Sarcopenia-related traits and coronary artery disease: a bi-directional Mendelian randomization study.
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ABSTRACT:
SUBMITTER: Liu HM
PROVIDER: S-EPMC7066916 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundWith the advancement of world population aging, age-related osteoporosis (OP) and sarcopenia (SP) impose enormous clinical and economic burden on society. Evidence from accumulating studies indicates that they mutually influence one another. However, an observational study may be affected by potential confounders. Meanwhile, a Mendelian randomization (MR) study can overcome these confounders to assess causality.ObjectivesThe aim of this study was to evaluate the causality between OP and SP, informing new strategies for prevention, diagnosis, and treatment of osteosarcopenia.MethodsInstrumental variables (IVs) at the genome-wide significance level were obtained from published summary statistics, and the inverse variance weighted method and several other MR methods were conducted to evaluate the bi-directional causality between SP and OP. Myopia was analyzed as a negative control outcome to test the validity of IVs.ResultsFemoral neck bone mineral density (FN BMD), lumbar spine BMD (LS BMD), and forearm BMD (FA BMD) had a direct causal effect on appendicular lean mass (ALM) [FA BMD-related analysis: odds ratio (OR) = 1.028, 95% confidence interval (CI) = (1.008,1.049), p = 0.006; FN BMD-related analysis: OR (95% CI) = 1.131 (1.092,1.170), p = 3.18E-12; LS BMD-related analysis: OR (95% CI) = 1.080 (1.062,1.098), p = 2.86E-19]. ALM had a significant causal effect on LS BMD [OR (95% CI) = (1.033,1.147), p = 0.001]. There was no evidence for causal association between BMD and low grip strength.ConclusionsOP and SP might mutually have a significant causal effect on each other. Our results supported the idea that the patient with severe OP was more susceptible to lose ALM and severe ALM loss might reduce LS BMD.
| S-EPMC9515352 | biostudies-literature
Project description: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, p-value = 0.001), fat-free mass (FFM; right leg FFM, β = 0.014, p-value = 0.003; left arm FFM, β = 0.014, p-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, p-value = 0.001; left-hand grip strength, β = 0.358, p-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.
| S-EPMC9365559 | biostudies-literature
Project description:BackgroundThe 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.MethodA 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.ResultsThe 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.ConclusionThere 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.
| S-EPMC10613058 | biostudies-literature
Project description:BackgroundPrevious 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.MethodsThe 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.ResultsLow hand-grip strength had a potential causal relationship with an increased incidence of T2DM (OR = 1.109; 95% CI, 1.008-1.222; p = 0.0350). T2DM risk was reduced by increasing ALM and walking pace: A 1 kg/m2 increase in ALM decreased the risk of T2DM by 10.2% (OR = 0.898; 95% CI, 0.830-0.952; p < 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; p < 0.001). The relationship was bidirectional, with T2DM as a causative factor of sarcopenia-related traits (p < 0.05) except for ALM (β = 0.018; 95% CI, -0.008 to -0.044; p = 0.168).ConclusionsHand-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.
| S-EPMC10031051 | biostudies-literature
Project description:The current body of research points to a notable correlation between an imbalance in gut microbiota and the development of type 2 diabetes mellitus (T2D) as well as its consequential ailment, coronary artery disease (CAD). The complexities underlying the association, especially in the context of diabetic coronary artery disease (DCAD), are not yet fully understood, and the causal links require further clarification. In this study, a bidirectional Mendelian randomization (MR) methodology was utilized to explore the causal relationships between gut microbiota, T2D, and CAD. By analyzing data from the DIAGRAM, GERA, UKB, FHS, and mibioGen cohorts and examining GWAS databases, we sought to uncover genetic variants linked to T2D, CAD, and variations in gut microbiota and metabolites, aiming to shed light on the potential mechanisms connecting gut microbiota with DCAD. Our investigation uncovered a marked causal link between the presence of Oxalobacter formigenes and an increased incidence of both T2D and CAD. Specifically, a ten-unit genetic predisposition towards T2D was found to be associated with a 6.1% higher probability of an increase in the Oxalobacteraceae family's presence (β = 0.061, 95% CI = 0.002-0.119). In a parallel finding, an augmented presence of Oxalobacter was related to an 8.2% heightened genetic likelihood of CAD (β = 0.082, 95% CI = 0.026-0.137). This evidence indicates a critical pathway by which T2D can potentially raise the risk of CAD via alterations in gut microbiota. Additionally, our analyses reveal a connection between CAD risk and Methanobacteria, thus providing fresh perspectives on the roles of TMAO and carnitine in the etiology of CAD. The data also suggest a direct causal relationship between increased levels of certain metabolites - proline, lysophosphatidylcholine, asparagine, and salicylurate - and the prevalence of both T2D and CAD. Sensitivity assessments reinforce the notion that changes in Oxalobacter formigenes could pose a risk for DCAD. There is also evidence to suggest that DCAD may, in turn, affect the gut microbiota's makeup. Notably, a surge in serum TMAO levels in individuals with CAD, coinciding with a reduced presence of methanogens, has been identified as a potentially significant factor for future examination.
| S-EPMC10758148 | biostudies-literature
Project description:BackgroundImmune system functioning is relevant to vulnerability to coronavirus disease (COVID-19). Cytokines are important to immunity. To further elucidate the role of the immune system in COVID-19, we used Mendelian randomization (MR) to assess comprehensively and bi-directionally the role of cytokines in COVID-19.MethodsWe assessed primarily whether genetically different levels of 41 cytokines affected risk of any COVID-19 (laboratory confirmed, physician confirmed or self-reported, 36,590 cases, 1,668,938 controls), and conversely if genetic risk of liability to any COVID-19 affected these cytokines (n ≤ 8293) using the most recent genome-wide association studies. We obtained inverse variance weighting (IVW) estimates, conducted sensitivity analyses and used a Benjamini-Hochberg correction to account for multiple comparisons. We also assessed whether any findings were evident for hospitalized COVID-19 (hospitalized laboratory confirmed, 12,888 cases, 1,295,966 controls).ResultsMacrophage inflammatory protein-1β (MIP1b; more commonly known as Chemokine (C-C motif) ligands 4 (CCL4) was inversely associated with COVID-19 [odds ratio (OR) 0.97 per SD, 95% confidence interval (CI) 0.96-0.99] but not after adjustment for multiple comparisons. This finding replicated for hospitalized COVID-19 (OR 0.93, 95% CI 0.89-0.98). Liability to any COVID-19 was nominally associated with several cytokines, such as granulocyte colony-stimulating factor (GCSF) and hepatocyte growth factor (HGF) but not after correction.ConclusionA crucial element of immune response to infection (CCL4) was related to COVID-19, whether it is a target of intervention to prevent COVID-19 warrants further investigation.
| S-EPMC8215612 | biostudies-literature
Project description:Mendelian randomization (MR) of lipid traits in CAD has provided evidence for causal associations of LDL-C and TGs in CAD, but many lipid trait genetic variants have pleiotropic effects on other cardiovascular risk factors that may bias MR associations. The goal of this study was to evaluate pleiotropic effects of lipid trait genetic variants and to account for these effects in MR of lipid traits in CAD. We performed multivariable MR using inverse variance-weighted and MR-Egger methods in large (n ≥ 300,000) GWAS datasets. We found that 30% of lipid trait genetic variants have effects on metabolic syndrome traits, including BMI, T2D, and systolic blood pressure (SBP). Nonetheless, in multivariable MR analysis, LDL-C, HDL-C, TGs, BMI, T2D, and SBP are independently associated with CAD, and each of these associations is robust to adjustment for directional pleiotropy. MR at loci linked to direct effects on HDL-C and TGs suggests locus- and mechanism-specific causal effects of these factors on CAD.
| S-EPMC7933489 | biostudies-literature
Project description:BackgroundEmerging 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.MethodsData 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.ResultsThere 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.ConclusionsOur 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.
| S-EPMC10206246 | biostudies-literature
Project description:BackgroundVitamin D deficiency is associated with nonalcoholic fatty liver disease (NAFLD) in many cross-sectional studies. However, the causality between them has not been established. We used bi-directional mendelian randomization (MR) analysis to explore the causal relationship between 25-hydroxyvitamin D [25(OH)D] and NAFLD.Methods9182 participants were included from a survey in East China from 2014 to 2016. We calculated weighted genetic risk scores (GRS) for 25(OH)D concentration and NAFLD based on 25(OH)D-related and NAFLD-related single nucleotide polymorphisms. Presence of liver steatosis was assessed using ultrasound. Instrumental variable was used to measure the causal relationship between them.ResultsAn SD increase in the 25(OH)D GRS was significantly associated with 25(OH)D (β 1.29, 95%CI -1.54, -1.04, P<0.05) but not with NAFLD (OR 0.97, 95%CI 0.92, 1.01). An SD increase in NAFLD GRS was also strongly associated with NAFLD (OR 1.09, 95%CI 1.04, 1.15, P<0.05) but not with 25(OH)D (β -0.15, 95%CI -0.41, 0.10). Using an instrumental variable estimator, no associations were found for genetically instrumented 25(OH)D with NAFLD and for genetically instrumented NAFLD with 25(OH)D.ConclusionOur results support the conclusion that there is no causal association between vitamin D and NAFLD using a bi-directional MR approach in a Chinese population.
| S-EPMC5835542 | biostudies-literature
Project description:BackgroundDiet is a key modifiable risk factor of coronary artery disease (CAD). However, the causal effects of specific dietary traits on CAD risk remain unclear. With the expansion of dietary data in population biobanks, Mendelian randomization (MR) could help enable the efficient estimation of causality in diet-disease associations.ObjectivesThe primary goal was to test causality for 13 common dietary traits on CAD risk using a systematic 2-sample MR framework. A secondary goal was to identify plasma metabolites mediating diet-CAD associations suspected to be causal.MethodsCross-sectional genetic and dietary data on up to 420,531 UK Biobank and 184,305 CARDIoGRAMplusC4D individuals of European ancestry were used in 2-sample MR. The primary analysis used fixed effect inverse-variance weighted regression, while sensitivity analyses used weighted median estimation, MR-Egger regression, and MR-Pleiotropy Residual Sum and Outlier.ResultsGenetic variants serving as proxies for muesli intake were negatively associated with CAD risk (OR: 0.74; 95% CI: 0.65-0.84; P = 5.385 × 10-4). Sensitivity analyses using weighted median estimation supported this with a significant association in the same direction. Additionally, we identified higher plasma acetate levels as a potential mediator (OR: 0.03; 95% CI: 0.01-0.12; P = 1.15 × 10-4).ConclusionsMuesli, a mixture of oats, seeds, nuts, dried fruit, and milk, may causally reduce CAD risk. Circulating levels of acetate, a gut microbiota-derived short-chain fatty acid, could be mediating its cardioprotective effects. These findings highlight the role of gut flora in cardiovascular health and help prioritize randomized trials on dietary interventions for CAD.
| S-EPMC11087059 | biostudies-literature