendelian randomization (UVMR) analyses were performed using the inverse variance weighted (IVW) method, MR-Egger, weighted median method, simple mode, and weighted mode, with the IVW method being the primary analytical technique. Subsequently, the independent causal effects of sarcopenia phenotype on osteoarthritis were investigated using multivariate Mendelian randomization (MVMR) analysis. To further explore the mechanisms involved, obesity and circulating inflammatory proteins were introduced as the mediator variables, and a two-step Mendelian randomization analysis was used to explore the mediating effects of obesity and circulating inflammatory proteins between ALM and KOA as well as the mediating proportions. RESULTS:UVMR analysis showed a causal relationship between ALM, LHG, UWP and KOA [(OR = 1.151, 95% CI: 1.087-1.218, P = 1.19 × 10, P = 7.14 × 10) (OR = 1.215, 95% CI: 1.004-1.470; P = 0.046, P = 0.055) (OR = 0.503, 95% CI: 0.292-0.867; P = 0.013, P = 0.027)], and a causal relationship between ALM, UWP and HOA [(OR = 1.181, 95% CI: 1.103-1.265, P = 2.05 × 10, P = 6.15 × 10) (OR = 0.438, 95% CI: 0.226-0.849, P = 0.014, P = 0.022)]. In the MVMR analyses adjusting for confounders (body mass index, insomnia, sedentary behavior, and bone density), causal relationships were observed between ALM, LHG, UWP and KOA [(ALM: OR = 1.323, 95%CI: 1.224- 1.431, P = 2.07 × 10), (LHG: OR = 1.161, 95%CI: 1.044- 1.292, P = 0.006), (UWP: OR = 0.511, 95%CI: 0.290- 0.899, P = 0.020)], and between ALM and HOA (ALM: OR = 1.245, 95%CI: 1.149- 1.348, P = 7.65 × 10). In a two-step MR analysis, obesity was identified to play a potential mediating role in ALM and KOA (proportion mediated: 5.9%). CONCLUSIONS:The results of this study suggest that decreased appendicular lean mass, grip strength, and walking speed increase the risk of KOA and decreased appendicular lean mass increases the risk of HOA in patients with sarcopenia in a European population. Obesity plays a mediator role in the occurrence of KOA due to appendicular lean body mass reduction. 10.1186/s12877-024-05098-8
The causal relationship of human blood metabolites with the components of Sarcopenia: a two-sample Mendelian randomization analysis. BMC geriatrics BACKGROUND:Sarcopenia is a progressive loss of muscle mass and function. Since skeletal muscle plays a critical role in metabolic homeostasis, identifying the relationship of blood metabolites with sarcopenia components would help understand the etiology of sarcopenia. METHODS:A two-sample Mendelian randomization study was conducted to examine the causal relationship of blood metabolites with the components of sarcopenia. Summary genetic association data for 309 known metabolites were obtained from the Twins UK cohort and KORA F4 study (7824 participants). The summary statistics for sarcopenia components [hand grip strength (HGS), walking pace (WP), and appendicular lean mass (ALM)] were obtained from the IEU Open GWAS project (461,089 participants). The inverse variance weighted method was used, and the MR-Egger, weighted median, and MR-PRESSO were used for the sensitivity analyses. Metabolic pathways analysis was further performed. RESULTS:Fifty-four metabolites associated with sarcopenia components were selected from 275 known metabolites pool. Metabolites that are causally linked to the sarcopenia components were mainly enriched in amino sugar and nucleotide sugar metabolism, galactose metabolism, fructose and mannose metabolism, carnitine synthesis, and biotin metabolism. The associations of pentadecanoate (15:0) with ALM, and 3-dehydrocarnitine and isovalerylcarnitine with HGS were significant after Bonferroni correction with a threshold of P < 1.82 × 10 (0.05/275). Meanwhile, the association of hyodeoxycholate and glycine with the right HGS, and androsterone sulfate with ALM were significant in the sensitivity analyses. CONCLUSION:Blood metabolites from different metabolism pathways were causally related to the components of sarcopenia. These findings might benefit the understanding of the biological mechanisms of sarcopenia and targeted drugs development for muscle health. 10.1186/s12877-024-04938-x
Sarcopenia and immune-mediated inflammatory diseases: Evaluating causality and exploring therapeutic targets for sarcopenia through Mendelian randomization. International immunopharmacology BACKGROUND:An increasing body of evidence has revealed the association between immune-mediated inflammatory diseases (IMIDs) and sarcopenia. However, a genetically direct causality between IMIDs and sarcopenia remains elusive. METHODS:To investigate the relationship between IMIDs and sarcopenia-related traits and identify potential therapeutic targets, a Mendelian randomization (MR) was performed. We collected publicly available genome-wide association studies (GWAS) data for seven common IMIDs, including systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PSO), ankylosing spondylitis (AS), and rheumatoid arthritis (RA). Additionally, summary-level GWAS data for sarcopenia-related traits, including appendicular lean mass (ALM), left-hand grip strength, and right-hand grip strength were collected. To search for therapeutic targets, we used two types of genetic instruments to proxy the exposure of druggable genes, including genetic variants within or nearby drug targets and expression quantitative trait loci (eQTLs) of drug targets. Two-sample MR and summary-data-based MR (SMR) were used to calculate effect estimates, and sensitivity analyses were implemented for robustness. Drug tractability, gene enrichment analysis, and protein-protein interaction (PPI) analysis were used to validate the biological and clinical significance of the selected drug targets. RESULTS:The two-sample MR analysis indicated the existence of casual associations between IMIDs and sarcopenia-related traits in the overall and sex-stratified populations. In particular, PSO had causal effects on decreased ALM, which showed significance in all six MR analysis tests with directional consistency in the overall population. Grounded in this robust association, HLA-DRB5, HLA-DRB1, and AGER were identified as potential therapeutic targets for ALM decline by drug target MR and further confirmed by SMR analysis. These genes were associated with therapeutic agents currently undergoing evaluations in clinical trials. Gene enrichment and PPI analysis indicated a strong association of these genes with immune functions. CONCLUSIONS:This MR study contributes novel genetic evidence supporting the causal link between IMIDs and sarcopenia, with a particular emphasis on the association between PSO and decreased ALM. Additionally, AGER, HLA-DRB1, and HLA-DRB5 emerge as potential therapeutic targets for ALM decline. 10.1016/j.intimp.2024.113687
An insight into the causal relationship between sarcopenia-related traits and venous thromboembolism: A mendelian randomization study. PloS one BACKGROUND:As a geriatric syndrome, sarcopenia has a high prevalence in the old population and represents an impaired state of health with adverse health outcomes. A strong clinical interest in its relationship with venous thromboembolism (VTE), which is a complex trait disease with a heterogeneous annual incidence rate in different countries, has emerged. The relationship between sarcopenia and venous thromboembolism has been reported in observational studies but the causality from sarcopenia to VTE remained unclarified. We aimed to assess the causal effect of sarcopenia on the risk of VTE with the two-sample Mendelian randomization (MR) method. METHODS:Two sets of single-nucleotide polymorphisms (SNPs), derived from two published genome-wide association study (GWAS) meta-analyses and genetically indexing muscle weakness and lean muscle mass separately, were pooled into inverse variance weighted (IVW), weighted median and MR-Egger analyses. RESULTS:No evidence was found for the causal effect of genetically predicted muscle weakness (IVW: OR = 0.90, 95% CI = 0.76-1.06, p = 0.217), whole body lean mass (IVW: OR = 1.01, 95% CI = 0.87-1.17, p = 0.881) and appendicular lean mass (IVW: OR = 1.13, 95% CI = 0.82-1.57, p = 0.445) on the risk of VTE. However, both genetically predicted whole-body lean mass and appendicular lean mass can causally influence diabetes mellitus (IVW of whole-body lean mass: OR = 0.87, 95% CI = 0.78-0.96, p = 0.008; IVW of appendicular lean mass: OR = 0.71, 95% CI = 0.54-0.94, p = 0.014) and hypertension (IVW of whole-body lean mass: OR = 0.92, 95% CI = 0.87-0.98, p = 0.007; IVW of appendicular lean mass: OR = 0.84, 95% CI = 0.73-0.96, p = 0.013). CONCLUSIONS:Genetically predicted sarcopenia does not causally influence VTE directly, but it might still have an indirect effect on VTE incidence via diabetes mellitus and hypertension. 10.1371/journal.pone.0303148
The relationship between inflammatory bowel disease and sarcopenia-related traits: a bidirectional two-sample mendelian randomization study. Frontiers in endocrinology Objective:Observational studies have revealed a link between inflammatory bowel disease (IBD) and sarcopenia. However, it remains unclear whether this correlation between IBD and sarcopenia is causal. Methods:The genetic instrumental variables (IVs) associated with IBD and sarcopenia-related traits were derived from publicly available genome-wide association studies. We employed a two-sample bidirectional Mendelian randomization (MR) method. we obtained genetic IVs for five phenotypes from 34,652 cases in IBD, 27,432 cases in ulcerative colitis (UC), 212356 cases in crohn's disease (CD), 9336415 cases in low hand grip strength (LHGS), and 450243 cases in appendicular lean mass (ALM), respectively. The inverse variance weighting and other MR methods were used to explore the bidirectional causal relationship. Furthermore, we performed heterogeneity test, pleiotropy test, leave-one-out sensitivity test, and multivariate MR to evaluate the robustness of the results. Results:The forward MR results showed that the UC (OR=0.994, 95% CI: 0.9876-0.9998, P = 0.044) and CD (OR=0.993, 95% CI: 0.988-0.998, P = 0.006) was negatively correlated with ALM. In the reverse MR analysis, we also found that LHGS was negatively correlated with the IBD (OR=0.76, 95% CI: 0.61-0.94, P = 0.012) and CD (OR=0.53, 95% CI: 0.40-0.70, P <0.001). Besides, genetically predicted higher ALM reduced IBD (OR=0.87, 95% CI: 0.79-0.95, P = 0.002), UC (OR=0.84, 95% CI: 0.76-0.93, P = 0.001), and CD (OR=0.87, 95% CI: 0.77-0.99, P = 0.029). However, the results of other MR Analyses were not statistically different. Conclusions:We found genetically predicted UC and CD are causally associated with reduced ALM, and higher hand grip strength reduced IBD and CD risk, and higher ALM reduced IBDs risk. This MR study provides moderate evidence for a bidirectional causal relationship between IBD and sarcopenia. 10.3389/fendo.2024.1402551
Telomere length and aging-related outcomes in humans: A Mendelian randomization study in 261,000 older participants. Kuo Chia-Ling,Pilling Luke C,Kuchel George A,Ferrucci Luigi,Melzer David Aging cell Inherited genetic variation influencing leukocyte telomere length provides a natural experiment for testing associations with health outcomes, more robust to confounding and reverse causation than observational studies. We tested associations between genetically determined telomere length and aging-related health outcomes in a large European ancestry older cohort. Data were from n = 379,758 UK Biobank participants aged 40-70, followed up for mean of 7.5 years (n = 261,837 participants aged 60 and older by end of follow-up). Thirteen variants strongly associated with longer telomere length in peripheral white blood cells were analyzed using Mendelian randomization methods with Egger plots to assess pleiotropy. Variants in TERC, TERT, NAF1, OBFC1, and RTEL1 were included, and estimates were per 250 base pairs increase in telomere length, approximately equivalent to the average change over a decade in the general white population. We highlighted associations with false discovery rate-adjusted p-values smaller than .05. Genetically determined longer telomere length was associated with lowered risk of coronary heart disease (CHD; OR = 0.95, 95% CI: 0.92-0.98) but raised risk of cancer (OR = 1.11, 95% CI: 1.06-1.16). Little evidence for associations were found with parental lifespan, centenarian status of parents, cognitive function, grip strength, sarcopenia, or falls. The results for those aged 60 and older were similar in younger or all participants. Genetically determined telomere length was associated with increased risk of cancer and reduced risk of CHD but little change in other age-related health outcomes. Telomere lengthening may offer little gain in later-life health status and face increasing cancer risks. 10.1111/acel.13017
The relationship between serum lipid with sarcopenia: Results from the NHANES 2011-2018 and bidirectional Mendelian randomization study. Experimental gerontology BACKGROUND:The relationship between serum lipids and sarcopenia remains unclear due to conflicting results in previous studies. OBJECTIVE:To explore the associations and potential causality between serum lipids, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and total cholesterol (TC), and sarcopenia. METHODS:Data from the National Health and Nutrition Examination Survey (NHANES) were analysed using multivariable regression and restricted cubic splines (RCSs) to assess the associations between serum lipids and sarcopenia. Bidirectional Mendelian randomization (MR) was employed to investigate the causal relationships with sarcopenia-related traits such as appendicular lean mass (ALM), hand grip strength, and usual walking pace. RESULTS:Serum HDL-C and TG levels were inversely associated with ALMBMI, with each 1-unit increase linked to a 0.13 % and 1.32 % decrease, respectively. Elevated TG, but not HDL-C, LDL-C, or TC levels, was significantly associated with an increased risk of sarcopenia (P for trend = 0.001). RCS analysis revealed a log-shaped dose-response relationship between TG and sarcopenia risk (P overall <0.001, P non-linear <0.001), with a cutoff value of 92.75 mg/dL. Genetically predicted HDL-C, LDL-C, and TG were associated with ALM. Conversely, ALM showed an inverse causal relationship with all four serum lipids. Additionally, genetically predicted usual walking pace influenced HDL-C and TG levels (P < 0.001). CONCLUSION:The study reveals a nonlinear association between TG levels and sarcopenia risk, and a bidirectional association between lipid profiles and muscle mass, underscoring the need for further research to elucidate these mechanisms. 10.1016/j.exger.2024.112560
Causal associations between the insulin-like growth factor family and sarcopenia: a bidirectional Mendelian randomization study. Frontiers in endocrinology Objective:Insulin-like growth factor (IGF) is closely associated with sarcopenia, yet the causal relationship of this association remains unclear. This study aims to explore the potential causal relationship between members of the IGF family and sarcopenia from a genetic perspective through bidirectional Mendelian randomization (MR) analysis using two-sample datasets. Methods:Five genetically predicted factors of the IGF family (IGF-1, IGF-1R, IGF-2R, IGFBP-3, IGFBP-7) as one sample, while four relevant features of sarcopenia (low hand grip strength, appendicular lean mass, whole body fat-free mass, and walking pace) as another sample, in conducting a two-sample MR analysis. Results:The forward MR results of the relationship between IGF and sarcopenia showed that elevated levels of IGF-1 reduced the risk of low hand grip strength (OR = 0.936, 95% CI=0.892-0.983, P = 0.008) and increased appendicular lean mass of the extremities and whole body fat-free mass (OR = 1.125, 95% CI=1.070-1.182,P = 0.000; OR =1.076, 95% CI=1.047-1.106, P=0.000), reduced the risk of sarcopenia. Elevated IGF-1R also favored an increase in whole body fat-free mass (OR=1.023, 95% CI=1.008-1.038, P =0.002), and the appendicular lean mass trait was more pronounced with elevated IGFBP-3 and IGFBP-7 (OR=1.034, 95% CI=1.024-1.044, P =0.000; OR=1.020, 95% CI=1.010-1.030, P=0.000). Inverse MR results of the effect of sarcopenia on IGF showed that decreased hand grip strength may elevate IGF-1 levels (OR=1.243, 95% CI=1.026-1.505,P =0.027), whereas improvements in appendicular lean mass, whole body fat-free mass traits, and increased walking pace decreased IGF-1 levels (OR=0.902, 95% CI: 0.877-0.927, P = 0.000; OR=0.903, 95% CI=0.859-0.949,P = 0.000; OR=0.209, 95% CI=0.051-0.862,P = 0.045). Also decreased hand grip strength may elevate IGF-1R levels (OR=1.454, 95% CI=1.108-1.909, P =0.007), and appendicular lean mass stimulated high expression of IGFBP-1 (OR=1.314, 95% CI=1.003-1.722, P =0.047). Heterogeneity and pleiotropy were not detected in all results, and the results were stable and reliable. Conclusion:There is a bi-directional causal association between IGF family members and the risk of sarcopenia, which provides a more adequate basis for early biological monitoring of sarcopenia and may provide new targets for early intervention and treatment of sarcopenia. 10.3389/fendo.2024.1422472
Genetic Influence of the Brain on Muscle Structure: A Mendelian Randomization Study of Sarcopenia. Journal of cachexia, sarcopenia and muscle BACKGROUND:The association between brain and sarcopenia has not been clarified. We aim to investigate the causal association between brain structure, function, gene expression and sarcopenia-related traits. METHODS:All participants were Europeans. GWAS data of Brain Imaging Data Structure (BIDs) was from the UK Biobank. Gene expression in 13 brain regions was acquired from the GTEx Consortium. The sarcopenia-related traits, including appendicular lean mass (ALM), whole body lean mass (WBLM), grip strength and sarcopenia diagnosed by the European Working Group on Sarcopenia in Older People (EWGSOP) or Foundation for the National Institutes of Health (FNIH), were from the IEU website. The inverse variance weighted (IVW), MR Egger, weighted median, weighted mode and Wald ratio methods were used for a two-sample Mendelian randomization (MR) analysis between brain structures and sarcopenia-related traits. The summary-data-based MR (SMR) was used to investigate brain genes causally influencing sarcopenia. We calculated the F-value, odds ratio with 95% CI and p-value. For the sensitivity analysis, the heterogeneity I statistic, Cochrane's Q test, Egger's intercept test, MR-PRESSO and the leave-one-out sensitivity test were used. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, protein-protein interaction (PPI), transcription factor interaction prediction and miRNA interaction prediction analysis were used to reveal potential signalling pathways and mechanisms. RESULTS:We included 3144 imaging phenotypes from 8428 participants in BIDs data. One hundred forty-one BIDs were identified to causally influence ALM, 160 BIDs showed significant causal effect on the WBLM, and 86 BIDs showed significant causal effect on grip strength. There were 48 or 32 BIDs causally associated with sarcopenia diagnosed by the EWGSOP or FNIH criteria respectively. After FDR correction, there were 35 BIDs showing causal effect on the ALM, 28 BIDs showing causal effect on the WBLM and 7 BIDs showing causal effect on grip strength (p < 0.05). Twelve to forty-eight genes in different brain regions showed causal effect on all the five sarcopenia-related traits. MMP24-AS1, HLA-DRB6, HLA-DQA2, DDX42, BAG6, NUSAP1, LINC00940, NME1-NME2 and AS3MT in the amygdala region showed detrimental effect on all the five sarcopenia-related traits, whereas HLA-DRB1, HLA-DQB1-AS1 and C6ORF3 showed protective effect (p < 0.05). The gene enrichment analysis indicated these screened genes was mainly enriched in immune-related signalling. CONCLUSION:We discovered the causal effect of BIDs and brain gene expression on sarcopenia. The positive genes were mainly enriched in immune-related signalling, suggesting an immune-based cross-organ regulation mechanism of brain-muscle axis. 10.1002/jcsm.13647
Appendicular lean mass and the risk of stroke and Alzheimer's disease: a mendelian randomization study. BMC geriatrics BACKGROUND:Appendicular lean mass (ALM) is a good predictive biomarker for sarcopenia. And previous studies have reported the association between ALM and stroke or Alzheimer's disease (AD), however, the causal relationship is still unclear, The purpose of this study was to evaluate whether genetically predicted ALM is causally associated with the risk of stroke and AD by performing Mendelian randomization (MR) analyses. METHODS:A two-sample MR study was designed. Genetic variants associated with the ALM were obtained from a large genome-wide association study (GWAS) and utilized as instrumental variables (IVs). Summary-level data for stroke and AD were generated from the corresponding GWASs. We used random-effect inverse-variance weighted (IVW) as the main method for estimating causal effects, complemented by several sensitivity analyses, including the weighted median, MR-Egger, and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods. Multivariable analysis was further conducted to adjust for confounding factors, including body mass index (BMI), type 2 diabetes mellitus (T2DM), low density lipoprotein-C (LDL-C), and atrial fibrillation (AF). RESULTS:The present MR study indicated significant inverse associations of genetically predicted ALM with any ischemic stroke ([AIS], odds ratio [OR], 0.93; 95% confidence interval [CI], 0.89-0.97; P = 0.002) and AD (OR, 090; 95% CI 0.85-0.96; P = 0.001). Regarding the subtypes of AIS, genetically predicted ALM was related to the risk of large artery stroke ([LAS], OR, 0.86; 95% CI 0.77-0.95; P = 0.005) and small vessel stroke ([SVS], OR, 0.80; 95% CI 0.73-0.89; P < 0.001). Regarding multivariable MR analysis, ALM retained the stable effect on AIS when adjusting for BMI, LDL-C, and AF, while a suggestive association was observed after adjusting for T2DM. And the estimated effect of ALM on LAS was significant after adjustment for BMI and AF, while a suggestive association was found after adjusting for T2DM and LDL-C. Besides, the estimated effects of ALM were still significant on SVS and AD after adjustment for BMI, T2DM, LDL-C, and AF. CONCLUSIONS:The two-sample MR analysis indicated that genetically predicted ALM was negatively related to AIS and AD. And the subgroup analysis of AIS revealed a negative causal effect of genetically predicted ALM on LAS or SVS. Future studies are required to further investigate the underlying mechanisms. 10.1186/s12877-024-05039-5
Sarcopenia-related traits and coronary artery disease: a bi-directional Mendelian randomization study. Liu Hui-Min,Zhang Qiang,Shen Wen-Di,Li Bo-Yang,Lv Wan-Qiang,Xiao Hong-Mei,Deng Hong-Wen Aging Previous Mendelian randomization (MR) studies have yielded a conflicting causal relationship between sarcopenia and coronary artery disease (CAD), and lack the association of CAD with sarcopenia. We performed a bi-directional MR approach to clarify the causality and causal direction between sarcopenia-related traits and CAD. In stage 1 analysis, estimates of inverse variance weighting (IVW) and several sensitivity analyses were obtained by applying genetic variants that predict sarcopenia-related traits to CAD. Conversely, we also applied genetic variants that predict CAD to sarcopenia-related traits in stage 2 analyses. IVW analysis showed that higher handgrip strength reduces risk for CAD: A 1-kilogram (kg) increase in genetically determined left handgrip strength reduced odds of CAD by 36% [odds ratio (OR) = 0.64, 95% confidence interval (CI) 0.498 - 0.821, = 4.56E-04], and right handgrip strength reduced odds of CAD by 41.1% (OR = 0.599, 95% CI 0.476 - 0.753, = 1.10E-05). However, genetically predicted CAD did not show any causal association with handgrip strength, and no significant causal relationship was detected between genetically instrumented body lean mass and CAD. Our results suggest that decreased muscle strength but not decreased muscle mass leads to the increased risk of CAD in sarcopenia. 10.18632/aging.102815
Causal association of circulating cytokines with sarcopenia-related traits: A Mendelian randomization study. Cytokine BACKGROUND:Observational studies have reported that circulating cytokines are associated with sarcopenia. However, the causal relationship between circulating cytokines and sarcopenia has not been elucidated. OBJECTIVES:This study aimed to investigate the causal relationship between circulating cytokines and sarcopenia with genetic data using Mendelian randomization (MR). METHODS:Two-sample bidirectional MR analysis was performed to investigate the causal relationship in individuals of European ancestry. The publicly available genome-wide association study statistics were used to select the key eligible single nucleotide polymorphisms significantly associated with circulating cytokines. Multiple MR analysis approaches, including inverse variance weighted (IVW), MR-Egger, weighted median method (WMM), and MR-Pleiotropy residual Sum and Outlier (MR-PRESSO) methods, were used for the analysis. Sarcopenia-related traits were appendicular lean mass (ALM) and grip strength. RESULTS:This study demonstrated the causal effect of genetically predicted circulating interleukin interleukin-16 (IL16) levels on both ALM [odds ratio (OR) = 0.990, 95% confidence interval (CI): 0.980-1.000, P = 0.049] and grip strength (OR = 0.971, 95% CI: 0.948-0.995, P = 0.020]. Additionally, C-X-C motif chemokine ligand 10 (CXCL10), interleukin-1beta (IL1B), and hepatocyte growth factor (HGF) were correlated with ALM, while vascular endothelial growth factor (VEGF), interleukin-12 (IL12), and interleukin-15 (IL15) were correlated with grip strength. The results of MR-Egger, weighted median, weighted mode, and simple mode methods were consistent with the IVW estimates. Sensitivity analysis revealed that horizontal pleiotropy did not bias the causal estimates. CONCLUSION:These findings indicate that inflammatory cytokines exert a significant causal effect on sarcopenia and provide promising leads for the development of novel therapeutic targets for the disease. By evaluating the role of circulating cytokines in the pathologic condition via a genetic epidemiological approach, our study made contributions to a further investigation of underlying mechanisms of sarcopenia. 10.1016/j.cyto.2024.156643
The association between inflammatory cytokines and sarcopenia-related traits: a bi-directional Mendelian randomization study. European journal of clinical nutrition BACKGROUND:Sarcopenia is among the most common musculoskeletal illnesses, yet its underlying biochemical mechanisms remain incompletely understood. Identifying the relationship of inflammatory cytokines with sarcopenia components would help understand the etiology of sarcopenia. We performed a bi-directional Mendelian randomization study to explore the causal relationship between 41 inflammatory cytokines and sarcopenia-related traits. METHODS:The study was performed in two stages using bidirectional dual-sample Mendelian randomization. We obtained aggregated statistical data on inflammatory factors, low grip strength, and ALM from genome-wide association studies. To explore the causal association between exposure and outcomes, we primarily utilized the inverse variance weighted strategy. Furthermore, we conducted sensitivity analyses through the use of Mendelian randomization (MR) Egger, weighted median and simple mode methods. To evaluate robustness of the results and to identify and adjust for horizontal pleiotropy, we performed the MR Pleiotropy RESidual Sum and Outlier test, the MR Egger intercept test, and a leave-one-out analysis. RESULTS:The results displayed a potential association between interleukin-10 (OR: 1.046, 95% CI: 1.002-1.093, p = 0.042) and vascular endothelial growth factor (OR: 1.024, 95% CI: 1.001-1.047, p = 0.038) and the risk of low hand-grip strength. Moreover, interferon gamma-induced protein 10 (OR: 1.010, 95% CI: 1.000-1.019, p = 0.042) and macrophage colony-stimulating factor (OR: 1.010, 95% CI: 1.003-1.017, p = 0.003) were significantly linked to a higher risk of ALM. CONCLUSION:We identified a causal relationship between multiple inflammatory factors and sarcopenia-related traits. Our study offers valuable insights into innovative methods for the sarcopenia prevention and treatment by regulating inflammatory factors. 10.1038/s41430-024-01486-w
Association between immune cells, inflammatory cytokines, and sarcopenia: Insights from a Mendelian randomization analysis. Archives of gerontology and geriatrics BACKGROUND:Recent studies have suggested a possible link between sarcopenia, immune dysregulation, and chronic inflammation, although the specific immune components implicated remain unclear. This investigation employs Mendelian Randomization (MR) to explore the reciprocal relationship between immune cells, inflammatory markers, and sarcopenia. METHOD:We performed two-sample and multivariate MR analyses using publicly accessible genome-wide association studies (GWAS) summary statistics. Our analyses included 731 immune cells, 41 inflammatory cytokines, and sarcopenia related traits (appendicular lean mass [ALM], low hand-grip strength [LHS], and walking pace [WP]), with additional sensitivity analyses conducted to confirm the findings. RESULTS:After false discovery rate (FDR) correction, significant associations were found between ten immune traits and ALM, with the CD127 marker in the Treg panel showing consistent positive correlation across four sites. In contrast, NKT%lymphocyte negatively correlated with WP (OR = 0.99, P = 0.023). In terms of inflammatory cytokines, macrophage colony-stimulating factor (MCSF) (OR = 1.03, P = 0.024) and hepatocyte growth factor (HGF) (OR = 1.03, P = 0.002) demonstrated positive associations with ALM, while interleukin-16 (IL-16) (OR = 0.99, P = 0.006) was inversely related. The reverse Mendelian randomization analysis found no direct causal links between sarcopenia traits and immune or inflammatory markers. Sensitivity analyses underscored the findings' resilience to pleiotropy, and adjusting for inter-trait dynamics weakened these relationships in the multivariable MR analysis. CONCLUSION:Our study reveals causal associations between specific immune phenotypes, inflammatory cytokines, and sarcopenia, providing insight into the development of sarcopenia and potential treatment strategies. 10.1016/j.archger.2024.105560
Sarcopenia as a predictor of nutritional status and comorbidities: a cross-sectional and mendelian randomization study. BMC geriatrics BACKGROUND:With the advancement of world population aging, age-related sarcopenia (SP) imposes enormous clinical burden on hospital. Clinical research of SP in non-geriatric wards has not been appreciated, necessitating further investigation. However, observational studies are susceptible to confounders. Mendelian randomization (MR) can effectively mitigate bias to assess causality. OBJECTIVE:To investigate the correlation between SP and comorbidities in orthopedic wards, and subsequently infer the causality, providing a theoretical basis for developing strategies in SP prevention and treatment. METHODS:Logistic regression models were employed to assess the correlation between SP and comorbidities. The MR analysis was mainly conducted with inverse variance weighted, utilizing data extracted from the UK and FinnGen biobank (Round 9). RESULTS:In the cross-sectional analysis, SP exhibited significant associations with malnutrition (P = 0.013) and some comorbidities, including osteoporosis (P = 0.014), body mass index (BMI) (P = 0.021), Charlson Comorbidity Index (CCI) (P = 0.006). The MR result also provided supporting evidence for the causality between SP and hypertension, osteoporosis and BMI. These results also withstood multiple sensitivity analyses assessing the validity of MR assumptions. CONCLUSION:The result indicated a significant association between SP and BMI, CCI, malnutrition, and osteoporosis. We highlighted that SP and comorbidities deserved more attention in non-geriatric wards, urging further comprehensive investigation. 10.1186/s12877-024-05341-2
Causal Relationship of Genetically Predicted Serum Micronutrients Levels With Sarcopenia: A Mendelian Randomization Study. Frontiers in nutrition Objectives:Previous observational studies have suggested associations between concentrations of several circulating micronutrients and sarcopenia. However, the causality inferred from those studies was subjected to residual confounding and reverse causation. Therefore, we aimed to examine the causal effects of the levels of genetically predicted serum micronutrients on sarcopenia. Methods:Single nucleotide polymorphisms (SNPs) were chosen from large-scale genome-wide association studies of participants only with European descent and were used as genetic instruments for the levels of 10 serum micronutrients (calcium, magnesium, selenium, copper, iron, zinc, Vitamin A, Vitamin B12, Vitamin D, and Vitamin E). Sarcopenia was defined by referencing to the 2019 definition given by the European Working Group on Sarcopenia in Older People (EWGSOP). A two-sample Mendelian randomization (MR) analysis was carried out to examine the associations between the levels of genetically predicted serum micronutrients and the risk of sarcopenia. Then, sensitivity analyses (including weighted median, MR-Egger and leave-one-out sensitivity analyses) were performed to evaluate the robustness of study findings. The estimates were presented as odds ratio (OR) with their 95% confidence intervals (CIs) per one standard deviation (SD) increase in the exposures. Results:A total of 378,635 UK Biobank participants, including 572 participants who were identified with sarcopenia, were included in this study. The iron status was shown to have a clear effect on the risk of sarcopenia based on MR analyses. The per one SD increment in the genetically-determined serum iron level corresponded to a 53% increase in the risk of sarcopenia (OR = 1.53, 95% CI: 1.31-1.78, = 0.001). The exclusion of SNPs of the circulating iron level (i.e., rs1799945 SNP, rs1800562 SNP or rs855791 SNP) did not attenuate the magnitude of the signal in MR analysis. There was little evidence supporting the associations between other remaining micronutrients and sarcopenia. Conclusions:An increased risk of sarcopenia was observed with a genetically higher concentration of iron, suggesting that iron may play a role in the occurrence or development of sarcopenia. 10.3389/fnut.2022.913155
The Impact of SGLT1 Inhibition on Frailty and Sarcopenia: A Mediation Mendelian Randomization Study. Journal of cachexia, sarcopenia and muscle BACKGROUND:Although pharmacological effects of SGLT2 inhibitors on the development of frailty and sarcopenia were known, the role of SGLT1 remained less clear. The present study investigated the possible effect of SGLT1 inhibition on these conditions and explored potential mediators. METHODS:A two-sample Mendelian randomization (MR) analysis was performed to assess the effect of SGLT1 inhibition on frailty index (FI) and low grip strength in individuals aged 60 years and older using both the FNIH and EWGSOP criteria. Subsequently, a two-step MR analysis was conducted to investigate the mediating role of insulin resistance phenotype and identify potential mediators of the effect of SGLT1 inhibition on the FI and low grip strength from 1558 plasma proteins and 1352 metabolites. RESULTS:Genetically predicted SGLT1 inhibition was associated with decreased FI (β: -0.290 [95% CI: -0.399, -0.181]) and reduced risk of low grip strength in individuals aged 60 years and older under both FNIH (β: -0.796 [95% CI: -1.216, -0.376]) and EWGSOP criteria (β: -0.287 [95% CI: -0.532, -0.041]). The two-step MR analysis demonstrated the role of insulin resistance phenotype in mediating SGTL1 inhibition on alleviating frailty (mediation proportion = 19.56% [95% CI: 8.42%, 30.70%]). After screening, 24 proteins and 16 metabolites were identified as mediators of the impact of SGLT1 inhibition on FI. Additionally, 13 proteins and 16 metabolites were found to mediate the effect of SGLT1 inhibition on low grip strength according to FNIH criteria while 22 proteins and 6 metabolites were shown to mediate the impact of SGLT1 inhibition on low grip strength under EWGSOP criteria. CONCLUSIONS:SGLT1 inhibition potentially mitigated frailty and sarcopenia through several biological mediators, shedding new light for therapeutic intervention. 10.1002/jcsm.13614
Metabolome-Wide Mendelian Randomization Assessing the Causal Relationship Between Blood Metabolites and Sarcopenia-Related Traits. The journals of gerontology. Series A, Biological sciences and medical sciences Sarcopenia is among the most common musculoskeletal illnesses, yet its underlying biochemical mechanisms remain incompletely understood. In this study, we used Mendelian randomization (MR) to investigate the causal relationship between the genetically determined blood metabolites and sarcopenia, with the overall objective of identifying likely molecular pathways for sarcopenia. We used 2-sample MR to investigate the effects of blood metabolites on sarcopenia-related traits. 452 metabolites were exposure, and 3 sarcopenia-related traits as the outcomes: handgrip strength, appendicular lean mass, and walking pace. The inverse-variance weighted (IVW) causal estimates were determined. For sensitivity analysis, methods such as MR-Egger regression, the weighted median, the weighted mode, and the heterogeneity test were used. Additionally, for complementation, we performed replication, meta-analysis, and metabolic pathway analyses. Candidate biomarkers were defined by meeting one of the following criteria: (1) significant metabolites are defined as pIVW < pBonferroni [1.11 × 10-4 (.05/452)]; (2) strong metabolites are defined as 4 MR methods p < .05; and (3) suggestive metabolites are defined as passing sensitivity analysis. Three metabolites (creatine, 1-arachidonoylglycerophosphocholine, and pentadecanoate [15:0]) with significant causality, 3 metabolites (glycine, 1-arachidonoylglycerophosphocholine, and epiandrosterone sulfate) with strong causality, and 25 metabolites (including leucylleucin, pyruvic acid, etc.) with suggestive causality were associated with sarcopenia-related traits. After further replication analyses and meta-analysis, these metabolites maintained substantial effects on sarcopenia-related traits. We additionally identified 14 important sarcopenia-related trait metabolic pathways. By combining metabolomics with genomics, these candidate metabolites and metabolic pathways identified in our study may provide new clues regarding the mechanisms underlying sarcopenia. 10.1093/gerona/glae051
Causal relationship of interleukin-6 and its receptor on sarcopenia traits using mendelian randomization. Nutrition journal BACKGROUND:Previous research has extensively examined the role of interleukin 6 (IL-6) in sarcopenia. However, the presence of a causal relationship between IL-6, its receptor (IL-6R), and sarcopenia remains unclear. METHOD:In this study, we utilized summary-level data from genome-wide association studies (GWAS) focused on appendicular lean mass (ALM), hand grip strength, and walking pace. Single nucleotide polymorphisms (SNPs) were employed as genetic instruments for IL-6 and IL-6R to estimate the causal effect of sarcopenia traits. We adopted the Mendelian randomization (MR) approach to investigate these associations using the inverse variance weighted (IVW) method as the primary analytical approach. Additionally, we performed sensitivity analyses to validate the reliability of the MR results. RESULT:This study revealed a significant negative association between main IL-6R and eQTL IL-6R on the left grip strength were - 0.013 (SE = 0.004, p < 0.001) and -0.029 (SE = 0.007, p < 0.001), respectively. While for the right grip strength, the estimates were - 0.011 (SE = 0.001, p < 0.001) and - 0.021 (SE = 0.008, p = 0.005). However, no evidence of an association for IL-6R with ALM and walking pace. In addition, IL-6 did not affect sarcopenia traits. CONCLUSION:Our study findings suggest a negative association between IL-6R and hand grip strength. Additionally, targeting IL-6R may hold potential value as a therapeutic approach for the treatment of hand grip-related issues. 10.1186/s12937-024-00958-w
Causal Relationship Between Gut Microbiota, Metabolites, and Sarcopenia: A Mendelian Randomization Study. The journals of gerontology. Series A, Biological sciences and medical sciences BACKGROUND:Gut microbiota imbalance and sarcopenia are frequently observed in older adults. Gut microbiota and their metabolites are considered risk factors contributing to the heightened risk of sarcopenia, but whether these associations are causal remains unclear. METHODS:We conducted linkage disequilibrium score regression and 2-sample Mendelian randomization (MR) methods with single-nucleotide polymorphisms sourced from large-scale genome-wide association studies as instrumental variables to examine the causal associations linking gut microbiota with their metabolites to the sarcopenia. Following the MR analysis, subsequent sensitivity analyses were conducted to reinforce the robustness and credibility of the obtained results. RESULTS:MR analysis yielded compelling evidence demonstrating the correlation between genetically predicted gut microbiota and metabolites and the risk of sarcopenia. The abundance of Porphyromonadaceae, Rikenellaceae, Terrisporobacter, and Victivallis was found to be associated with walking pace. Our study also found suggestive associations of 12 intestinal bacteria with appendicular lean mass, and of Streptococcaceae, Intestinibacter, Paraprevotella, Ruminococcaceae UCG009, and Sutterella with grip strength. Specifically, we identified 21 gut microbiota-derived metabolites that may be associated with the risk of sarcopenia. CONCLUSIONS:Utilizing a 2-sample MR approach, our study elucidates the causal interplay among gut microbiota, gut microbiota-derived metabolites, and the occurrence of sarcopenia. These findings suggest that gut microbiota and metabolites may represent a potential underlying risk factor for sarcopenia, and offer the promise of novel therapeutic focal points. 10.1093/gerona/glae173
The causal association of sarcopenia with osteoporosis and obesity: a Mendelian randomization analysis. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 10.1007/s00198-022-06628-z
Educational attainment, brain cortical structure, and sarcopenia: a Mendelian randomization study. Frontiers in public health Background:Previous observational studies have suggested associations between high-level educational attainment (EA) and a lower risk of sarcopenia. However, the causality inferred from those studies was subjected to residual confounding and reverse causation. The protective effect of EA on sarcopenia may be mediated via changes in brain cortical structure. The aim of this study was to use a two-step Mendelian randomization (MR) analysis to illustrate the causal relationship between EA, brain cortical structure, and sarcopenia. Methods:Instrumental variables at the genome-wide significance level were obtained from publicly available datasets, and inverse variance weighted as the primary method was used for MR analysis. We perform several sensitivity analyses, including Cochran Q test, MR-Egger intercept test, leave-one-out analyses, and MR Pleiotropy Residual Sum and Outlier to evaluate the reliability of the results. Results:EA was causally associated with increased appendicular lean mass ( = 0.25, 95% confidence interval (CI): 0.19 to 0.31,  = 2.25 × 10), hand grip strength (left:  = 0.042, 95% CI: 0.013 to 0.071,  = 4.77 × 10 and right:  = 0.050, 95% CI: 0.022 to 0.079,  = 5.17 × 10), and usual walking pace (β = 0.20, 95% CI: 0.18 to 0.22,  = 6.16 × 10). In addition, EA was associated with increased brain cortical surface area ( = 4082.36, 95% CI: 2513.35 to 5681.38,  = 3.40 × 10) and cortical thickness (TH) ( = 0.014, 95% CI: 0.0045 to 0.023,  = 3.45 × 10). Regarding the causal effect of EA on usual walking pace, the mediatory effect of TH was 0.0069 and the proportion of mediation by TH was 3.43%. Conclusion:The study will have revealed the protective causal effect of EA on sarcopenia, which provides a reference for the prevention of sarcopenia at the public health level. We also will have found EA could affect the brain cortical structure, and the brain cortical structure could mediate the protective effect of EA against sarcopenia risk. 10.3389/fpubh.2024.1415343
Leukocyte telomere length and sarcopenia-related traits: A bidirectional Mendelian randomization study. PloS one Accumulating evidence indicated that leukocyte telomere length (LTL) was related to sarcopenia. However, it is still not clear whether the association of changes in LTL with sarcopenia is likely to be causal, or could be explained by reverse causality. Thus, we carried on bidirectional Mendelian randomization (MR) and multivariable MR analyses to identify the causal relationship between LTL and sarcopenia-related traits. Summary-level data and independent variants used as instruments came from large genome-wide association studies of LTL (472,174 participants), appendicular lean mass (450,243 participants), low grip strength (256,523 participants), and walking pace (450,967 participants). We identified suggestive association of longer LTL with larger appendicular lean mass [odds ratio (OR) = 1.053; 95% confidence interval (CI), 1.009-1.099; P = 0.018], and causal association of longer LTL with a lower risk of low grip strength (OR = 0.915; 95% CI, 0.860-0.974; P = 0.005). In the reverse MR analysis, we also observed a positive causal association between walking pace and LTL (OR = 1.252; 95% CI, 1.121-1.397; P < 0.001). Similar results can be repeated in sensitivity analyses. While in the multivariable MR analysis, the estimate of the impact of walking pace on LTL underwent a transformation after adjusting for T2DM (OR = 1.141; 95%CI: 0.989-1.317; P = 0.070). The current MR analysis supported a causal relationship between shorter telomere length and both low muscle mass and strength. Additionally, walking pace may affect LTL through T2DM. 10.1371/journal.pone.0296063
A causal relationship between sarcopenia and cognitive impairment: A Mendelian randomization study. PloS one OBJECTIVE:Sarcopenia and cognitive impairment often coexist in the elderly. In this study, we investigated the causal relationship between sarcopenia-related muscle characteristics and cognitive performance. METHODS:We used linkage disequilibrium score regression (LDSC) and Mendelian Randomization (MR) analyses to estimate genetic correlations and causal relationships between genetically predicted sarcopenia-related muscle traits and cognitive function, as well as cognitive function-based discovery samples and replicated samples. Estimated effect sizes were derived from a fixed-effects meta-analysis. RESULTS:Our univariate genome-wide association study (GWAS) meta-analysis indicated a causal relationship between appendicular lean mass (ALM) (β = 0.049; 95% confidence interval (CI): 0.032-0.066, P < 0.001) and walking pace (β = 0.349; 95% CI: 0.210-0.487, P < 0.001) with cognitive function, where a causal relationship existed between ALM in both male and female (βALM-Male(M) = 0.060; 95% CI: 0.031-0.089, PALM-M < 0.001; βALM-Female(F) = 0.045; 95% CI: 0.020-0.069, PALM-F < 0.001) with cognitive function. Low grip strength was not causally associated with cognitive function (β = -0.045; 95% CI: -0.092 - -0.002, P = 0.062). A reverse causality GWAS meta-analysis showed a causal relationship between cognitive function and ALM (β = 0.033; 95% CI: 0.018-0.048, P < 0.001) and walking pace (β = 0.039; 95% CI: 0.033-0.051, P < 0.001), where ALM in both male and female showed a causality (βALM-M = 0.041; 95% CI: 0.019-0.063, PALM-M < 0.001; βALM-F = 0.034; 95% CI: 0.010-0.058, PALM-F = 0.005). Cognitive function was not causally related to low grip strength (β = -0.024; 95% CI: -0.073-0.025, P = 0.344). Multivariable MR1 (MVMR1) analyses showed a significant causal relationship for ALM (β = 0.077; 95% CI: 0.044-0.109, P = 0.000) and walking pace (β = 0.579; 95% CI: 0.383-0.775, P = 0.000) and cognitive function. Multivariable MR2 (MVMR2) multivariate analysis showed that ALM causality remained (β = 0.069; 95% CI: 0.033-0.106, P = 0.000), and walking pace (β = 0.589; 95% CI: 0.372-0.806, P = 0.000). CONCLUSIONS:Bidirectional two-sample MR demonstrated that sarcopenia-related muscle characteristics and cognitive performance were positive causal genetic risk factors for each other, while a multivariable MR study demonstrated that low ALM and a slow walking pace were causally involved in reduced cognitive performance. This study suggests a causal relationship between sarcopenia and cognitive impairment in older adults and provide new ideas for prevention and treatment. 10.1371/journal.pone.0309124
Circulating inflammatory cytokines and sarcopenia-related traits: a mendelian randomization analysis. Frontiers in medicine Objective:To explore the causal relationships between 91 circulating inflammatory cytokines and sarcopenia-related traits (low hand grip strength, appendicular lean mass, and usual walking pace) by Mendelian randomized analysis. Methods:Independent genetic variations of inflammatory cytokines and sarcopenia-related traits were selected as instrumental variables from publicly available genome-wide association studies (GWAS). The MR analysis was primarily conducted using the inverse variance-weighted (IVW) method. Sensitivity analyses included Steiger filtering and MR PRESSO, with additional assessments for heterogeneity and pleiotropy. Results:The IVW method indicated a causal relationship between Vascular Endothelial Growth Factor A (VEGF-A) and low hand grip strength (OR = 1.05654, 95% CI: 1.02453 to 1.08956, = 0.00046). Additionally, Tumor Necrosis Factor-beta (TNF-β) was found to have a causal relationship with appendicular lean mass (ALM) (β = 0.04255, 95% CI: 0.02838 to 0.05672, = 3.96E-09). There was no evidence suggesting a significant causal relationship between inflammatory cytokines and usual walking pace. Conclusion:Our research substantiated the causal association between inflammatory cytokines, such as VEGF-A and TNF-β, and sarcopenia. This finding may provide new avenues for future clinical treatments. 10.3389/fmed.2024.1351376
COVID-19 and sarcopenia-related traits: a bidirectional Mendelian randomization study. Frontiers in endocrinology Background:Emerging evidence suggested that coronavirus disease 2019 (COVID-19) patients were more prone to acute skeletal muscle loss and suffer sequelae, including weakness, arthromyalgia, depression and anxiety. Meanwhile, it was observed that sarcopenia (SP) was associated with susceptibility, hospitalization and severity of COVID-19. However, it is not known whether there is causal relationship between COVID-19 and SP-related traits. Mendelian randomization (MR) was a valid method for inferring causality. Methods:Data was extracted from the COVID-19 Host Genetic Initiative and the UK Biobank without sample overlapping. The MR analysis was performed with inverse variance weighted, weighted median, MR-Egger, RAPS and CAUSE, MR-APSS. Sensitivity analysis was conducted with MR-Egger intercept test, Cochran's Q test, MR-PRESSO to eliminate pleiotropy. Results:There was insufficient result in the MR-APSS method to support a direct causal relationship after the Bonferroni correction. Most other MR results were also nominally consistent with the MR-APSS result. Conclusions:Our study first explored the causal relationship between COVID-19 and SP-related traits, but the result indicated that they may indirectly interact with each other. We highlighted that older people had better absorb enough nutrition and strengthen exercise to directly cope with SP during the COVID-19 pandemic. 10.3389/fendo.2023.1162936
Identifying genetic determinants of sarcopenia-related traits: a Mendelian randomization study of druggable genes. Metabolism: clinical and experimental BACKGROUND:Sarcopenia, characterized by progressive muscle mass and function loss, particularly affects the elderly, and leads to severe consequences such as falls and mortality. Despite its prevalence, targeted pharmacotherapies for sarcopenia are lacking. Utilizing large-sample genome-wide association studies (GWAS) data is crucial for cost-effective drug discovery. METHODS:Herein, we conducted four studies to understand the putative causal effects of genetic components on muscle mass and function. Study 1 employed a two-sample Mendelian randomization (MR) on 15,944 potential druggable genes, investigating their potential causality with muscle quantity and quality in a European population (N up to 461,089). Study 2 validated MR results through sensitivity analyses and colocalization analyses. Study 3 extended validation across other European cohorts, and study 4 conducted quantitative in vivo verification. RESULTS:MR analysis revealed significant causality between four genes (BLOC-1 related complex subunit 7, BORCS7; peptidase m20 domain containing 1, PM20D1; nuclear casein kinase and cyclin dependent kinase substrate 1, NUCKS1 and ubiquinol-cytochrome c reductase complex assembly factor 1, UQCC1) and muscle mass and function (p-values range 5.98 × 10 to 9.26 × 10). To be specific, BORCS7 and UQCC1 negatively regulated muscle quantity and quality, whereas enhancing PM20D1 and NUCKS1 expression showed promise in promoting muscle mass and function. Causal relationships remained robust across sensitivity analyses, with UQCC1 exhibiting notable colocalization effects (PP·H4 93.4 % to 95.8 %). Further validation and in vivo replication verified the potential causality between these genes and muscle mass as well as function. CONCLUSIONS:Our druggable genome-wide MR analysis identifies BORCS7, PM20D1, NUCKS1, and UQCC1 as causally associated with muscle mass and function. These findings offer insights into the genetic basis of sarcopenia, paving the way for these genes to become promising drug targets in mitigating this debilitating condition. 10.1016/j.metabol.2024.155994
The causal relationship between sarcopenia-related traits and ischemic stroke: Insights from univariable and multivariable Mendelian randomization analyses. CNS neuroscience & therapeutics AIMS:The causal relationship between sarcopenia-related traits and ischemic stroke (IS) remains poorly understood. This study aimed to explore the causal impact of sarcopenia-related traits on IS and to identify key mediators of this association. METHODS:We conducted univariable, multivariable two-sample, and two-step Mendelian randomization (MR) analyses using genome-wide association study (GWAS) data. This included data for appendicular lean mass (ALM), hand grip strength (HGS), and usual walking pace (UWP) from the UK Biobank, and IS data from the MEGASTROKE consortium. Additionally, 21 candidate mediators were analyzed based on their respective GWAS data sets. RESULTS:Each 1-SD increase in genetically proxied ALM was associated with a 7.5% reduction in the risk of IS (95% CI: 0.879-0.974), and this correlation remained after controlling for levels of physical activity and adiposity-related indices. Two-step MR identified that six mediators partially mediated the protective effect of higher ALM on IS, with the most significant being coronary heart disease (CHD, mediating proportion: 39.94%), followed by systolic blood pressure (36.51%), hypertension (23.87%), diastolic blood pressure (15.39%), type-2 diabetes mellitus (T2DM, 12.71%), and low-density lipoprotein cholesterol (7.97%). CONCLUSION:Our study revealed a causal protective effect of higher ALM on IS, independent of physical activity and adiposity-related indices. Moreover, we found that higher ALM could reduce susceptibility to IS partially by lowering the risk of vascular risk factors, including CHD, hypertension, T2DM, and hyperlipidemia. In brief, we elucidated another modifiable factor for IS and implied that maintaining sufficient muscle mass may reduce the risk of such disease. 10.1111/cns.14759
Mapping the causal associations of cytokines with sarcopenia and aging traits: Evidence from bidirectional Mendelian randomization. Journal of cachexia, sarcopenia and muscle BACKGROUND:Cytokines and growth factors may serve as a bridge in studying the causal relationships between inflammaging and sarcopenia due to their roles in inflammaging. In this study, we aim to explore the causal association of cytokines with sarcopenia and aging traits and further identify the significant inflammation factors. METHODS:Bidirectional Mendelian randomization (MR) analysis was used to identify the causality. Forty-one kinds of circulation cytokines and growth factors were set as exposures, and the data were from a summary genome-wide association study (GWAS) containing three cohorts with 8293 healthy participants of European ancestry from 1983 to 2011. Hand grip strength, adjusted appendicular lean mass (AALM), usual walking pace, moderate-to-vigorous physical activity (MVPA) levels, able to walk or cycle unaided for 10 min (AWCU10) and telomere length were selected as outcomes. Data for outcomes were obtained from meta-GWAS and the UK Biobank, and sample sizes ranged from 69 537 to 472 174. Low hand grip strength was defined by the European Working Group on Sarcopenia in Older People (EWGSOP) and Foundation for the National Institutes of Health (FNIH) cut-off points, respectively. Other outcome traits were defined and measured according to the UK Biobank and raw cohorts' criteria. We set two significance thresholds for single nucleotide polymorphisms (SNPs) associated with exposures to obtain adequate SNPs (5 × 10 and 5 × 10). Inverse-variance weighted, MR-Egger and weighted median were employed to estimate the causality. RESULTS:Twenty-seven factors were identified to relate to sarcopenia and aging traits causally, and most were associated with only one outcome trait. IL16 (interleukin-16), CTACK (cutaneous T-cell attracting chemokine), MIP1b (macrophage inflammatory protein 1b) and PDGFbb (platelet-derived growth factor BB) were proven to relate causally to at least one sarcopenia and aging trait in both analyses with two significance thresholds. IL16 was causally associated with hand grip strength (0.977 [0.956-0.998] for EWGSOP and 0.933 [0.874-0.996] for FNIH), AALM (0.991 [0.984, 0.998]), MVPA (0.997 [0.995-1.000]) and AWCU10 (1.008 [1.003-1.013]). CTACK was proven to relate causally to hand grip strength (1.013 [1.007-1.019] for EWGSOP and 1.090 [1.041-1.142] for FNIH), AWCU10 (0.990 [0.986-0.994]) and telomere length (0.998 [0.983-0.994]). The results indicated that MIP1b has a causal effect on hand grip strength (1.032 [1.001-1.063] for EWGSOP), AWCU10 (0.994 [0.988-1.000] and 0.993 [0.988-0.998]) and telomere length (1.006 [1.000-1.012]). PDGFbb may causally relate to AALM (1.016 [1.001-1.030]) and telomere length (1.011 [1.007-1.015]). Reserve MR analyses also proved their unidirectional causal effects. CONCLUSIONS:Twenty-seven factors were causally related to sarcopenia and aging traits, and the causal effects of IL16, CTACK, MIP1b and PDGFbb were proven in both analyses with two significance thresholds. 10.1002/jcsm.13456
Association between appendicular lean mass and chronic obstructive pulmonary disease: epidemiological cross-sectional study and bidirectional Mendelian randomization analysis. Frontiers in nutrition Background:The association of BMI with COPD, and sarcopenia in COPD have been both confirmed by several studies, but research on the relationship and causality of body lean mass and the risk of chronic obstructive pulmonary disease (COPD) remains to be discovered. The purpose of this study was to explore the association between lean mass and COPD risk as well as to further examine the causal relationship in the findings. Methods:Three thousand four hundred fifty-nine participants from NHANES 2013-2018 were included in the epidemiological cross-sectional study to assess the association between relative lean mass and COPD by restricted spline analysis (RCS) and weighted multiple logistic regression. Furthermore, to verify the causality between lean mass and COPD, a two-sample Mendelian randomization (MR) with inverse variance weighting (IVW) method was used to analyze GWAS data from European ancestry. Genetic data from the United Kindom Biobank for appendicular lean mass (450,243 cases) and lung function (FEV/FVC) (400,102 cases) together with the FinnGen platform for COPD (6,915 cases and 186,723 controls) were used for MR. Results:Weighted multiple logistic regression showed a significant correlation between relative appendicular lean mass and COPD after adjusting for confounders (OR = 0.985, 95% CI: 0.975-0.995). Compared to the lower mass (155.3-254.7) g/kg, the high mass (317.0-408.5) g/kg of appendicular lean apparently decreases the risk of COPD (OR = 0.214, 95% CI: 0.060-0.767). Besides, in the analysis of MR, there was a forward causality between appendicular lean mass and COPD (IVW: OR = 0.803; 95%CI: 0.680-0.949;  = 0.01), with a weak trend of causality to lung function. Conclusion:Our study not only found an inverse association between appendicular lean mass and COPD but also supported a unidirectional causality. This provided possible evidence for further identification of people at risk for COPD and prevention of COPD based on limb muscle exercise and nutritional supplementation to maintain skeletal muscle mass. 10.3389/fnut.2023.1159949
Casual associations between brain structure and sarcopenia: A large-scale genetic correlation and mendelian randomization study. Aging cell Sarcopenia presenting a critical challenge in population-aging healthcare. The elucidation of the interplay between brain structure and sarcopenia necessitates further research. The aim of this study is to explore the casual association between brain structure and sarcopenia. Linkage disequilibrium score regression (LDSC) was conducted to estimate the genetic correlations; MR was then performed to explore the causal relationship between Brain imaging-derived phenotypes (BIDPs) and three sarcopenia-related traits: handgrip strength, walking pace, and appendicular lean mass (ALM). The main analyses were conducted using the inverse-variance weighted method. Moreover, weighted median and MR-Egger were conducted as sensitivity analyses. Genetic association between 6.41% of BIDPs and ALM was observed, and 4.68% of BIDPs exhibited causal MR association with handgrip strength, 2.11% of BIDPs were causally associated with walking pace, and 2.04% of BIDPs showed causal association with ALM. Volume of ventromedial hypothalamus was associated with increased odds of handgrip strength (OR: 1.18, 95% CI: 1.02 to 1.37) and ALM (OR: 1.05, 95% CI: 1.01 to 1.09). Mean thickness of G-pariet-inf-Angular was associated with decreased odds of handgrip strength (OR: 0.83, 95% CI: 0.70 to 0.97) and walking pace (OR: 0.97, 95% CI: 0.93 to 0.99). As part of the brain structure forward causally influences sarcopenia, which may provide new perspectives for the prevention of sarcopenia and offer valuable insights for further research on the brain-muscle axis. 10.1111/acel.14252
Sarcopenia and risk of cardio-cerebrovascular disease: A two-sample Mendelian randomization study. Bioscience trends Based on the association between sarcopenia and the risk of developing cardio-cerebrovascular disease (CCVD) established by a meta-analysis by Fang et al.(Biosci Trends. 2023; 17:293-301), we have used Mendelian randomization (MR) analysis to test the authenticity and accuracy of such an association. In this MR study, appendicular lean mass, handgrip strength, and walking pace were used as sarcopenia-related traits, with cardiovascular diseases and stroke set as outcomes of CCVD. MR analysis was performed using inverse-variance weighting, the MR Egger, weighted median, simple mode, and weighted mode. No heterogeneity or horizontal pleiotropy in MR estimates was observed (Cochran's Q P value > 0.05, MR-PRESSO global test P value > 0.05, and MR-Egger intercept P value > 0.05). Results of that analysis proved a causal relationship between sarcopenia-related traits and cardio-cerebrovascular disease, with a causal association between appendicular lean mass and cardiovascular diseases and an inverse causal relationship between appendicular lean mass and stroke. However, such a relationship was absent in the case of handgrip strength and the risk of cardiovascular diseases as well as in the case of walking pace and lacunar/ischemic stroke. Therefore, the effect of sarcopenia on CCVD should be carefully explained. 10.5582/bst.2023.01246
Genetically Predicted Levels of Serum Metabolites and Risk of Sarcopenia: A Mendelian Randomization Study. Nutrients Metabolites' connection to sarcopenia through inflammation and mitochondrial dysfunction is presumed, but their impact remains unclear due to limitations in conventional observational studies caused by confounding bias and reverse causation. We conducted a Mendelian randomization (MR) analysis to elucidate the association of serum metabolites with sarcopenia and its related traits, i.e., appendicular lean mass and grip strength. Genetic instruments to proxy the serum metabolites were extracted from the most comprehensive genome-wide association study on the topic published so far. The corresponding summary statistics for the associations of genetic instruments with outcomes were calculated from the UK Biobank (n = 324,976 participants). The primary analyses were assessed by an inverse-variance weighted (IVW) method. The weighted median and MR-PRESSO methods were used as sensitive analyses. Fourteen genetically predicted serum metabolites were associated with the risk of sarcopenia ( < 0.05). Two metabolites showed the overlapped association with sarcopenia and its related traits, which were isovalerylcarnitine (sarcopenia: odds ratio [OR] = 4.00, 95% confidence interval [CI] = 1.11~14.52, = 0.034; appendicular lean mass: β = -0.45 kg, 95% CI = -0.81~-0.09, = 0.015; grip strength: β = -1.51 kg, 95% CI = -2.31~-0.71, = 2.19 × 10) and docosapentaenoate (sarcopenia: OR = 0.16, 95% CI = 0.03~0.83, = 0.029; appendicular lean mass: β = -0.45 kg, 95% CI = 0.08~0.81, = 0.016). Twenty-seven metabolites were suggestive associated with appendicular lean mass or grip strength. This MR study provided evidence for the potential effects of metabolites on sarcopenia. 10.3390/nu15183964
The relationship between sarcopenia and mortality in Chinese community-dwelling adults: a 7-year cohort study with propensity score matching and Mendelian randomization. Frontiers in endocrinology Background:Sarcopenia has been linked to adverse health outcomes, including an increased risk of mortality. This study aimed to assess the 7-year mortality risk of sarcopenia in a community-based population in China and explore the causal relationship between components of sarcopenia and any death. Methods:Data were sourced from the China Health and Retirement Longitudinal Study (CHARLS) conducted between 2011 and 2018. Sarcopenia was diagnosed using the Asian Working Group for Sarcopenia (AWGS) 2019 criteria. Logistic regression, Kaplan-Meier (KM) survival analysis, and propensity score matching with inverse probability of treatment weighting were used. Mendelian randomization (MR) analyses, conducted using European population data, were utilized to assess causality between sarcopenia and any death. Results:The study included 9,006 participants: 3,892 had no sarcopenia, 3,570 had possible sarcopenia, 1,125 had sarcopenia, and 419 had severe sarcopenia. Over 7 years of follow-up, there were 871 deaths, including 196 with sarcopenia and 133 with severe sarcopenia. The KM curves showed that sarcopenia had a higher risk of mortality. Compared to those of no sarcopenia, the odds ratios (ORs) of sarcopenia for 7-year mortality were 1.41 (95% CI, 1.06-1.87) after adjusting for confounding variables ( < 0.05). The ORs of severe sarcopenia were 2.11 (95% CI, 1.51-2.95). Propensity score matching analysis and inverse probability of treatment weighting analysis confirmed these findings. The adjusted ORs of sarcopenia and 7-year mortality were 2.94 (95% CI, 1.6-5.39) in the 45-60 age group, 1.72 (95% CI, 1.11-2.68) in the 60-80 age group, and 5.03 (95% CI, 0.48-52.65) in the ≥80 age group. The ORs of severe sarcopenia and 7-year mortality were 6.92 (95% CI, 1.95-24.5) in the 45-60 age group, 2.59 (95% CI, 1.61-4.17) in the 60-80 age group, and 12.52 (95% CI, 1.18-133.18) in the ≥80 age group. The MR analyses, leveraging the inverse variance weighted (IVW) method, unveiled substantial causal links between low hand grip strength in individuals aged 60 and older, the usual walking pace, and mortality risk. Conclusion:This study underscores the significant impact of sarcopenia and its components on mortality risk within the Chinese population. Particularly, low hand grip strength and usual walking pace emerged as noteworthy contributors to mortality risk. 10.3389/fendo.2023.1215512
Association between sarcopenia-related traits and cardiovascular diseases: a bi-directional Mendelian randomization study. Frontiers in endocrinology Background:The two geriatric diseases, sarcopenia and cardiovascular disease (CVD), often coexist, yet the causal relationship is unclear. However, few studies focus on the effect of muscle mass on CVD. This comprehensive study is dedicated to unearthing the potential connection between sarcopenia-related traits and CVD at the genetic level. Method:A two-sample bi-directional Mendelian randomization (MR) study was conducted. In the first stage, we performed MR analysis regarding coronary heart disease (CHD), stroke, and myocardial infarction (MI) as exposure factors to reveal their effect on appendicular lean mass (ALM) and hand grip strength. In the second stage, we reverse the position of exposures and outcomes. The inverse variance weighted (IVW) method was used as the primary approach to reveal the potential causation between the exposure and outcome. Results:The results of the IVW method revealed a negative causal effect of ALM on CHD (OR = 0.848, 95% CI = 0.804 to 0.894, p = 8.200E-10), stroke (OR = 0.931, 95% CI = 0.890 to 0.975, p = 2.220E-03), and MI (OR = 0.810, 95% CI = 0.694 to 0.901, p = 1.266E-13). Additionally, the left-hand grip strength is a significant protective factor for CHD (OR = 0.737, 95% CI = 0.601 to 0.904, p = 3.353E-03) and MI (OR = 0.631, 95% CI = 0.515 to 0.765, p = 2.575E-06), but is not causally linked to the stroke (OR = 0.971, 95% CI =0.829 to 1.139, p = 0.720). Meanwhile, the same conclusion about the effect of right-hand grip strength on CHD (OR = 0.681, 95% CI = 0.558 to 0.832, p = 1.702E-05), MI (OR = 0.634, 95% CI = 0.518 to 0.776, p = 9.069E-06), and stroke (OR = 1.041, 95% CI = 0.896 to 1.209, p = 0.604) was obtained. However, no significant causal effect of CVD (CHD, stroke, MI) on sarcopenia-related traits (ALM, handgrip strength) was found. Conclusion:There is a unidirectional causal relationship between sarcopenia and CVD. The loss of muscle mass and strength has a significant causal role in promoting the occurrence and development of CVD, providing a reference for the prevention and treatment of comorbidities in older people. 10.3389/fendo.2023.1237971
A bidirectional Mendelian randomization study of sarcopenia-related traits and inflammatory bowel diseases. Frontiers in immunology Background:There is increasing evidence pointing to a close relationship between sarcopenia and inflammatory bowel disease. However, it remains unclear whether or in which direction causal relationships exist, because these associations could be confounded. Methods:We conducted a two-sample bidirectional mendelian randomization analysis using data from European genome-wide association studies of the appendicular lean mass(n = 450,243), walking pace(n = 459,915), grip strength (left hand, n = 461,026; right hand, n = 461,089), inflammatory bowel disease (25,042 patients and 34,915 controls), ulcerative colitis (12,366 patients and 33,609 controls), and Crohn's disease (12,194 patients and 28,072 controls) to investigate the causal relationship between sarcopenia-related traits and inflammatory bowel disease and its subtypes on each other. The inverse-variance weighted method was used as the primary analysis method to assess the causality, and a comprehensive sensitivity test was conducted. Results:Genetically predicted appendicular lean mass was significantly associated with inflammatory bowel disease (OR = 0.916, 95%CI: 0.853-0.984, = 0.017), ulcerative colitis (OR =0.888, 95%CI: 0.813-0.971, = 0.009), and Crohn's disease (OR = 0.905, 95%CI: 0.820-0.999, = 0.049). Similar results also revealed that the usual walking pace was causally associated with Crohn's disease (OR = 0.467, 95%CI: 0.239-0.914, = 0.026). Reverse mendelian randomization analysis results found that genetic susceptibility to inflammatory bowel disease, and Crohn's disease were associated with lower appendicular lean mass. A series of sensitivity analyses ensured the reliability of the present research results. Conclusion:The mendelian randomization study supports a bidirectional causality between inflammatory bowel disease, Crohn's disease and appendicular lean mass, but no such bidirectional causal relationship was found in ulcerative colitis. In addition, genetically predicted usual walking pace may reduce the risk of Crohn's disease. These findings have clinical implications for sarcopenia and inflammatory bowel disease management. 10.3389/fimmu.2023.1240811
Causal Roles of Lifestyle, Psychosocial Characteristics, and Sleep Status in Sarcopenia: A Mendelian Randomization Study. The journals of gerontology. Series A, Biological sciences and medical sciences BACKGROUND:Many studies reported that lifestyle, psychosocial characteristics, and sleep status related to sarcopenia, although few studies provided evidence of causal relationships between them. METHODS:The data used in our study were from UK Biobank, FinnGen Release 8, and large genome-wide association study meta-analyses. Two-sample Mendelian randomization was conducted to identify the causal associations of 21 traits of lifestyle, psychosocial characteristics, and sleep status with 6 traits of sarcopenia. Benjamini-Hochberg correction was performed to reduce the bias caused by multiple tests. Risk factor analyses were performed to explore the potential mechanism behind the exposures. RESULTS:Mendelian randomization analyses after adjustment proved the causal roles of coffee intake, education years, smoking, leisure screen time, and moderate-to-vigorous intensity physical activity during leisure time in sarcopenia was proven although providing no significant evidence for causal roles for carbohydrates intake, protein intake, alcohol, and sleep status in sarcopenia. CONCLUSIONS:Our results strongly support that coffee intake, education years, smoking, leisure screen time, and moderate-to-vigorous intensity physical activity during leisure time played significantly causal roles in sarcopenia, which may provide new intervention strategies for preventing the development of sarcopenia. 10.1093/gerona/glad191
Depression and risk of sarcopenia: a national cohort and Mendelian randomization study. Frontiers in psychiatry Background:Depression and the increased risk of sarcopenia are prevalent among the elderly population. However, the causal associations between these factors remain unclear. To investigate the potential association between depression and the risk of sarcopenia in older adults, this study was performed. Methods:In the baseline survey, a total of 14,258 individuals aged 40 and above from the China Health and Retirement Longitudinal Study (2015) participated. We initially described the baseline prevalence of the disease. Then, logistic regression and restricted cubic spline (RCS) regression were conducted to assess the relationship between depression and sarcopenia. Subgroup analysis was performed to validate the robustness of the findings. Additionally, we conducted Mendelian randomization analysis using the inverse variance weighting estimator to assess the causal relationship between depression and sarcopenia. Furthermore, we adopted six methods, including MR-Egger, simple median, weighted median, maximum likelihood, robust adjusted profile score (RAPS), and MR Pleiotropy Residual Sum and Outlier (MR-PRESSO), for sensitivity analyses. Results:Depression patients exhibited higher risks of sarcopenia in all five models adjusting for different covariates ( < 0.05). The RCS analysis demonstrated a linear relationship between depression and sarcopenia ( < 0.05). In the subgroup analysis, increased risk was observed among participants aged 60-70, married or cohabiting individuals, non-smokers, non-drinkers, those with less than 8 h of sleep, BMI below 24, and individuals with hypertension (all < 0.05). Mendelian randomization results revealed that genetically proxied depression led to a reduction in appendicular skeletal muscle mass (all < 0.05). Conclusion:Our study provides observational and causal evidences that depression can lead to sarcopenia. This finding emphasizes the importance of timely identification and management of depression, as well as implementing targeted educational programs as part of comprehensive strategies to prevent sarcopenia. 10.3389/fpsyt.2023.1263553
Muscle Traits, Sarcopenia, and Sarcopenic Obesity: A Vitamin D Mendelian Randomization Study. Nutrients (1) Background: Observational studies associate vitamin D deficiency with muscle disorders, while some clinical trial data support a minor association between the vitamin and skeletal muscle performance in healthy subjects. Vitamin D receptor knockout mice studies confirm the relationship between vitamin D and skeletal muscle; however, causal inference in humans is challenging due to the ethical implications of including vitamin D-deficient participants in randomized trials. This study uses genetic methods to safely explore causal underpinnings for the relationship between 25(OH)D concentrations and skeletal muscle-related traits, including grip strength and combined arm skeletal muscle mass, and extends this analysis to suspected pathophysiology in the form of probable sarcopenia and sarcopenic obesity. (2) Methods: We conducted Mendelian randomization (MR) analyses in up to 307,281 participants from the UK Biobank of whom 25,414 had probable sarcopenia and 16,520 had sarcopenic obesity. In total, 35 variants were used to instrument 25(OH)D and MR analyses conducted using multiple approaches. (3) Results: Genetic analyses provided support for a relationship between genetically predicted higher 25(OH)D and skeletal muscle traits, with linear MR analyses for grip strength showing 0.11 kg (95% CI 0.04, 0.19) greater contractile force per 10 unit higher 25(OH)D, while there was a modest association with skeletal muscle mass (0.01 kg (95% CI 0.003, 0.02) greater muscle mass). For probable sarcopenia risk, there was suggestive evidence for lower odds by higher 25(OH)D (OR 0.96 (95% CI 0.92, 1.00)); however, this did not reflect an association with sarcopenic obesity (OR 0.97 (95% CI 0.93, 1.02)), but was seen in probable sarcopenia cases who were not obese (OR 0.92 (95% CI 0.86, 0.98)). Results were similar across multiple MR approaches. (4) Conclusions: Our study supports a causal relationship between 25(OH)D and skeletal muscle health. While evidence for benefit did not extend to lower risk of sarcopenic obesity, effective vitamin D-deficiency prevention strategies may help reduce age-related muscle weakness. 10.3390/nu15122703
Causal linkage of tobacco smoking with ageing: Mendelian randomization analysis towards telomere attrition and sarcopenia. Journal of cachexia, sarcopenia and muscle BACKGROUND:Ageing traits and frailty are important health issues in modern medicine. Evidence supporting the causal effects of tobacco smoking on various ageing traits is required. METHODS:This study performed Mendelian randomization (MR) analysis instrumenting 377 genetic variants associated with being an ever-smoker at a genome-wide significance level to test the causal estimates from tobacco smoking. The outcome data were obtained from 337 138 white British ancestry participants from the UK Biobank. Leucocyte telomere length, appendicular lean mass index, subjective walking pace, handgrip strength, and wristband accelerometry-determined physical activity degree were collected as ageing-related outcomes. Summary-level MR analysis was performed using the inverse variance-weighted method and pleiotropy-robust MR methods, including weighted median and MR-Egger. Observational association between the outcome traits and phenotypically being an ever-smoker was also investigated. RESULTS:Summary-level MR analysis indicated that a higher genetic predisposition for tobacco smoking was significantly associated with shorter leucocyte telomere length (twofold increase in prevalence of smoking towards standardized Z-score, -0.041 [-0.054, -0.028]), lower appendicular lean mass index (-0.007 [-0.010, -0.005]), slower walking pace (ordinal category, -0.047 [-0.054, -0.033]) and lower time spent on moderate-to-vigorous physical activity (hours per week, -0.39 [-0.56, -0.23]). The causal estimates were non-significant towards handgrip strength phenotype (kg, 0.074 [-0.055, 0.204]). Pleiotropy-robust MR results generally supported the main causal estimates. The observational findings also showed significant association between being an ever-smoker and the ageing traits. CONCLUSIONS:Genetically predicted and observational tobacco smoking status are significantly associated with poor ageing phenotypes. Healthcare providers may continue to reduce tobacco use, which may be helpful in reducing the burden of ageing and frailty. 10.1002/jcsm.13174
A bi-directional Mendelian randomization study of the sarcopenia-related traits and osteoporosis. Aging Both sarcopenia and osteoporosis are common geriatric diseases causing huge socioeconomic burdens, and clinically, they often occur simultaneously. Observational studies have found a controversial correlation between sarcopenia and osteoporosis and their causal relationship is not clear. Therefore, we performed a bi-directional two-sample Mendelian randomization (MR) analysis to assess the potential causal relationship between sarcopenia-related traits (hand grip strength, lean mass, walking pace) and osteoporosis. Our analysis was performed by applying genetic variants obtained from the UK Biobank and the GEnetic Factors for OSteoporosis (GEFOS) datasets. We used inverse-variance weighted (IVW) and several sensitivity analyses to estimate and cross-validate the potential causal relationship in this study. We found that bone mineral density (BMD) was causally positively associated with left-hand grip strength (β = 0.017, -value = 0.001), fat-free mass (FFM; right leg FFM, β = 0.014, -value = 0.003; left arm FFM, β = 0.014, -value = 0.005), but not walking pace. Higher hand grip strength was potentially causally associated with increased LS-BMD (right-hand grip strength, β = 0.318, -value = 0.001; left-hand grip strength, β = 0.358, -value = 3.97 × 10-4). In conclusion, osteoporosis may be a risk factor for sarcopenia-related traits and muscle strength may have a site-specific effect on BMD. 10.18632/aging.204145
A bi-directional Mendelian randomization study of sarcopenia-related traits and type 2 diabetes mellitus. Frontiers in endocrinology Background:Previous studies have reported an association between sarcopenia and type 2 diabetes mellitus (T2DM), but causation was prone to confounding factors. A more robust research approach is urgently required to investigate the causal relationship between sarcopenia and T2DM. Methods:The bi-directional two-sample MR study was carried out in two stages: Sarcopenia-related traits were investigated as exposure while T2DM was investigated as an outcome in the first step, whereas the second step was reversed. The GWAS summary data for hand-grip strength (n = 256,523), appendicular lean mass (ALM, n = 450,243), and walking pace (n = 459,915) were obtained from the UK Biobank. T2DM data were obtained from one of the biggest case-control studies on diabetes (DIAGRAM; n = 180,834 cases and 492,191 controls), which was published in 2022. The inverse-variance weighted (IVW) approach was used to obtain MR estimates, and various sensitivity analysis was also performed. Results:Low hand-grip strength had a potential causal relationship with an increased incidence of T2DM (OR = 1.109; 95% CI, 1.008-1.222; = 0.0350). T2DM risk was reduced by increasing ALM and walking pace: A 1 kg/m increase in ALM decreased the risk of T2DM by 10.2% (OR = 0.898; 95% CI, 0.830-0.952; < 0.001). A 1 m/s increase in walking pace decreased the risk of T2DM by 90.0% (OR = 0.100; 95% CI, 0.053-0.186; < 0.001). The relationship was bidirectional, with T2DM as a causative factor of sarcopenia-related traits ( < 0.05) except for ALM (β = 0.018; 95% CI, -0.008 to -0.044; = 0.168). Conclusions:Hand-grip strength and T2DM had a potential bidirectional causal relationship, as did walking pace and T2DM. We suggest that sarcopenia and T2DM may mutually have a significant causal effect on each other. 10.3389/fendo.2023.1109800
Genetic Association and Potential Mediators between Sarcopenia and Coronary Heart Disease: A Bidirectional Two-Sample, Two-Step Mendelian Randomization Study. Nutrients OBJECTIVE:To elucidate the bidirectional correlation of sarcopenia with coronary heart disease (CHD), as well as to investigate the mediating role of cardiometabolic factors and inflammatory biomarkers, a bidirectional two-sample, two-step Mendelian randomization (MR) study was conducted. METHODS:Summary statistics were obtained from genome-wide association studies (GWAS). In our bidirectional two-sample MR, genetic variants associated with sarcopenia-related traits and CHD were instrumented for the estimation of bidirectional correlations. Besides, genetic variants associated with thirteen cardiometabolic factors and six inflammatory biomarkers were selected for further mediation analyses. To confirm the consistency of the results, several sensitivity analyses were carried out. RESULTS:Genetically predicted higher appendicular lean mass (OR = 0.835, 95% CI: 0.790-0.882), left hand grip strength (OR = 0.703, 95% CI: 0.569-0.869), right hand grip strength (OR = 0.685, 95% CI: 0.555-0.844), and walking pace (OR = 0.321, 95% CI: 0.191-0.539) reduced CHD risk, while genetic predisposition to CHD did not affect any of the sarcopenia-related traits. Seven mediators were identified for the effects of appendicular lean mass on CHD, including waist-to-hip ratio, hip circumference, systolic blood pressure, low-density lipoprotein cholesterol, total cholesterol, triglycerides, and fasting insulin. The mediation proportion ranged from 10.23% for triglycerides to 35.08% for hip circumference. Hip circumference was found to mediate the relationships between both left (mediation proportion: 24.61%) and right-hand grip strength (24.14%) and CHD, and the link between walking pace and CHD was partially mediated by waist-to-hip ratio (31.15%) and body mass index (26.66%). CONCLUSION:Our results showed that higher appendicular lean mass, hand grip strength, and walking pace reduced CHD risk, but the causal relationship was not bidirectional. Several mediators were found to mediate the causal pathways between sarcopenia-related traits and CHD, and intervention of these factors may be helpful in terms of CHD prevention in sarcopenia patients. 10.3390/nu15133013
Systematic druggable genome-wide Mendelian randomization identifies therapeutic targets for sarcopenia. Journal of cachexia, sarcopenia and muscle BACKGROUND:There are no effective pharmacological treatments for sarcopenia. We aim to identify potential therapeutic targets for sarcopenia by integrating various publicly available datasets. METHODS:We integrated druggable genome data, cis-eQTL/cis-pQTL from human blood and skeletal muscle tissue, and GWAS summary data of sarcopenia-related traits to analyse the potential causal relationships between drug target genes and sarcopenia using the Mendelian Randomization (MR) method. Sensitivity analyses and Bayesian colocalization were employed to validate the causal relationships. We also assessed the side effects or additional indications of the identified drug targets using a phenome-wide MR (Phe-MR) approach and investigated actionable drugs for target genes using available databases. RESULTS:MR analysis identified 17 druggable genes with potential causation to sarcopenia in human blood or skeletal muscle tissue. Six of them (HP, HLA-DRA, MAP 3K3, MFGE8, COL15A1, and AURKA) were further confirmed by Bayesian colocalization (PPH4 > 90%). The up-regulation of HP [higher ALM (beta: 0.012, 95% CI: 0.007-0.018, P = 1.2*10) and higher grip strength (OR: 0.96, 95% CI: 0.94-0.98, P = 4.2*10)], MAP 3K3 [higher ALM (beta: 0.24, 95% CI: 0.21-0.26, P = 1.8*10), higher grip strength (OR: 0.82, 95% CI: 0.75-0.90, P = 2.1*10), and faster walking pace (beta: 0.03, 95% CI: 0.02-0.05, P = 8.5*10)], and MFGE8 [higher ALM (muscle eQTL, beta: 0.09, 95% CI: 0.06-0.11, P = 6.1*10; blood pQTL, beta: 0.05, 95% CI: 0.03-0.07, P = 3.8*10)], as well as the down-regulation of HLA-DRA [lower ALM (beta: -0.09, 95% CI: -0.11 to -0.08, P = 5.4*10) and lower grip strength (OR: 1.13, 95% CI: 1.07-1.20, P = 1.8*10)] and COL15A1 [higher ALM (muscle eQTL, beta: -0.07, 95% CI: -0.10 to -0.04, P = 3.4*10; blood pQTL, beta: -0.05, 95% CI: -0.06 to -0.03, P = 1.6*10)], decreased the risk of sarcopenia. AURKA in blood (beta: -0.16, 95% CI: -0.22 to -0.09, P = 2.1*10) and skeletal muscle (beta: 0.03, 95% CI: 0.02 to 0.05, P = 5.3*10) tissues showed an inverse relationship with sarcopenia risk. The Phe-MR indicated that the six potential therapeutic targets for sarcopenia had no significant adverse effects. Drug repurposing analysis supported zinc supplementation and collagenase clostridium histolyticum might be potential therapeutics for sarcopenia by activating HP and inhibiting COL15A1, respectively. CONCLUSIONS:Our research indicated MAP 3K3, MFGE8, COL15A1, HP, and HLA-DRA may serve as promising targets for sarcopenia, while the effectiveness of zinc supplementation and collagenase clostridium histolyticum for sarcopenia requires further validation. 10.1002/jcsm.13479
Causality between sarcopenia and diabetic nephropathy: a bidirectional Mendelian randomization study. Frontiers in endocrinology Background and purpose: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. Methodology: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. Results: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. Conclusion: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. 10.3389/fendo.2023.1188972
Causal associations of sarcopenia-related traits with cardiometabolic disease and Alzheimer's disease and the mediating role of insulin resistance: A Mendelian randomization study. Aging cell The causal influence of sarcopenia on cardiometabolic disease and Alzheimer's disease and whether and to what extent insulin resistance plays a mediating role therein were unclear. We performed two-step, two-sample Mendelian randomization applying genetic instruments of sarcopenia-related traits based on GWASs from the UK Biobank (up to 461,026 European participants) to examine their causal associations with six cardiometabolic diseases and Alzheimer's disease extracted from large-scale European descent GWASs with adjustment for body fat percentage and physical activity, and to assess proportions of the causal effects mediated by insulin resistance. Genetic instruments of insulin resistance were derived from the GWASs by Meta-Analyses of Glucose and Insulin-related traits Consortium and Global Lipids Genetics Consortium. Each 1-SD lower grip strength, appendicular lean mass (ALM) and whole-body lean mass (WBLM), as well as lower walking pace, were causally associated with higher risks of diabetes (odds ratio [OR] range: 1.20 [95% confidence interval: 1.10-1.32] for ALM to 2.30 [1.14-4.68] for walking pace), nonalcoholic fatty liver disease ([NAFLD], 1.33 [1.08-1.64] for ALM to 2.30 [1.02-5.18] for grip strength), hypertension (1.12 [1.05-1.20] for ALM to 4.43 [2.68-7.33] for walking pace), coronary heart disease ([CHD], 1.20 [1.13-1.27] for ALM to 2.73 [1.84-4.05] for walking pace), myocardial infarction ([MI], 1.18 [1.11-1.25] for ALM to 2.47 [1.63-3.73] for walking pace), small vessel stroke (1.25 [1.15-1.37] for ALM to 1.29 [1.10-1.52] for WBLM), and Alzheimer's disease (1.10 [1.05-1.15] for ALM to 1.28 [1.19-1.38] for WBLM). These causal associations were largely independent of body fat percentage and physical activity. Insulin resistance mediated 16%-34% of the effect of grip strength and 7%-28% of the effect of ALM on diabetes, NAFLD, hypertension, CHD, and MI. The direct effect of WBLM on diabetes diminished toward null with adjustment for insulin resistance. We found no evidence that insulin resistance was on the causal pathways from walking pace to the studied disease outcomes. Causal findings from the inverse-variance weighted method were validated by sensitivity analyses. These findings support improving sarcopenia-related traits as precautions against major cardiometabolic diseases and Alzheimer's disease, with particular emphasis on insulin resistance as a target in the intervention of sarcopenia-related cardiometabolic risk. 10.1111/acel.13923
A Bidirectional Mendelian Randomization Study of Sarcopenia-Related Traits and Knee Osteoarthritis. Clinical interventions in aging Background:With the development of population aging worldwide, sarcopenia and knee osteoarthritis (KOA), two age-related diseases, will continue to impose increasing medical and economic burdens on the society. Previous studies have discovered an association between the two, but the causality remains controversial, and it is difficult to eliminate confounding factors. Therefore, a Mendelian randomization (MR) study was conducted to overcome these confounding factors and investigate the causal relationship between sarcopenia and KOA. Objective:The present work focused on assessing the causality between KOA and sarcopenia, so as to provide new strategies to prevent and treat these two conditions in clinic. Methods:We registered the title with PROSPERO (ID: CRD42023421096). The two-sample bidirectional MR analysis was conducted in two steps, with sarcopenia being the exposure whereas KOA being the outcome in the first step, and vice versa in the second step. Genome-wide association studies (GWAS) data on low hand-grip strength (n=256,523), walking pace (n=459,915), appendicular lean mass (ALM, n=450,243), and KOA (n=403,124) were obtained from the UK Biobank. Methods such as the inverse variance weighted (IVW) and weighted median were utilized for assessing the causality of KOA with sarcopenia, and sensitivity analyses were also conducted. Results:In the main MR analysis using the IVW method, evidence suggested that low hand-grip strength, walking pace, and ALM had adverse effects on KOA (p-value 0.0001, odds ratio (OR) 1.4569, 95% confidence interval (CI) 1.2007-1.7677 for low hand-grip strength; p-value 0.0003, OR 1.1500, 95% CI 1.050-1.183 for ALM; p-value 5.29E-19, OR 0.0932, 95% CI 0.0553-0.1572 for walking pace). However, there was no causality of KOA with sarcopenia in the opposite direction. Conclusion:Our study suggests an obvious unidirectional causality of KOA with sarcopenia, and supports the notion that patients with sarcopenia are more susceptible to the development of KOA. 10.2147/CIA.S424633
Genetic Variants, Serum 25-Hydroxyvitamin D Levels, and Sarcopenia: A Mendelian Randomization Analysis. JAMA network open Importance:Vitamin D deficiency is commonly associated with sarcopenia; however, the latest International Clinical Practice Guidelines for Sarcopenia do not recommend vitamin D supplementation for sarcopenia owing to a lack of an apparent therapeutic effect on the indices of sarcopenia among participants with replete vitamin D concentration (ie, 25-hydroxyvitamin D [25(OH)D] level >20 ng/mL) from randomized clinical trials. While there is consensus in all vitamin D guidelines that serum levels of 25(OH)D less than 10 ng/mL should be corrected, approximately 30% of the world population's 25(OH)D levels range from 10 to 20 ng/mL, and it remains unclear whether such suboptimal levels can maintain optimal health, including sarcopenia risk. Objective:To investigate the association of serum 25(OH)D level, especially suboptimal levels, with sarcopenia risk. Design, Setting, and Participants:This genome-wide genetic association study was performed from August 2022 to February 2023 among the 295 489 unrelated European participants from the UK Biobank (2006-2010). Nonlinear and standard mendelian randomization analyses were used to examine the association of serum 25(OH)D concentration with sarcopenia risk. Exposures:A weighted genetic risk score using 35 unrelated single-nucleotide variants from the UK Biobank and weights from the SUNLIGHT Consortium was selected as an instrumental variable for serum 25(OH)D concentration. Main Outcomes and Measures:The primary outcome was sarcopenia, and the secondary outcomes consisted of grip strength, appendicular lean mass index, and gait speed. Results:The final genetic analyses included 295 489 participants (mean [SD] age, 56.3 [8.1] years; 139 216 female [52.9%]). There was an L-shaped association between genetically predicted serum 25(OH)D concentration and sarcopenia risk. The risk of sarcopenia decreased rapidly as 25(OH)D concentration increased until 20 ng/mL and then leveled off. The odds ratio of sarcopenia for serum 25(OH)D level of 10 vs 20 ng/mL was 1.74 (95% CI, 1.17-2.59). Similar patterns were also observed when the association between serum 25(OH)D concentration and risks of each of the sarcopenia indices were evaluated. Conclusions and Relevance:In this mendelian randomization genetic association study of adults in the UK Biobank, the findings supported a nonlinear association between suboptimal 25(OH)D levels and sarcopenia risk. Randomized clinical trials among participants with suboptimal 25(OH)D levels are required to verify the potential causality. 10.1001/jamanetworkopen.2023.31558
Epidemiology of sarcopenia: Prevalence, risk factors, and consequences. Metabolism: clinical and experimental Sarcopenia is a geriatric condition featured by a progressive loss of muscle mass and function and associated with various adverse health outcomes. In this review, we aimed to summarize the epidemiological features of sarcopenia as well as consequences and risk factors of the disease. We performed a systematic review of meta-analysis on sarcopenia to collect data. The prevalence of sarcopenia varied between studies and depending on definition used. Sarcopenia was estimated to influence 10 %-16 % of the elderly worldwide. The prevalence of sarcopenia was higher among patients compared to general populations. The prevalence of sarcopenia ranged from 18 % in diabetic patients to 66 % in patients with unresectable esophageal cancer. Sarcopenia is associated with a high risk of a wide range of adverse health outcomes, including poor overall and disease-progression free survival rate, postoperative complications, and longer hospitalization in patients with different medical situations as well as falls and fracture, metabolic disorders, cognitive impairment, and mortality in general populations. Physical inactivity, malnutrition, smoking, extreme sleep duration, and diabetes were associated with an increased risk of sarcopenia. However, these associations were mainly based on non-cohort observational studies and need confirmation. High-quality cohort, omics, and Mendelian randomization studies are needed to deeply understand the etiological basis of sarcopenia. 10.1016/j.metabol.2023.155533