Role of Transitional %B cells in Mediating the Effect of Phosphatidylinositol (16:0_18:1) on Aortic Dissection.

Aortic dissection is a life-threatening condition with complex immunological underpinnings. This study was aimed at exploring the causal relationships among immune cells, inflammatory proteins, and aortic dissection, through Mendelian randomization analysis. We used a two-step Mendelian randomization approach to assess potential mediators, focusing on the roles of blood immune cells and inflammatory proteins. We analyzed GWAS data for 731 immune cell traits, 91 inflammatory proteins, and aortic dissection. Single-nucleotide polymorphisms were used as instrumental variables, and analyses were conducted with inverse variance weighting and sensitivity tests to ensure robustness. Our results identified 11 immune cells, including myeloid dendritic cells and monocytes, with significant protective or risk-enhancing effects on aortic dissection. Specifically, CD62L-CD86+ myeloid dendritic cells and CD86+ myeloid dendritic cells demonstrated protective effects, whereas CD14+ CD16+ monocytes were identified as risk factors. Furthermore, the inflammatory protein TRAIL mediated the relationships between specific immune cell types and aortic dissection. Monocyte cell count was identified as a key mediator between myeloid dendritic cells and aortic dissection, thus revealing an immune-mediated pathway that might potentially be targeted for therapeutic intervention. These findings provide new insights into the immunological mechanisms contributing to aortic dissection.

Benign paroxysmal vertigo (BPV) is a common cause of dizziness, and some patients are comorbid with psychiatric disorders such as depression, requiring intervention with antidepressants. However, the causal association between BPV, depression and antidepressants has not been clearly established. We used two-sample bidirectional Mendelian randomization (MR) to analyze the causal association between BPV, depression, and antidepressants. From a Finnish database, 43,280 patients with depression and 329,192 controls, and 106,785 patients with antidepressants and 88,536 controls were selected. Independent single nucleotide polymorphisms (SNPs) for depression and antidepressants were used as instrumental variables (IVs) with genomic significance (p < 5 × 10–8). Similarly, genome-wide association study (GWAS) data for BPV were selected from a Finnish database consisting of 8280 cases and 359,094 controls. Afterwards, a two-sample MR study was performed using R’s Two Sample MR and MR-PRESSO software packages. The multiplicity and heterogeneity of the data, as well as the effect of individual SNPs on the results were investigated. The main statistical analyses were weighted median, weighted mode, MR-Egger and weighted inverse variance weighting (IVW) for random effects. Finally, we identified associations between BPV, antidepressants and depression. Four outliers (rs3773087, rs4619804, rs62099231, rs7192848) were found to be associated with depression. After removing the outliers, the statistics showed no heterogeneity (p > 0.05) and horizontal pleiotropy (p > 0.05). Antidepressants were also found to have a random effect IVW (β = 0.440; p = 9.692 × 10–6; OR = 1.553; 95% CI 1.278–1.887). The inverse MR random effects IVW results showed a causal association between BPV and antidepressants (β = 0.051; p = 0.045; OR = 1.052; 95% CI 1.001–1.1066). In conclusion, there was a significant causal association between antidepressants and BPV at the genetic level. Clinicians should pay attention to patients with BPV combined with depressive disorders and develop timely interventions.

Background:This study investigates the causal relationships between 731 immune cell traits and aortic dissection (AD) using Mendelian randomisation (MR). By identifying specific immune cell phenotypes contributing to AD, we explore their clinical implications for risk stratification and therapeutic interventions.Methods:A bivariate MR framework analysed the causal dynamics between immune cell attributes and AD, using genetic variants as instrumental variables. Summary statistics from a genome-wide association study for 731 immune phenotypes were obtained. Univariable MR analysis was conducted using the inverse-variance weighted method supplemented by sensitivity analyses. Horizontal pleiotropy was assessed using MR-Egger and MR pleiotropy residual sum and outlier. Significant cis-expression quantitative trait loci (eQTL) were identified via the Genotype-Tissue Expression (GTEx) database, followed by tissue-specific expression and pathway analyses.Results:Four immunophenotypes exhibited positive causal effects on AD, while one showed a negative effect. Pathogenic traits included the median fluorescence intensity of CD19 on transitional B cells, immunoglobulin D- CD38dim B cells, CD3 on CD39+ CD4+ Treg cells, and CD3 on CD39+ activated Treg cells. The protective trait was the absolute count of CD86+ myeloid dendritic cells. Sensitivity analyses validated these associations. Pathway enrichment analysis highlighted significant arterial enrichments and key biological processes, identifying SLAMF6 and CD28 as key genes.Conclusion:This study suggests potential causal roles for specific immune cell traits in AD pathogenesis, although these findings should be interpreted with caution due to study limitations. The identified immune cell types and associated eQTL genes offer promising targets for clinical risk stratification and therapeutic interventions. Future research should focus on translating these findings into practical strategies for patient care.

Causal association between uric acid levels and the risk of aortic aneurysm and aortic dissection: A two-sample Mendelian randomization study

Aortic Dissection (AD) is a severe vascular disease with high mortality. While its progression is rapid, the development of AD is a chronic disease process. The gut microbiome may play a crucial role in this process. This study aims to explore the potential causal association between gut microbiome and AD using Mendelian Randomization (MR). This study employed a two-sample MR approach using Genome-Wide Association Study (GWAS) data from the Finnish population to investigate the causal association between gut microbiota and AD. Single Nucleotide Polymorphisms (SNPs) associated with 473 gut microbiota taxa were selected as instrumental variables, and various MR methods were applied to evaluate the causal effects. Sensitivity analyses were conducted to assess the robustness of the results, and a reverse MR analysis was performed to validate the directionality of the associations. The MR analysis confirmed that Actinomycetales, Bacillales A, Lawsonibacter sp002161175, Prevotella sp002933775, Saccharomonospora, Acidaminococcus fermentans, CAG-110, CAG-177 sp002451755, CAG-177 sp003514385, and Eisenbergiella sp900066775 may exert protective effects, whereas koll11, Magnetospirillum A, Poseidoniaceae, Pseudomonas aeruginosa, Bacteroides eggerthii, CAG-269 sp002372935, and Dorea phocaeense may increase the risk of AD. Sensitivity analyses confirmed the robustness of these findings. This study provides new insights into the role of gut microbiome in AD, identifying specific taxa that may serve as protective or risk factors. Further research is needed to validate these findings in broader populations.

This study investigates the causal associations between interleukin receptor-related factors and the development of endometriosis, as their etiology and pathophysiology remain largely unknown. A two-sample Mendelian randomization (MR) approach was employed to analyze genetic variants associated with interleukin receptor related factors as instrumental variables (IVs). The F-values have to be > 10 to exclude weak instrumental bias. The primary analysis was conducted using the inverse variance weighted (IVW) method, with confirmation using the MR-Egger, weighted median (WM), simple mode, and weighted mode methods. Sensitivity analyses were performed to ensure robustness, including tests for heterogeneity, pleiotropy, and leave-one-out. Multivariable MR (MVMR) analysis was used to assess the direct and mediated effects of immune cells. The results indicated significant causal associations between interleukin receptor factors prot-a-1542 (IL-6Rβ), prot-a-1530 (IL-3Rα), and prot-b-38 (IL-1RL1) and endometriosis. Reverse MR analysis showed that endometriosis did not significantly affect prot-a-1530 or prot-b-38. After adjusting for confounders like body mass index and smoking, these factors retained their significance. Additionally, immune cells(ebi-a-GCST90001951) were found to mediate the relationship between prot-b-38 and endometriosis, with an indirect effect accounting for approximately 6.38% of the total effect. This study provides new insights into endometriosis mechanisms involving specific interleukin receptor factors.

Editor's evaluation: Phenome-wide Mendelian randomisation analysis identifies causal factors for age-related macular degeneration

Previous studies suggests that gut microbiomes are associated with the formation and progression of aneurysms. However, the causal association between them remains unclear. A two-sample Mendelian randomization was conducted to investigate whether gut microbiomes have a causal effect on the risk of intracerebral aneurysm (IA), thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA), and aortic aneurysm (AA). Single nucleotide polymorphisms (SNPs) smaller than the locus-wide significance level (1 × 10-5) were selected as instrumental variables. We used inverse-variance weighted (IVW) test as the primary method for the evaluation of causal association. MR-Egger, weighted median, weighted mode, and MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) methods were conducted for sensitive analysis. The p-value was adjusted by the false discovery rate (FDR) which adjust the results of multiple comparisons, a p < 0.05 and q < 0.1 was considered a significant causal association. Additionally, a p < 0.05 and q > 0.1 was considered a suggestive causal effect. Additionally, reverse MR was also performed to exclude the possibility of reverse causality. The phylum Firmicutes (OR = 0.62; 95% CI, 0.48-0.81), class Lentisphaeria (OR = 0.75; 95% CI, 0.62-0.89), and order Victivallales (OR = 0.75; 95% CI, 0.62-0.89) have a causal protective effect on the risk of AAA. Additionally, class Verrucomicrobia, class Deltaproteobacteria, order Verrucomicrobiale, family Verrucomicrobiacea, genus Eubacterium rectale group, genus Akkermansia, and genus Clostridium innocuum group were negatively associated with the risk of different types of aneurysms, whereas class Negativicutes, order Selenomonadales, and genus Roseburia had positive causal association with different types of aneurysms (p < 0.05; q > 0.1). Further sensitivity analysis validated the robustness of our MR results, and no reverse causality was found with these gut microbiomes (p > 0.05). Our MR analysis confirmed the causal association of specific gut microbiomes with AAA, and these microbiomes were considered as protective factors. Our result may provide novel insights and theoretical basis for the prevention of aneurysms through regulation of gut microbiomes.

Although a growing number of studies have attempted to uncover the relationship between plasma lipids and the risk of aortic aneurysm (AA), it remains controversial. Meanwhile, the relationship between plasma lipids and the risk of aortic dissection (AD) has not been reported on. We conducted a two-sample Mendelian randomization (MR) analysis to evaluate the potential relationship between genetically predicted plasma levels of lipids and the risk of AA and AD. Summary data on the relationship between genetic variants and plasma lipids were obtained from the UK Biobank and Global Lipids Genetics Consortium studies, and data on the association between genetic variants and AA or AD were taken from the FinnGen consortium study. Inverse-variance weighted (IVW) and four other MR analysis methods were used to evaluate effect estimates. Results showed that genetically predicted plasma levels of low-density lipoprotein cholesterol, total cholesterol, or triglycerides were positively correlated with the risk of AA, and plasma levels of high-density lipoprotein cholesterol were negatively correlated with the risk of AA. However, no causal relationship was found between elevated lipid levels and the risk of AD. Our study revealed a causal relationship between plasma lipids and the risk of AA, while plasma lipids had no effect on the risk of AD.

This study aimed to investigate the potential causal relationship between screen time and the risk of developing type 2 diabetes mellitus (T2DM) using Mendelian randomization. Two-sample Mendelian randomization was conducted, utilizing genetic variants associated with different types of screen time as instrumental variables. Single nucleotide polymorphisms (SNPs) were used to assess the primary outcome, which was the risk of developing T2DM. The analysis revealed a significant positive causal association between television viewing time and the risk of T2DM. Specifically, excessive television viewing time was found to increase the risk of developing T2DM (OR: 2.39, 95% CI: 1.90 to 3.00, P < 0.01). However, no significant causal relationship was observed between computer usage time and the risk of T2DM. Additionally, mobile phone use time showed a positive correlation with the risk of T2DM (OR: 1.31, 95% CI: 1.04 to 1.64, P = 0.02), albeit to a lesser extent than television viewing time. The findings of this study indicate a significant causal association between certain types of screen time, specifically television viewing and mobile phone use, and an increased risk of T2DM.

Ischemic stroke (IS) is a global health issue linked to lipid metabolism and immune cell responses. This study uses Mendelian randomization (MR) to identify genetic risk factors for IS subtypes using comprehensive genetic data from lipidomic and immune cell profiles. We assessed genetic susceptibility to IS across 179 lipids and 731 immune cell phenotypes using instrumental variables (IVs) from recent genome-wide association studies. A two-sample MR approach evaluated correlations, and a two-step MR mediation analysis explored the role of immune cell phenotypes in the lipid-IS pathway. Sensitivity analyses, including MR-Egger and Cochran Q tests, ensured robust results. Genetic IVs for 162 lipids and 614 immune cell phenotypes were identified. Significant genetic causality was found between 35 lipids and large artery stroke (LAS), with 12 as risk factors (sterol esters, phosphatidylcholines, phosphatidylethanolamines) and 23 as protective factors (phosphatidylcholines, phosphatidylethanolamines, phosphatidylinositols). For small vessel stroke (SVS), 8 as risk factors (sterol esters, phosphatidylcholines), and 2 as protective factors (phosphatidylinositol, sphingomyelin). For cardioembolic stroke (CS), 2 as risk factors, and 4 as protective factors. Mediation analysis revealed that CCR2 on granulocytes, CD11c on CD62L+ myeloid dendritic cells, and FSC-A on granulocytes mediated the lipid-immune cell-LAS pathway, while CD4 on activated CD4 regulatory T cells and CD4 on activated & secreting CD4 regulatory T cells mediated the lipid-immune cell-SVS pathway. This study identifies genetic links between specific lipids and IS subtypes, highlights immune cells' role in IS risk and mediation, suggests new therapeutic targets, and uncovers IS genetic drivers.

Background: Liver failure is a critical clinical condition with complex pathophysiology, where the role of immune cells has been increasingly recognized. However, establishing causality between immune cell activity and liver failure has been challenging. We aimed to investigate the causal role of specific immune cell populations in the development of liver failure using Mendelian randomization (MR) techniques. Methods: Genetic data from the Genome-wide association study (GWAS) database, focusing on 731 immunophenotypes and a liver failure dataset was utilised. Single nucleotide polymorphisms (SNPs) associated with immune cell exposures were identified and used as instrumental variables. MR analyses were performed using the TwoSampleMR package in R, employing various MR techniques, including weighted median, MR Egger, inverse-variance weighted (IVW), and others. The robustness of the MR findings was assessed through heterogeneity, pleiotropy, and leave-one-out sensitivity analyses. Results: Our MR study revealed significant causal associations between several immune cell populations and liver failure. Notably, genetic variants associated with CD28 on CD39+ CD4+ T cells and CD3 on CD39+ secreting T Reg cells were found to be causally linked to an increased risk of liver failure. The IVW MR method, which has been previously validated for its performance, provided the most consistent results across immune cell exposures. Conclusion: Our findings suggest a direct causal role for specific immune cells in liver failure, offering potential targets for future therapeutic strategies.

BackgroundRecent evidence has suggested a potential link between bone mineral density (BMD) and cervical spondylosis (CS), while the specific relationship has yet to be comprehensively elucidated. Our study aimed to implement a comprehensive analytical framework incorporating bidirectional two-sample Mendelian randomization (MR) and multivariable MR (MVMR) to investigate the causal relationship between BMD and CS.MethodsGenome-wide association summary statistics for BMDs across four skeletal sites and five age groups, and CS, were obtained from public databases. Single Nucleotide Polymorphisms (SNPs) that had a significant genetic association with exposures were used as instrumental variables (IVs). We employed inverse variance weighting (IVW) analysis as the primary analytical method to estimate potential causal effects, whereas Weighted median, MR-Egger regression, weighted mode, and simple mode were served as supplements. Furthermore, several sensitivity analyses (MR-Egger intercept, MR-PRESSO, Cochran’s Q test, and Leave-one-out test) were utilized to assess the robustness, heterogeneity, and horizontal pleiotropy of the findings.ResultsAfter applying the Bonferroni correction, BMDs in three skeletal sites exhibited significant positive causal associations with CS risk, including total body (TB), femoral neck (FN), and heel bone (HB). Notably, based on MR analyses of TB-BMD data stratified by five age brackets, the positive causal relationship was especially pronounced in the 45–60-year-old group. Further MVMR analysis revealed that, even after controlling for confounding factors, higher TB-BMD (OR = 1.14, 95% CI: 1.01–1.29; P = 3.12E−02) and HB-BMD (OR = 1.11, 95% CI: 1.01–1.22; P = 2.45E−02) still maintained an independent and significant causal association with CS. However, we did not find evidence to suggest that CS has an impact on BMD in reverse MR analysis.ConclusionThis study provides genetic support for a causal relationship between BMD and CS susceptibility. Specifically, individuals with high BMD are at greater risk of developing CS, offering valuable insights for future clinical research.

BackgroudPlasma lipids and alcohol intake frequency have been reported to be associated with the risk of osteoarthritis (OA). However, it remains inconclusive whether plasma lipids and alcohol intake frequency play a role in the development of OA.MethodsThe study employed a comprehensive genome-wide association database to identify independent genetic loci strongly linked to plasma lipids and alcohol intake frequency, which were used as instrumental variables. The causal association between plasma lipids, alcohol intake frequency, and the risk of OA was then analyzed using two-sample Mendelian randomization methods such as inverse variance weighted (IVW), MR-Egger regression, and weighted median estimator (WME), with odds ratios (ORs) as the evaluation criteria.ResultsA total of 392 SNPs were included as instrumental variables in this study, including 32 for total cholesterol (TC), 39 for triglycerides (TG), 170 for high-density lipoproteins (HDL), 60 for low-density lipoproteins (LDL), and 91 for alcohol intake frequency. Using the above two-sample Mendelian Randomization method to derive the causal association between exposure and outcome, with the IVW method as the primary analysis method and other MR analysis methods complementing IVW. The results of this study showed that four exposure factors were causally associated with the risk of OA. TC obtained a statistically significant result for IVW (OR = 1.207, 95% CI: 1.018–1.431, P = 0.031); TG obtained a statistically significant result for Simple mode (OR = 1.855, 95% CI: 1.107–3.109, P = 0.024); LDL obtained three statistically significant results for IVW, WME and Weighted mode (IVW: OR = 1.363, 95% CI: 1.043–1.781, P = 0.023; WME: OR = 1.583, 95% CI: 1.088–2.303, P = 0.016; Weighted mode: OR = 1.521, 95% CI: 1.062–2.178, P = 0.026). Three statistically significant results were obtained for alcohol intake frequency with IVW, WME and Weighted mode (IVW: OR = 1.326, 95% CI: 1.047–1.678, P = 0.019; WME: OR = 1.477, 95% CI: 1.059–2.061, P = 0.022; Weighted mode: OR = 1.641, 95% CI: 1.060–2.541, P = 0.029). TC, TG, LDL, and alcohol intake frequency were all considered as risk factors for OA. The Cochran Q test for the IVW and MR-Egger methods indicated intergenic heterogeneity in the SNPs contained in TG, HDL, LDL, and alcohol intake frequency, and the test for pleiotropy indicated a weak likelihood of pleiotropy in all causal analyses.ConclusionsThe results of two-sample Mendelian randomization analysis showed that TC, TG, LDL, and alcohol intake frequency were risk factors for OA, and the risk of OA increased with their rise.

BackgroundObservational epidemiologic investigations into the link between diabetes mellitus and preeclampsia (PE) have been conducted, but genetic evidence is still lacking. We utilized a two-sample Mendelian randomization (MR) analysis to shed light on the potential influence of type 2 diabetes mellitus (T2DM) on PE at the genetic prediction level.MethodsWe carried out a two-sample bidirectional MR analysis, utilizing genetic variants associated with T2DM (N=461,920) and PE (N=219,817) from the largest available genome-wide association studies. Using inverse variance weighting (IVW) and five validated approaches—MR-Egger, MR-RAPS, ConMix, weighted median, and weighted mode—we derived a potential causal association between T2DM and PE. The relationship between PE and T2DM was explored using reverse MR analysis.ResultsThe two-sample MR analysis indicated a causal link between T2DM and PE, with an odds ratio of 1.10 (95% CI, 1.02–1.18; P=0.01). The weighted mode method yielded an odds ratio of 1.22 (95% CI, 1.06–1.40; P=0.019), and the weighted median method produced an odds ratio of 1.19 (95% CI, 1.04–1.36; P=0.022). However, no significant association was detected in the MR-Egger analysis. Heterogeneity was noted in the analysis of T2DM and PE, but no significant horizontal pleiotropy was observed. The results of the reverse MR analysis indicated no significant causal association between PE and T2DM.ConclusionFor the first time, MR analysis showed a positive causal link from T2DM to PE, but not vice versa. The limited number of SNPs in reverse analysis may affect reliability. Future studies should use more instrumental variables to strengthen findings. Further experiments are also needed to explore underlying mechanisms.