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BACKGROUND: Chronic inflammation has been connected by epidemiological evidence to coronary artery disease (CAD) along with myocardial infarction (MI). Nevertheless, it is still unclear whether reverse causality or confounders account for these connections. Our objectives are to examine the causality between inflammatory cytokines and CAD/MI as well as the potential mediating influence of lipid characteristics. METHODS: We acquired instrumental variables through genome-wide association studies meta-analyses of 41 inflammatory cytokines (8293 individuals). Genetic associations with CAD (122 733 cases and 424 528 controls), MI (~61 505 cases and 577 716 controls) and five candidate lipid mediators were obtained from the corresponding genome-wide association studies. A two-step, two-sample Mendelian randomization analysis was applied, followed with comprehensive sensitivity analyses. RESULTS: Genetically determined growth regulated oncogene-α was causally linked to a decreased incidence of CAD [odds ratio (OR), 0.97; 95% confidence interval (CI), 0.95-0.99; P = .007] and MI (OR, 0.95; 95% CI, 0.92-0.98; P = .002). There is suggestive evidence indicating a causal impact of macrophage inflammatory protein-1ß upon CAD (OR, 1.04; 95% CI, 1.01-1.07; P = .010) and MI (OR, 1.07; 95% CI, 1.02-1.11; P = .002). Furthermore, we discovered suggestive causal connections between tumor necrosis factor-related apoptosis-inducing ligand and CAD (OR, 0.97; 95% CI, 0.95-1.00; P = .020). Two-step Mendelian randomization analysis revealed that triglycerides partially mediate the effect of growth regulated oncogene-α on CAD (proportion-mediated: 13.28%) and MI (8.05%). CONCLUSIONS: We provided novel genetic evidence supporting the causality of inflammatory cytokines on CAD/MI and elucidate the mediating effect of triglycerides in the causal pathways linking inflammatory cytokines and CAD/MI.
Asunto(s)
Enfermedad de la Arteria Coronaria , Citocinas , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Infarto del Miocardio , Humanos , Enfermedad de la Arteria Coronaria/genética , Infarto del Miocardio/genética , Citocinas/metabolismo , Citocinas/genética , Inflamación/genética , Predisposición Genética a la Enfermedad , Lípidos/sangre , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND AND AIMS: Observational studies have shown an association between mental health and coronary artery disease (CAD) in patients with diabetes. Nevertheless, whether these associations are causal is still unknown. In this two-sample Mendelian randomization (MR) study, we aimed to assess the causality between mental health and CAD in patients with diabetes. METHODS AND RESULTS: Single-nucleotide polymorphisms (SNPs) associated with: depression (807,553 individuals), anxiety (83,556 individuals) and neuroticism (329,821 individuals) were identified from the largest genome-wide association studies (GWAS). Summary-level data for CAD were extracted from the recently published GWAS of 15,666 diabetic patients (3968 CAD cases and 11,696 controls). The inverse-variance weighted (IVW) method was used for the main analysis. Sensitivity analyses included weighted median, maximum likelihood, and the MR-Egger method. Genetic liability to depression was significantly associated with a higher risk of CAD in patients with diabetes (odds ratio [OR], 1.286; 95%CIï¼1.018-1.621ï¼p = 0.035). For anxiety and neuroticism, no causal association with CAD in patients with diabetes was observed. Consistent results were obtained in most sensitivity analyses. CONCLUSIONS: This MR study provides genetic evidence that depression is a potential risk factor for CAD in patients with diabetes. However, anxiety and neuroticism were not causally associated with CAD in patients with diabetes. Mental health treatments should be enhanced to prevent CAD in patients with diabetes.
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Enfermedad de la Arteria Coronaria , Diabetes Mellitus , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/genética , Diabetes Mellitus/genética , Estudio de Asociación del Genoma Completo/métodos , Humanos , Análisis de la Aleatorización Mendeliana/métodos , Salud Mental , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Epidemiological evidence has linked circulating cytokines to venous thromboembolism (VTE). However, it remains uncertain whether these associations are causal due to confounding factors or reverse causality. We aim to explore the causality between circulating cytokines and VTE, encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE). METHODS: In the current bidirectional Mendelian randomization (MR) study, instrumental variables of 41 circulating cytokines were obtained from the genome-wide association study meta-analyses (8,293 individuals). Summary statistics for the association of VTE (17,048 cases and 325,451 controls), DVT (8,077 cases and 295,014 controls), and PE (8,170 cases and 333,487 controls) were extracted from the FinnGen Study. A multivariable MR study was conducted to adjust for potential confounders. The inverse-variance weighted method was employed as the main analysis, and comprehensive sensitivity analyses were conducted in the supplementary analyses. RESULTS: The MR analysis indicated stromal cell-derived factor-1α was suggestively associated with a reduced risk of VTE (odds ratio [OR]: 0.90; 95% confidence interval [CI]: 0.81-0.99; p = 0.033) and DVT (OR: 0.85; 95% CI: 0.75-0.97; p = 0.015). In addition, suggestive association of granulocyte colony-stimulating factor with PE (OR: 1.20; 95% CI: 1.06-1.37; p = 0.005) was observed. Multivariable MR analysis showed that the effect of cytokines on VTE was partly mediated through hemoglobin A1c and systolic blood pressure. Reverse MR analysis revealed that VTE was linked to decreased levels of several cytokines. CONCLUSION: We provide suggestive genetic evidence supporting the bidirectional causal effect between circulating cytokines and VTE, highlighting the importance of targeting circulating cytokines to reduce the incidence of VTE.
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Citocinas , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Embolia Pulmonar , Tromboembolia Venosa , Trombosis de la Vena , Humanos , Tromboembolia Venosa/sangre , Tromboembolia Venosa/genética , Tromboembolia Venosa/epidemiología , Citocinas/sangre , Embolia Pulmonar/sangre , Embolia Pulmonar/genética , Embolia Pulmonar/epidemiología , Trombosis de la Vena/sangre , Trombosis de la Vena/genética , Trombosis de la Vena/epidemiología , Factores de Riesgo , Femenino , Estudios de Casos y Controles , Masculino , Oportunidad Relativa , Polimorfismo de Nucleótido SimpleRESUMEN
Background: Numerous observational studies have suggested an association between psychiatric traits and carotid intima-media thickness (cIMT). However, whether these associations have a causal relationship remains unknown, largely due to issues of reverse causality and potential confounders. This study aims to elucidate the potential causal role of psychiatric traits in the risk of arterial injury as measured by cIMT. Methods: We utilized instrumental variables for attention deficit/hyperactivity disorder (ADHD, n = 226,534), bipolar disorder (n = 353,899), major depressive disorder (n = 142,646), post-traumatic stress disorder (n = 174,494), obsessive-compulsive disorder (n = 9,725), autism spectrum disorder (n = 173,773), and anxiety disease (n = 17,310), derived from the largest corresponding genome-wide association studies (GWAS). Summary statistics for cIMT associations were obtained from a meta-analysis combining GWAS data from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortia (n = 71,128) and the UK Biobank study (n = 45,185). The inverse-variance weighted method served as the primary analytical tool, supplemented by additional statistical methods in the secondary analyses to corroborate the findings. Adjustments were made according to the Bonferroni correction threshold. Results: The Mendelian randomization analyses indicated a suggestive causal link between genetically predicted ADHD and cIMT (beta = 0.05; 95% confidence interval, 0.01-0.09; p = 0.018). Sensitivity analyses largely concurred with this finding. However, no significant associations were found between other psychiatric traits and cIMT. Conclusions: This study provides insights into the risk effect of ADHD on cIMT, suggesting that arteriopathy and potential associated complications should be considered during the treatment and monitoring of patients with ADHD.
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Up-to-date knowledge of gut microbial taxa associated with ischemic heart disease (IHD). Microbial metabolites for mechanistic dissection of IHD pathology. Microbiome-based therapies in IHD prevention and treatment.
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Background: Observational studies have reported inconsistent associations between micronutrient levels and the risk of coronary artery disease (CAD) in diabetic patients. We aim to explore the causal association between genetically predicted concentrations of micronutrients (phosphorus, magnesium, selenium, iron, zinc, and copper) and CAD in patients with diabetes. Methods: Single nucleotide polymorphisms (SNPs) connected to serum micronutrient levels were extracted from the corresponding published genome-wide association studies (GWASs). Summary-level statistics for CAD in diabetic patients were obtained from a GWAS of 15,666 patients with diabetes. The primary analysis was carried out with the inverse variance weighted approach, and sensitivity analyses using other statistical methods were further employed to assess the robustness of the results. Results: Genetically predicted selenium level was causally associated with a higher risk of CAD in diabetic patients (odds ratio [OR]: 1.25; 95% confidence interval [CI]: 1.10-1.42; p = 5.01 × 10-4). While, genetically predicted iron concentrations in patients with diabetes were inversely associated with the risk of CAD (OR: 0.82; 95% CI: 0.75-0.90; p = 2.16 × 10-5). The association pattern kept robust in most sensitivity analyses. Nominally significant associations were observed for magnesium and copper with the risk of CAD in patients with diabetes. No consistent evidence was found for the causal associations between phosphorus and zinc levels, and the risk of CAD in patients with diabetes. Conclusion: We provide consistent evidence for the causal effect of increased selenium and decreased iron levels on CAD in patients with diabetes, highlighting the necessity of micronutrient monitoring and application in these patients.
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Background: Observational studies suggested that multiple sclerosis (MS) is associated with cardiovascular diseases (CVDs). However, the causal association has not been fully elucidated. Thus, we aim to assess the causality of the associations of MS with risk of CVDs. Methods: A two-sample Mendelian randomization (MR) study was performed to explore the causality. Genetic instruments were identified for MS from a genome-wide association study (GWAS) involving 115,803 individuals. Summary-level data for CVDs were obtained from different GWAS meta-analysis studies. MR analysis was conducted mainly using the inverse-variance weighted (IVW) method. Sensitivity analyses were further performed to ensure the robustness of the results. Results: This MR study found suggestive evidence that genetic liability to MS was associated with an increased risk of coronary artery disease (CAD) [odds ratio (OR), 1.02; 95% confidence interval (CI), 1.00-1.04; p = 0.03], myocardial infarction (MI) (OR, 1.03; 95% CI, 1.00-1.06; p = 0.01), heart failure (HF) (OR, 1.02; 95% CI, 1.00-1.04; p = 0.02), all-cause stroke (AS) (OR, 1.02; 95% CI, 1.00-1.05; p = 0.02), and any ischemic stroke (AIS) (OR, 1.02; 95% CI, 1.00-1.05; p = 0.04). The null-association was observed between MS and the other CVDs. Further analyses found little evidence of pleiotropy. Conclusions: We provided suggestive genetic evidence for the causal associations of MS with increased risk of CAD, MI, HF, AS, and AIS, which highlighted the significance of active monitoring and prevention of cardiovascular risk to combat cardiovascular comorbidities in MS patients.