Genetically predicted TWEAK mediates the association between lipidome and Keratinocyte Carcinomas
Ontology highlight
ABSTRACT:
SUBMITTER: Lei H
PROVIDER: S-EPMC11208293 | biostudies-literature | 2024 Jun
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:ObjectiveTo investigate the causal relationship between lipidome and malignant melanoma of skin (MMOS), while identifying and quantifying the role of metabolites as potential mediators.MethodsA two-sample Mendelian randomization (MR) analysis of lipid species (n=7174) and MMOS was performed using pooled data from genome-wide association studies (GWAS). In addition, we quantified the proportion of metabolite-mediated lipidome effects on MMOS by two-step MR.ResultsThis study identified potential causal relationships between 11 lipids and MMOS, and 40 metabolites and MMOS, respectively. Phosphatidylethanolamine (18:0_18:2) levels mined from 179 lipids by MR Analysis increased the risk of MMOS (OR: 1.962; 95%CI:1.298,2.964; P=0.001). There is no strong evidence for a relationship between genetically predicted MMOS and phosphatidylethanolamine (18:0_18:2) levels (P=0.628). The proportion of gene predictions for phosphatidylethanolamine (18:0_18:2) levels mediated by 1-stearoyl-(glycosylphosphatidylinositol) GPI (18:0) levels was 12.40%.ConclusionThis study identifies 1-stearoyl-GPI (18:0) levels as a potential mediator that may mediate the causal relationship between phosphatidylethanolamine (18:0_18:2) levels and MMOS, This provides direction for the investigation of MMOS, but further research of other possible potential mediators is still needed.
| S-EPMC11419955 | biostudies-literature
Project description:Immune and metabolic factors play an important role in the onset and development of insomnia. This study aimed to investigate the causal relationship between insomnia and immune cells and metabolites. Data for 731 immune cell phenotypes, 1400 metabolites, and insomnia in this study were obtained from the GWAS open-access database. Two-way Mendelian randomization was used to (1) detect the causal relationship between immune cells and insomnia and (2) identify potential mediating metabolites. Mendelian randomization analysis identified eight immune cell phenotypes with a causal relationship to insomnia, and two immune cell phenotypes were protective factors for insomnia, namely CD8br %T cells and CD80 on CD62L + myeloid dendritic cells. The other six immune cell phenotypes were risk factors for insomnia, i.e., CD4/CD8br, CD16-CD56 on NKT, CCR2 on myeloid dendritic cells, CD40 on monocytes, CD38 on CD3-CD19-, and CD25 on CD45RA + CD4 not Treg. Further Mendelian randomization revealed 11 metabolites that were causally related to insomnia. Five metabolites were protective factors for insomnia, i.e., 3-hydroxy-3-methylglutarate, cholate, dodecanedioate, N-formylmethionine, and x-26054. Six metabolites were risk factors for insomnia, 3-amino-2-piperidone, 6-oxopiperdine-2-carboxylate, caffeine to theophylline ratio, leucine, maltose, and x-24736. In addition, our analysis showed that leucine mediated the association between CD4/CD8br and insomnia. From genetic information, we confirmed the causal relationship between insomnia, eight immune cell phenotypes, and eleven metabolite levels. Notably, we found a relationship between leucine-mediated CD4/CD8br and insomnia, providing evidence supporting the causal relationship between immune cell and insomnia, with plasma metabolites serving as mediators.
| S-EPMC11754360 | biostudies-literature
Project description:ObjectiveInvestigating the causal relationship between rheumatoid arthritis (RA) and atlantoaxial subluxation (AAS) and identifying and quantifying the role of C-reactive protein (CRP) as a potential mediator.MethodsUsing summary-level data from a genome-wide association study (GWAS), a two-sample Mendelian randomization (MR) analysis of genetically predicted rheumatoid arthritis (14,361 cases, and 43,923 controls) and AAS (141 cases, 227,388 controls) was performed. Furthermore, we used two-step MR to quantitate the proportion of the effect of c-reactive protein-mediated RA on AAS.ResultsMR analysis identified higher genetically predicted rheumatoid arthritis (primary MR analysis odds ratio (OR) 0.61/SD increase, 95% confidence interval (CI) 1.36-1.90) increased risk of AAS. There was no strong evidence that genetically predicted AAS had an effect on rheumatoid arthritis risk (OR 1.001, 95% CI 0.97-1.03). The proportion of genetically predicted rheumatoid arthritis mediated by C-reactive protein was 3.7% (95%CI 0.1%-7.3%).ConclusionIn conclusion, our study identified a causal relationship between RA and AAS, with a small proportion of the effect mediated by CRP, but a majority of the effect of RA on AAS remains unclear. Further research is needed on additional risk factors as potential mediators. In clinical practice, lesions of the upper cervical spine in RA patients need to be given more attention.
| S-EPMC9800511 | biostudies-literature
Project description: Not available
| S-EPMC11581845 | biostudies-literature
Project description:BackgroundBreast cancer (BC) remains a significant contributor to female mortality globally, with inflammation and the immune system implicated in its pathogenesis. To elucidate potential causal relationships, we evaluated the relationship among 731 immune cell phenotypes and BC be at risk by using Mendelian randomization (MR), while also exploring inflammatory proteins as mediators in this association.MethodsWe obtained immune cell genome-wide association study (GWAS) summary data and 91 inflammatory factors from the GWAS Catalog. BC GWAS data was obtained from the IEU Open GWAS project (ukb-b-16890 for discovery and GCST004988 for validation). We investigated the causal link between immune cells and BC risk by employing a two-sample MR method. Furthermore, we use a two-step MR to quantify the percentage of mediation of immune cell-BC causal effects mediated by inflammatory proteins. To make sure the causal findings were robust, a sensitivity analysis was done.ResultsIn both discovery and validation GWAS, a critical inverse correlation between CD4+ T cells and BC risk was found using MR analysis (Discovery: OR, 0.996; P = 0.030. Validation: OR, 0.843; P = 4.09E-07) with Caspase 8 levels mediating 18.9% of the reduced BC risk associated with immune cells(Mediation proportion=a×b/c, Discovery:0.151×-0.005/-0.004 = 18.9%; Validation:0.151×-0.214/-0.171 = 18.9%).ConclusionOur study establishes a causal connection linking CD4+ T cells and BC, with Caspase 8 levels partially mediating this relationship. These findings enhance our genetic and molecular comprehension of BC, suggesting potential pathways for future BC immunotherapy drug development.
| S-EPMC11464308 | biostudies-literature
Project description:BackgroundRecent studies have increasingly emphasized the strong correlation between the lipidome and the risk of pancreatic diseases. To determine causality, a Mendelian randomization (MR) analysis was performed to identify connections between the lipidome and pancreatic diseases.MethodsStatistics from a genome-wide association study of the plasma lipidome, which included a diverse array of 179 lipid species, were obtained from the GeneRISK cohort study with 7,174 participants. Genetic associations with four types of pancreatitis and pancreatic cancer were sourced from the R11 release of the FinnGen consortium. Two pancreatitis datasets from UK Biobank were employed as the validation cohort. MR analysis was conducted to assess the relationship between the genetically predicted plasma lipidome and these pancreatic diseases. Inverse variance weighted was adopted as the main statistical method. Bayesian weighted MR was employed for further verification. The MR-Egger intercept test for pleiotropy and Cochrane's Q statistics test for heterogeneity were performed to ensure the robustness.ResultsMR analysis yielded significant evidence that 26, 25, 2, and 19 lipid species were correlated with diverse outcomes of pancreatitis, and 8 lipid species were correlated with pancreatic cancer. Notably, sterol ester (27:1/20:2) levels (OR: 0.84, 95% CI: 0.78-0.90, P = 5.79 × 10-7) were significantly associated with acute pancreatitis, and phosphatidylcholine (17:0_20:4) levels (OR: 0.89, 95% CI: 0.84-0.94, P = 1.78 × 10-4) and sterol ester (27:1/20:4) levels (OR: 0.90, 95% CI: 0.86-0.95, P = 2.71 × 10-4) levels were significantly associated with chronic pancreatitis after the Bonferroni-corrected test. As for validation, 14 and 9 lipid species were correlated with acute and chronic pancreatitis of UK Biobank. Some lipid classes showed significant effects both in the FinnGen consortium and UK Biobank datasets.ConclusionsThe findings of this study indicate a potential genetic predisposition linking the plasma lipidome to pancreatic diseases and good prospects for future pancreatic disease clinical trials.
| S-EPMC11774697 | biostudies-literature
Project description:ObjectiveThis study sought to explore the potential causal relationships among immune cell traits, Guillain-Barre syndrome (GBS) and metabolites.MethodsEmploying a two-sample Mendelian randomization (MR) approach, the study investigated the causal associations between 731 immune cell traits, 1400 metabolite levels and GBS leveraging summary-level data from a genome-wide association study (GWAS). To ensure the reliability of our findings, we further assessed horizontal pleiotropy and heterogeneity and evaluated the stability of MR results using the Leave-one-out method.ResultsThis study revealed a causal relationship between CD3 on activated & secreting Tregs and GBS. Higher CD3 on activated and secreting Regulatory Tregs increased the risk of GBS (primary MR analysis odds ratio (OR) 1.31/SD increase, 95% confidence interval (CI) 1.08-1.58, p = 0.005). There was no reverse causality for GBS on CD3 on activated & secreting Tregs (p = 0.36). Plasma metabolite N-Acetyl-L-Alanine (ALA) was significantly positively correlated with GBS by using the IVW method (OR = 2.04, 95% CI, 1.26-3.30; p = 0.00038). CD3 on activated & secreting Tregs was found to be positively associated with ALA risk (IVW method, OR, 1.04; [95% CI, 1.01-1.07], p = 0.0078). Mediation MR analysis indicated the mediated proportion of CD3 on activated & secreting Tregs mediated by ALA was 10% (95%CI 2.63%, 17.4%).ConclusionIn conclusion, our study identified a causal relationship between the level of CD3 on activated & secreting Tregs and GBS by genetic means, with a considerable proportion of the effect mediated by ALA. In clinical practice, thus providing guidance for future clinical research.
| S-EPMC11450862 | biostudies-literature
Project description:BackgroundParkinson's disease (PD) is a neurodegenerative disorder, primarily characterized by motor impairments. Vitamin D has several regulatory functions in nerve cell survival and gene expression via its receptors. Although research has shown that vitamin D deficiency is prevalent among PD patients, the causal link to PD risk remains unclear. This study aims to investigate the causal relationship between vitamin D and PD using a bidirectional two-sample Mendelian randomization (MR) analysis method.MethodsThis study applied a bidirectional two-sample MR analysis to explore the causal link between vitamin D and PD. We selected statistically significant single nucleotide polymorphisms (SNPs) related to 25-hydroxyvitamin D (25(OH)D) as instrumental variables (IVs), ensuring no association with known confounders. The analysis used GWAS data from over 1.2 million Europeans across four major published datasets, elucidating the genetic correlation between vitamin D levels and PD.ResultsWe identified 148 instrumental SNPs associated with 25(OH)D. After adjustment for confounding-related SNPs, 131 SNPs remained in the analysis. Data from three PD cohorts revealed no significant correlation between 25(OH)D levels and PD risk using the IVW method (Pcohort1 = 0.365, Pcohort2 = 0.525, Pcohort3 = 0.117). The reverse MR analysis indicated insufficient evidence of PD causing decreased vitamin D levels (P = 0.776).ConclusionThis is the first study to use bidirectional MR across three PD cohorts to investigate the causal relationship between vitamin D and PD. The results indicate that vitamin D levels are not significantly causally related to PD risk at the genetic level. Therefore, future studies should exercise caution when investigating the relationship between vitamin D levels and PD risk. While no direct causal link exists between vitamin D levels and PD, this does not preclude the potential of vitamin D levels as a biomarker for PD diagnosis. Furthermore, larger-scale longitudinal studies are necessary to evaluate the diagnostic and predictive value of vitamin D levels in PD.
| S-EPMC11567546 | biostudies-literature
Project description:Polymorphisms thiopurine-S-methyltransferase ( TPMT ) and nudix hydrolase 15 ( NUDT15 ) can increase the risk of azathioprine myelotoxicity, but little is known about other genetic factors that increase risk for azathioprine-associated side effects. PrediXcan is a gene-based association method that estimates the expression of individuals’ genes and examines their correlation to specified phenotypes. As proof of concept for using PrediXcan as a tool to define the association between genetic factors and azathioprine side effects, we aimed to determine whether the genetically predicted expression of TPMT or NUDT15 was associated with leukopenia or other known side effects. In a retrospective cohort of 1364 new users of azathioprine with EHR-reported White race, we used PrediXcan to impute expression in liver tissue, tested its association with pre-specified phecodes representing known side effects (e.g., skin cancer), and completed chart review to confirm cases. Among confirmed cases, patients in the lowest tertile (i.e., lowest predicted) of TPMT expression had significantly higher odds of developing leukopenia (OR=3.30, 95%CI: 1.07-10.20, p=0.04) versus those in the highest tertile; no other side effects were significant. The results suggest that this methodology could be deployed on a larger scale to uncover associations between genetic factors and drug side effects for more personalized care.
| S-EPMC9882694 | biostudies-literature
Project description:BackgroundInsulin resistance is tightly related to cognition; however, the causal association between them remains a matter of debate. Our investigation aims to establish the causal relationship and direction between insulin resistance and cognition, while also quantifying the mediating role of brain cortical structure in this association.MethodsThe publicly available data sources for insulin resistance (fasting insulin, homeostasis model assessment beta-cell function and homeostasis model assessment insulin resistance, proinsulin), brain cortical structure, and cognitive phenotypes (visual memory, reaction time) were obtained from the MAGIC, ENIGMA, and UK Biobank datasets, respectively. We first conducted a bidirectional two-sample Mendelian randomization (MR) analysis to examine the susceptibility of insulin resistance on cognitive phenotypes. Additionally, we applied a two-step MR to assess the mediating role of cortical surficial area and thickness in the pathway from insulin resistance to cognitive impairment. The primary Inverse-variance weighted, accompanied by robust sensitivity analysis, was implemented to explore and verify our findings. The reverse MR analysis was also performed to evaluate the causal effect of cognition on insulin resistance and brain cortical structure.ResultsThis study identified genetically determined elevated level of proinsulin increased reaction time (beta=0.03, 95% confidence interval [95%CI]=0.01 to 0.05, p=0.005), while decreasing the surface area of rostral middle frontal (beta=-49.28, 95%CI=-86.30 to -12.27, p=0.009). The surface area of the rostral middle frontal mediated 20.97% (95%CI=1.44% to 40.49%) of the total effect of proinsulin on reaction time. No evidence of heterogeneity, pleiotropy, or reverse causality was observed.ConclusionsBriefly, our study noticed that elevated level of insulin resistance adversely affected cognition, with a partial mediation effect through alterations in brain cortical structure.
| S-EPMC11774689 | biostudies-literature