UNASSIGNED: Observational studies have shown that heart rate (HR), heart rate variability (HRV), P-wave terminal force, P-wave duration, T-wave amplitude and PR interval are associated with risk factors for atrial fibrillation (AF) or bradycardia. Arrhythmias are associated with many causes of hospitalization. However, observational studies are susceptible to confounding factors that have not yet been identified. The objective of this study was to clarify the causal relationships by Mendelian randomization analysis.
UNASSIGNED: We conducted a two-sample and multivariate Mendelian randomization (MVMR) analysis using genome-wide association study (GWAS) data from a European population to assess the total and direct causal effects of HR, three HRV traits, P-wave terminal force, P-wave duration, T-wave top amplitude in five-lead modes, and the PR interval on the risk of AF (N=191,205), bradycardia (N=463,010), and supraventricular tachycardia (SVT) (N=463,010).
UNASSIGNED: The results of the univariate MR analysis revealed the following significant causal effects: the higher the genetically predicted PR interval, the lower the risk of AF; the higher the HR and T-wave top amplitude (aVR leads and V3 + V4 + aVL leads), the lower the risk of bradycardia; and the higher HR and the lower PR interval, the higher the risk of SVT. The multivariate MR results indicated that the HRV_standard deviation of the normal-to-normal (SDNN) interval had an independent causal effect on the risk of AF [odds ratio (OR): 0.515; 95% confidence interval (CI): 0.278-0.954; P=0.03], and the T-wave top amplitude in the aVR leads (OR: 0.998; 95% CI: 0.996-0.999; P<0.001) and the HRV_SDNN (OR: 0.988; 95% CI: 0.976-1.000; P=0.045) had independent causal effects on the risk of bradycardia.
UNASSIGNED: The HRV_SDNN had an independent causal effect on AF, while the HRV_SDNN and T-wave top amplitude in the aVR leads had independent causal effects on bradycardia, which suggests that some of the electrocardiographic parameters have preventive effects on the incidence of AF and bradycardia.

BACKGROUND: Previous research has revealed the potential impact of circadian rhythms on pulmonary diseases; however, the connection between circadian rhythm-associated Thyrotroph Embryonic Factor (TEF) and Pulmonary Arterial Hypertension (PAH) remains unclear. We aim to assess the genetic causal relationship between TEF and PAH by utilizing two sets of genetic instrumental variables (IV) and publicly available Pulmonary Arterial Hypertension Genome-Wide Association Studies (GWAS).
METHODS: Total of 23 independent TEF genetic IVs from recent MR reports and PAH GWAS including 162,962 European individuals were used to perform this two-sample MR study. Gain- and loss-of-function experiments were used to demonstrate the role of TEF in PAH.
RESULTS: Our analysis revealed that as TEF levels increased genetically, there was a corresponding increase in the risk of PAH, as evidenced by IVW (OR = 1.233, 95% CI: 1.054-1.441; P = 0.00871) and weighted median (OR = 1.292, 95% CI for OR: 1.064-1.568; P = 0.00964) methods. Additionally, the up-regulation of TEF expression was associated with a significantly higher likelihood of abnormal circadian rhythm (IVW: P = 0.0024733, β = 0.05239). However, we did not observe a significant positive correlation between circadian rhythm and PAH (IVW: P = 0.3454942, β = 1.4980398). In addition, our in vitro experiments demonstrated that TEF is significantly overexpressed in pulmonary artery smooth muscle cells (PASMCs). And overexpression of TEF promotes PASMC viability and migratory capacity, as well as upregulates the levels of inflammatory cytokines.
CONCLUSIONS: Our analysis suggests a causal relationship between genetically increased TEF levels and an elevated risk of both PAH and abnormal circadian rhythm. Consequently, higher TEF levels may represent a risk factor for individuals with PAH.

UNASSIGNED: Different dietary habits can have varying effects on human health and metabolism, and these can be intervened and regulated. Kidney stones, as a disease caused by multiple factors, are largely attributed to diet and metabolism, but the potential causal relationship with dietary intake habits remains unclear. Therefore, this study aims to link the predicted dietary intake based on 45 genetic factors with urolithiasis and explore the potential causal relationship.
UNASSIGNED: We extracted complete genome-wide association studies (GWASs) data on 45 dietary intake traits from the UK Biobank study. Data on kidney stones were obtained from the FinnGen database. In both univariable and multivariable Mendelian randomization analyses, we used inverse variance weighted (IVW) as the primary method to calculate P values, odds ratios (ORs), and 95% confidence intervals (CIs). We examined result heterogeneity using Cochran\'s Q test. We also carefully investigated potential sources of horizontal pleiotropy using the Mendelian randomization (MR)-PRESSO and MR-Egger methods, and conducted linkage disequilibrium score regression (LDSC) analysis on the corrected P values.
UNASSIGNED: Through univariable analysis, we identified 11 dietary habits that potentially causally associate with kidney stones among the 45 examined traits, including 9 protective factors and 2 risk factors. Based on the corrected results with false discovery rate (FDR) and sensitivity analysis, we found one relatively robust evidence. We controlled for common stone risk factors, such as body mass index and smoking, as confounders in multivariable analysis, and no significant results were observed after controlling for these confounders. Based on the LDSC analysis, most of the evidence supports significant genetic correlations with urolithiasis among the 11 traits with potential causal associations.
UNASSIGNED: This study confirms the impact of certain dietary factors on the development of kidney stones. Our findings contribute to providing evidence for dietary adjustments in daily life or dietary guidance specifically targeting kidney stone patients.

UNASSIGNED: Keratoconus is a diseased corneal dilation of unknown etiology. Studies have shown that inflammation may play a role in keratoconus. Inflammatory enteritis (IBD), including ulcerative colitis (UC), is a chronic, systemic inflammatory disease. We used Mendelian randomization to assess the causal relationship among IBD, UC and keratoconus.
UNASSIGNED: The instrumental variable of IBD and UC was selected, the information of the instrumental variable in keratoconus outcome was extracted, and the causal relationship was assessed by the inverse variance weighted method by primary analysis, and its relevant sensitivity analysis.
UNASSIGNED: A causal relationship between IBD and keratoconus was observed significantly (P = 0.017, OR = 1.21, 95% CI = 1.03-1.41), and same as to UC and keratoconus (P = 0.038, OR = 1.25, 95% CI = 1.01-1.54).
UNASSIGNED: IBD may play a causal role in the development of keratoconus, but the mechanism needs to be further elucidated.

UNASSIGNED: Several studies have reported associations between various autoimmune diseases and migraine. Using Mendelian randomization (MR), this study aimed to evaluate the interplay between autoimmune diseases and migraine.
UNASSIGNED: Here, instrumental variables, exposure factors, and outcome factors for 10 common autoimmune diseases and migraine and its subtypes were screened. This screening utilized comprehensive statistics from Europe\'s largest genome-wide association study and performed reverse MR analysis on positive results. The causality between autoimmune diseases and migraine was comprehensively assessed using multiple analytical methods. Additionally, sensitivity analyses, such as the horizontal diversity heterogeneity and leave-one-out method, were performed.
UNASSIGNED: Random-effects inverse variance weighting analysis revealed a causal correlation between autoimmune hyperthyroidism and migraine (p = 0.0002), and this association was consistent across both migraine with aura (MA; p = 0.006) and migraine without aura (MO; p = 0.017). In addition, there was a positive causal association between systemic lupus erythematosus (SLE) and MA (p = 0.001) and between hypothyroidism and MO (p = 0.038). There is insufficient evidence to substantiate a causal link between outcomes and other autoimmune-related disorders, and reverse MR results did not reveal a causal relationship between migraines and these autoimmune disorders. The validity of the results was demonstrated by a sensitivity analysis; horizontal pleiotropy and heterogeneity were not observed.
UNASSIGNED: This study observed a positive genetic association between autoimmune hyperthyroidism and migraines. In addition, SLE positively affects MA, and hypothyroidism contributes to the incidence of MO. These results have great significance for future research and prevention of migraine.

The communication mechanism of the gut-lung axis has received increasing attention in recent years, particularly in acute respiratory infectious diseases such as influenza. The peripheral immune system serves as a crucial bridge between the gut and the lungs, two organs that are not in close proximity to each other. However, the specific communication mechanism involving gut microbiota, immune cells, and their anti-influenza effects in the lung remains to be further elucidated. In this study, the effects of 731 species of peripheral immune cells and 211 different gut microbiota on influenza outcomes were analyzed using a two-sample Mendelian randomization analysis. After identifying specific species of gut microbiota and peripheral immune cells associated with influenza outcomes, mediation analyses were conducted to determine the mediating effects of specific immune cells in the protective or injurious effects of influenza mediated by gut microbiota. 19 species of gut microbiota and 75 types of peripheral immune cells were identified as being associated with influenza susceptibility. After rigorous screening, 12 combinations were analyzed for mediated effects. Notably, the down-regulation of CD64 on CD14- CD16- cells mediated 21.10% and 18.55% of the protective effect of Alcaligenaceae and Dorea against influenza, respectively. In conclusion, focusing on influenza, this study genetically inferred different types of gut microbiota and peripheral immune cells to determine their protective or risk factors. Furthermore, mediation analysis was used to determine the proportion of mediating effects of peripheral immune cells in gut microbiota-mediated susceptibility to influenza. This helps elucidate the gut-lung axis mechanism by which gut microbiota affects influenza susceptibility from the perspective of regulation of peripheral immune cells.

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UNASSIGNED: Insulin-like Growth Factor-1 (IGF-1) plays a crucial role in the growth and metabolic functions of various tissues and cells in the body. Recently, there has been increased attention to the association between IGF-1 and osteoarthritis (OA). However, there is controversy in current research regarding the correlation between IGF-1 levels and OA. Furthermore, the specific manner in which Body Mass Index (BMI), a key risk factor for OA, mediates the impact of IGF-1 levels on OA remains unclear.
UNASSIGNED: This study aimed to investigate the bidirectional causal link between IGF-1 levels and OA in four body regions, and to explore how BMI influences the impact of IGF-1 on these types of OA.
UNASSIGNED: Two-sample Mendelian Randomization (MR) and its combined forms were utilized to investigate the bidirectional relationship between IGF-1 levels and four types of OA, as well as the mediating role of BMI in the impact of IGF-1 levels on OA. Data from various Genome-Wide Association Studies (GWAS) and multiple analytical methods, including inverse variance weighted, MR-Egger regression, and weighted median were utilized. Sensitivity analyses, such as MR-Egger intercept, Cochran Q test, leave-one-out, and MR-PRESSO, were conducted to ensure the robustness of the results.
UNASSIGNED: Higher IGF-1 levels are correlated with an increased risk for knee (OR, 1.07; 95% CI, 1.01-1.03; p = 1.49e-01; q = 9.86e-03), hip (OR, 1.13; 95% CI, 1.06-1.20; p = 7.61e-05; q = 7.44e-05), and hand OA (OR, 1.09; 95% CI, 1.01-1.17; p = 1.88e-02; q = 1.15e-02), but not spine OA but not spine OA (OR, 1.05; 95% CI, 0.99-1.10; p = 9.20e-02; q = 5.52e-02). Different types of OA do not affect IGF-1 levels. BMI mediates the increase in OA risk associated with higher IGF-1, including indirect spine OA risk through BMI.
UNASSIGNED: The study elucidates the bidirectional causality between IGF-1 levels and OA in various body parts, highlighting BMI\'s mediating role in the impact of IGF-1 levels on OA. This provides valuable insights for OA prevention, diagnosis, and treatment strategies. Future research will expand our study to include a broader spectrum of ethnicities and explore the underlying mechanisms involved.

UNASSIGNED: Observational studies have indicated that immune dysregulation in primary sclerosing cholangitis (PSC) primarily involves intestinal-derived immune cells. However, the causal relationship between peripheral blood immune cells and PSC remains insufficiently understood.
UNASSIGNED: A bidirectional two-sample Mendelian randomization (MR) analysis was implemented to determine the causal effect between PBC and 731 immune cells. All datasets were extracted from a publicly available genetic database. The standard inverse variance weighted (IVW) method was selected as the main method for the causality analysis. Cochran\'s Q statistics and MR-Egger intercept were performed to evaluate heterogeneity and pleiotropy.
UNASSIGNED: In forward MR analysis, the expression ratios of CD11c on CD62L+ myeloid DC (OR = 1.136, 95% CI = 1.032-1.250, p = 0.009) and CD62L-myeloid DC AC (OR = 1.267, 95% CI = 1.086-1.477, p = 0.003) were correlated with a higher risk of PSC. Each one standard deviation increase of CD28 on resting regulatory T cells (Treg) (OR = 0.724, 95% CI = 0.630-0.833, p < 0.001) and CD3 on secreting Treg (OR = 0.893, 95% CI = 0.823-0.969, p = 0.007) negatively associated with the risk of PSC. In reverse MR analysis, PSC was identified with a genetic causal effect on EM CD8+ T cell AC, CD8+ T cell AC, CD28- CD127- CD25++ CD8+ T cell AC, CD28- CD25++ CD8+ T cell AC, CD28- CD8+ T cell/CD8+ T cell, CD28- CD8+ T cell AC, and CD45 RA- CD28- CD8+ T cell AC.
UNASSIGNED: Our study indicated the evidence of causal effects between PSC and immune cells, which may provide a potential foundation for future diagnosis and treatment of PSC.

UNASSIGNED: Studying the relationship between strenuous sports or other exercises (SSOE) and lung cancer risk remains underexplored. Traditional observational studies face challenges like confounders and inverse causation. However, Mendelian randomization (MR) provides a promising approach in epidemiology and genetics, using genetic variants as instrumental variables to investigate causal relationships. By leveraging MR, we have scrutinized the causal link between SSOE and lung cancer development.
UNASSIGNED: Twelve single-nucleotide polymorphisms (SNPs) associated with SSOE, as identified in previously published genome-wide association studies, were utilized as instrumental variables in our investigation. Summary genetic data at the individual level were obtained from relevant studies and cancer consortia. The study encompassed a total of 11,348 cases and 15,861 controls. The statistical technique of inverse variance-weighting (IVW), commonly employed in meta-analyses and MR studies, was employed to assess the causal relationship between SSOE and lung cancer risk.
UNASSIGNED: The MR risk analysis indicated a causal relationship between SSOE and the incidence of lung cancer, with evidence of a reduced risk for overall lung cancer [odds ratio (OR) =0.129; 95% confidence interval (CI): 0.021-0.779; P=0.03], lung adenocarcinoma (OR =0.161; 95% CI: 0.012-2.102; P=0.16) and squamous cell lung cancer (OR =0.045; 95% CI: 0.003-0.677; P=0.03). The combined OR for lung cancer from SSOE (controlling for waist circumference and smoking status) was 0.054 (95% CI: 0.010-0.302, P<0.001).
UNASSIGNED: Our MR analysis findings indicate a potential correlation between SSOE and a protective effect against lung cancer development. Further investigation is imperative to uncover the precise mechanistic link between them.