logo logo
Causal associations between type 1 diabetes mellitus and cardiovascular diseases: a Mendelian randomization study. Cardiovascular diabetology BACKGROUND:The presence of type 1 diabetes mellitus (T1DM) has been demonstrated to pose an increased risk for developing cardiovascular diseases (CVDs). However, the causal relationships between T1DM and CVDs remain unclear due to the uncontrolled confounding factors and reverse causation bias of the observational studies. METHODS:Summary statistics of T1DM and seven CVDs from the largest available genome-wide association studies (GWAS) of European ancestry and FinnGen biobank were extracted for the primary MR analysis, and the analysis was replicated using UK biobank (UKBB) for validation. Three complementary methods: inverse variance weighted (IVW), weighted median, and MR-Egger were used for the MR estimates. The potential pleiotropic effects were assessed by MR-Egger intercept and MR-PRESSO global test. Additionally, multivariable MR (MVMR) analysis was performed to examine whether T1DM has independent effects on CVDs with adjustment of potential confounding factors. Moreover, a two-step MR approach was used to assess the potential mediating effects of these factors on the causal effects between T1DM and CVDs. RESULTS:Causal effects of T1DM on peripheral atherosclerosis (odds ratio [OR] = 1.06, 95% confidence interval [CI]: 1.02-1.10; p = 0.002)] and coronary atherosclerosis (OR = 1.03, 95% CI: 1.01-1.05; p = 0.001) were found. The results were less likely to be biased by the horizontal pleiotropic effects (both p values of MR-Egger intercept and MR-PRESSO Global test > 0.05). In the following MVMR analysis, we found the causal effects of T1DM on peripheral atherosclerosis and coronary atherosclerosis remain significant after adjusting for a series of potential confounding factors. Moreover, we found that hypertension partly mediated the causal effects of T1DM on peripheral atherosclerosis (proportion of mediation effect in total effect: 11.47%, 95% CI: 3.23-19.71%) and coronary atherosclerosis (16.84%, 95% CI: 5.35-28.33%). We didn't find significant causal relationships between T1DM and other CVDs, including heart failure (HF), coronary artery disease (CAD), atrial fibrillation (AF), myocardial infarction (MI) and stroke. For the reverse MR from CVD to T1DM, no significant causal relationships were identified. CONCLUSION:This MR study provided evidence supporting the causal effect of T1DM on peripheral atherosclerosis and coronary atherosclerosis, with hypertension partly mediating this effect. 10.1186/s12933-023-01974-6
Causal relationships between body mass index, smoking and lung cancer: Univariable and multivariable Mendelian randomization. International journal of cancer At the time of cancer diagnosis, body mass index (BMI) is inversely correlated with lung cancer risk, which may reflect reverse causality and confounding due to smoking behavior. We used two-sample univariable and multivariable Mendelian randomization (MR) to estimate causal relationships of BMI and smoking behaviors on lung cancer and histological subtypes based on an aggregated genome-wide association studies (GWASs) analysis of lung cancer in 29 266 cases and 56 450 controls. We observed a positive causal effect for high BMI on occurrence of small-cell lung cancer (odds ratio (OR) = 1.60, 95% confidence interval (CI) = 1.24-2.06, P = 2.70 × 10 ). After adjustment of smoking behaviors using multivariable Mendelian randomization (MVMR), a direct causal effect on small cell lung cancer (OR = 1.28, 95% CI = 1.06-1.55, P = .011), and an inverse effect on lung adenocarcinoma (OR = 0.86, 95% CI = 0.77-0.96, P = .008) were observed. A weak increased risk of lung squamous cell carcinoma was observed for higher BMI in univariable Mendelian randomization (UVMR) analysis (OR = 1.19, 95% CI = 1.01-1.40, P = .036), but this effect disappeared after adjustment of smoking (OR = 1.02, 95% CI = 0.90-1.16, P = .746). These results highlight the histology-specific impact of BMI on lung carcinogenesis and imply mediator role of smoking behaviors in the association between BMI and lung cancer. 10.1002/ijc.33292
A bidirectional Mendelian randomization study investigating the relationship between genetically predicted systemic inflammatory regulators and chronic obstructive pulmonary disease. Heliyon Research has shown a connection between inflammation and chronic obstructive pulmonary disease (COPD), however the relationship between inflammation mediators and COPD causation remains unknown. To investigate the causal relationship of mediators of inflammation and COPD, we conducted a two-sample Mendelian randomization (MR) study. In our study, we incorporated 41 regulators of inflammation from 8293 Finnish individuals from genome-wide association studies (GWASs) of COPD corresponding to GWAS summary data for 2115 cases and 454,233 healthy individuals in Europe. Our research validated that higher levels of interleukin 8 (IL-8) are related with a decrease occurrence of COPD (OR = 0.795, 95 % CI = 0.642-0.984, p = 0.035) but that elevated levels of interleukin 18(IL-18) and interleukin 2 (IL-2) may be connected to an amplified risk of COPD (OR = 1.247, 95 % CI = 1.011-1.538; p = 0.039; OR = 1.257, 95 % CI = 1.037-1.523, p = 0.020, respectively). According to our research, cytokines play a crucial role in the development of COPD, and further investigation is necessary to explore the potential of utilizing these cytokines as targets for treatment and prevention of COPD. 10.1016/j.heliyon.2024.e24109
The causality between systemic inflammatory regulators and chronic respiratory diseases: A bidirectional Mendelian-randomization study. Cytokine INTRODUCTION:Accumulative evidence suggests the associations between systemic inflammatory regulators and chronic respiratory diseases (CRDs). However, the intrinsic causation remains implicit. Therefore, this study aimed to examine causative associations by mendelian randomization (MR) and to identify valuable active factors. METHODS:Based on data from the GWAS database, we performed MR analyses of 41 serum cytokines from 8,293 Finnish and European descent cohorts from GBMI and UKBB for five major CRDs. We mainly applied inverse variance weighted regression, supplemented by MR-Egger regression, weighted median, maximum likelihood, weighted mode, and simple mode algorithms. Moreover, sensitivity analyses were conducted using Cochrane's Q test, MR-Egger intercept, MR-PRESSO Global test and MR-Steiger filtering. Eventually, the consistency of MR results was assessed by leave-one-out. RESULTS:Our results suggest that 12 genetically predicted systemic inflammatory regulators probably participate in the progression of CRDs, including four risk factors (IL-1RA, IL-4, MIP-1A, PDGF-BB) and one protective factor (IL-6) in IPF, two protective factors (SCF, SDF-1A) in COPD, and two protective factors (SCF, SDF-1A) in asthma, two protective factors (GROA, IL-2RA) were also included in asthma, whereas only one factor (HGF) was protective against bronchiectasis. Additionally, two protective factors (FGF-BASIC, G-CSF) were identified in sarcoidosis. Sensitivity analyses showed no horizontal pleiotropy and significant heterogeneity. Finally, based on the findings of inverse MR analysis, no inverse causal association was uncovered, confirming the robustness of results. CONCLUSION:Our study unearths potential associations between systemic inflammatory modulators and common CRDs, providing new insights for inflammation-mediated CRD prevention and therapeutic approaches. 10.1016/j.cyto.2023.156470
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
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 causal association between circulating cytokines with the risk of frailty and sarcopenia under the perspective of geroscience. Frontiers in endocrinology Introduction:Circulating cytokines were considered to play a critical role in the initiation and propagation of sarcopenia and frailty from observational studies. This study aimed to find the casual association between circulating cytokines and sarcopenia and frailty from a genetic perspective by two-sample Mendelian randomization (MR) analysis. Methods:Data for 41 circulating cytokines were extracted from the genome-wide association study dataset of 8,293 European participants. Inverse-variance weighted (IVW) method, MR-Egger, and weighted median method were applied to assess the relationship of circulating cytokines with the risk of aging-related syndromes and frailty. Furthermore, MR-Egger regression was used to indicate the directional pleiotropy, and Cochran's Q test was used to verify the potential heterogeneity. The "leave-one-out" method was applied to visualize whether there was a causal relationship affected by only one anomalous single-nucleotide polymorphisms. Results:Genetic predisposition to increasing levels of interleukin-10 (IL-10), IL-12, and vascular endothelial growth factor (VEGF) was associated with the higher risk of low hand grip strength according to the IVW method [R = 1.05, 95% CI = 1.01-1.10, = 0.028, false discovery rate (FDR)-adjusted = 1.000; OR = 1.03, 95% CI = 1.00-1.07, = 0.042, FDR-adjusted = 0.784; OR = 1.02, 95% CI = 1.00-1.05, = 0.038, FDR-adjusted = 0.567]. Furthermore, genetically determined higher macrophage colony-stimulating factors (M-CSFs) were associated with a lower presence of appendicular lean mass (OR = 1.01, 95% CI = 1.00-1.02, = 0.003, FDR-adjusted = 0.103). Monokine induced by interferon-γ (MIG) and tumor necrosis factor-beta (TNF-β) were associated with a higher risk of frailty (OR = 1.03, 95% CI = 1.01-1.05, < 0.0001, FDR-adjusted  = 0.012; OR = 1.01, 95% CI = 1.00-1.03, = 0.013, FDR-adjusted = 0.259). In this study, we did not find heterogeneity and horizontal pleiotropy between the circulating cytokines and the risk of frailty and sarcopenia. Conclusion:Genetic predisposition to assess IL-10, IL-12, and VEGF levels was associated with a higher risk of low hand grip strength and M-CSF with the presence of appendicular lean mass. The high levels of TNF-β and MIG were associated with a higher risk of frailty. More studies will be required to explore the molecular biological mechanisms underlying the action of inflammatory factors. 10.3389/fendo.2024.1293146
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
Exploring the causal link between circulating cytokines and sarcopenia traits: A Mendelian randomization analysis. Environmental toxicology BACKGROUND:Previous observational studies have linked circulating cytokines to sarcopenia, but their causal relationship remains unclear. This study employed Mendelian Randomization (MR) to investigate the causal links between circulating cytokines and sarcopenia-related traits using genetic data. METHODS:A two-sample bidirectional MR analysis was conducted using data from individuals of European ancestry, utilizing genome-wide association studies (GWAS) statistics. The study selected instrumental single nucleotide polymorphisms (SNPs) significantly associated with circulating cytokines and applied multiple MR methods, including inverse variance weighted (IVW), Weighted Median, MR-Egger, Weighted Mode, Simple Mode, and MR-PRESSO. The traits analyzed were appendicular lean mass (ALM) and grip strength. Heterogeneity, robustness, and consistency of results were assessed using Cochran's Q statistic, MR-Egger regression, and "leave-one-out" sensitivity analyses. RESULTS:The IVM-MR analysis showed a casual association between genetically predicted circulating levels of interleukin-16 and both ALM and grip strength (ALM: OR = 0.990, 95% CI: 0.980-1.000, p = .049; grip strength: OR = 0.971, 95% CI: 0.948-0.995, p = .020). Additionally, interferon-gamma-induced protein 10 (IP-10), interleukin-1-beta (IL-1β), and hepatocyte growth factor (HGF) were correlated with ALM and vascular endothelial growth factor (VEGF), interleukin-12 (IL-12), and interleukin-5 (IL-5) with grip strength. Comparable results were confirmed via the MR-Egger, Weighted Median, Weighted Mode, and Simple Mode methods. Sensitivity analysis showed no horizontal pleiotropy to bias the causal estimates. CONCLUSION:The results suggest a significant causal effect of inflammatory cytokines on sarcopenia, offering new avenues for therapeutic target development. However, the study's focus on a European ancestry cohort limits its generalizability to other populations. Future research should aim to include diverse ethnic groups to validate and broaden these findings, thereby enhancing our understanding of sarcopenia's mechanisms in a global context. 10.1002/tox.24206
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
Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women. Nature communications Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10), arthritis (GDF5 p = 4 × 10), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing. 10.1038/s41467-021-20918-w
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 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
Causal associations between hand grip strength and pulmonary function: a two-sample Mendelian randomization study. BMC pulmonary medicine BACKGROUND:Several observational studies have reported an association between hand grip strength (HGS) and pulmonary function (PF). However, causality is unclear. To investigate whether HGS and PF are causally associated, we performed Mendelian randomization (MR) analyses. METHODS:We identified 110 independent single nucleotide polymorphisms (SNPs) for right-hand grip strength (RHGS) and 103 independent SNPs for left-hand grip strength (LHGS) at the genome-wide significant threshold (P < 5 × 10) from MRC-IEU Consortium and evaluated these related to PF. MR estimates were calculated using the inverse-variance weighted (IVW) method and multiple sensitivity analyses were further performed. RESULTS:Genetical liability to HGS was positively causally associated with forced vital capacity (FVC) and forced expiratory volume in one second (FEV1), but not with FEV1/FVC. In addition, there was positive causal association between RHGS and FVC (OR=1.519; 95% CI, 1.418-1.627; P=8.96E-33), and FEV1 (OR=1.486; 95% CI, 1.390-1.589; P=3.19E-31); and positive causal association between LHGS and FVC (OR=1.464; 95% CI, 1.385-1.548; P=2.83E-41) and FEV1 (OR=1.419; 95% CI, 1.340-1.502; P=3.19E-33). Nevertheless, no associations were observed between RHGS and FEV1/FVC (OR=0.998; 95% CI, 0.902-1.103; P=9.62E-01) and between LHGS and FEV1/FVC (OR=0.966; 95% CI, 0.861-1.083; P=5.52E-01). Similar results were shown in several sensitivity analyses. CONCLUSION:Our study provides support at the genetic level that HGS is positively causally associated with FVC and FEV1, but not with FEV1/FVC. Interventions for HGS in PF impairment deserve further exploration as potential indicators of PF assessment. 10.1186/s12890-023-02720-0
The association between walking pace and hand grip strength with the risk of chronic obstructive pulmonary disease: a bidirectional Mendelian randomization study. BMC pulmonary medicine BACKGROUND:Chronic Obstructive Pulmonary Disease (COPD) currently ranks as the third leading cause of mortality worldwide, imposing substantial burdens on societal and individual health. Amongst health research tools, walking pace (WP) and hand grip strength (HGS) are cornerstones, extensively associated with diverse health conditions. However, the intricate interplay between these factors and COPD risk remains ambiguous. This study aims to elucidate the causal association of WP, HGS, with COPD risk through a bidirectional Mendelian randomization (MR) approach. METHODS:Bidirectional MR analysis was performed using Genome-wide association study (GWAS) data of European individuals for WP, HGS, and COPD. Inverse Variance Weighted (IVW) served as the primary MR analysis approach. To supplement the IVW findings, four additional MR methods [MR-Egger, weighted median, maximum likelihood, simple median] were used. To assess heterogeneity and pleiotropy, sensitivity analyses were performed. In addition, multivariate MR (MVMR) analysis was used to assess causality after adjustment for potential confounders. RESULTS:IVW method results show a significant negative association between WP and COPD risk in both initial (genome-wide threshold, odds ratio (OR) = 0.21, 95% confidence interval (CI) 0.09-0.51, P = 5.06 × 10) and secondary (locus-wide threshold, OR = 0.27, 95%CI: 0.18-0.41, P = 4.88 × 10) MR analysis. The reverse MR analysis suggested that COPD also diminishes WP. Additionally, a causal risk reduction for COPD with right HGS (OR = 0.74, 95% CI: 0.58-0.94, P = 1.44 × 10) was only found in secondary MR analysis. The outcomes of the four additional MR methods also suggested similar causal relationships, and sensitivity analyses endorsed their robustness. Lastly, the MVMR analysis demonstrated that the WP's effect on reducing COPD risk persisted independently of potential confounding variables. CONCLUSION:A bidirectional causal relationship exists between typical WP and COPD risk. Conversely, a decrease in right HGS is unidirectionally associated with an increased risk of COPD. The study suggests that WP may serve as a predictive factor for COPD or as a simple evaluative indicator for prognosis. 10.1186/s12890-023-02759-z
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