Bidirectional Mendelian Randomization Research Articles

Prostatitis, benign prostatic hyperplasia, and prostate cancer: a bidirectional Mendelian randomization study and clinical implications for these patients’ populations

BackgroundNo authoritative books or guidelines are currently available for revealing the interrelationships of prostatitis, benign prostatic hyperplasia (BPH), and prostate cancer (PCa). Moreover, no consensus on this issue has been reached among previously published epidemiological studies or meta-analyses.PurposeWe first took advantage of Mendelian randomization to clarify this issue and provide clinical implications for these patients’ populations.MethodsBidirectional two-sample and mediator Mendelian randomization were applied to explore the causal relationships among prostatitis, BPH, and PCa. Sensitivity analyses, including phenotype scanning, heterogeneity, pleiotropy, leave-one-out analysis, and the Steiger test, were conducted to evaluate the robustness and reliability of our results.ResultsOur results revealed the interrelationships among prostatitis, BPH, and PCa via Mendelian randomization, confirming that genetic susceptibility to prostatitis or BPH could lead to increased risks of PCa directly or indirectly (P < 0.05). Moreover, mediator Mendelian randomization revealed four potential mediator pathways, including the prostatitis-BPH-PCa, the BPH-PCa-prostatitis, the PCa-prostatitis-BPH, and the PCa-BPH-prostatitis pathways. Based on these, we also provided clinical implications for prostatitis, BPH, and PCa patients’ populations, respectively. Interestingly, a total of three vicious circles were revealed by us, including the prostatitis-BPH circle, the BPH-PCa circle, and the prostatitis-BPH-PCa circle. All of these three vicious circles contributed to the progression of benign prostate diseases to malignant diseases.ConclusionWe successfully clarified the interrelationships among prostatitis, BPH, and PCa, providing clinical implications for these patients’ populations. A total of three vicious circles were also revealed by us to provide novel ideas for future drug development and guide clinical decision-making.

Causal relationship between gut microbiota and lung squamous cell carcinoma: a bidirectional two-sample Mendelian randomization study.

This study aims to explore the potential causal relationship between gut microbiota and lung squamous cell carcinoma (LUSC). A bidirectional two-sample Mendelian randomization analysis was conducted using genome-wide association study (GWAS) data from gut microbiota and LUSC. Gut microbiota served as the exposure factor, with instrumental variables selected from a GWAS involving 18 340 participants. LUSC data were drawn from a European cohort including 29 266 LUSC cases and 56 450 controls. Inverse-variance weighted (IVW) method was used as the primary method, with the Benjamini-Hochberg method applied to adjust for multiple comparisons. An independent dataset (ieu-a-967, containing 3275 LUSC cases and 15 038 controls) was used for replication analysis to ensure robustness. IVW analysis found that Butyricicoccus (OR = 0.79, 95% CI: 0.63-0.99, P = .042) and Coprobacter (OR = 0.85, 95% CI: 0.74-0.97, P = .018) were significantly protective against LUSC. In contrast, Victivallis (OR = 1.11, 95% CI: 1.00-1.23, P = .045) and Ruminococcus (OR = 1.28, 95% CI: 1.03-1.60, P = .028) increased LUSC risk. Replication analysis in the independent dataset confirmed significant associations for Ruminococcus and Coprobacter. No reverse causality or pleiotropy was detected. This study provides evidence of a causal relationship between specific gut microbiota and LUSC risk, highlighting new microbial targets for potential prevention and treatment strategies in lung cancer. Key messages What is already known on this topic? Previous studies have suggested potential links between gut microbiota composition and the development of various cancers, including lung cancer. However, the exact causal relationship between specific gut microbiota and lung squamous cell carcinoma (LUSC) has remained unclear. Traditional observational studies have struggled to determine the direction of causality due to confounding factors, making further investigation necessary through more robust methods such as Mendelian randomization (MR). What this study adds? This bidirectional MR study provides novel genetic evidence indicating that certain gut microbiotas are causally associated with LUSC risk. Specifically, Butyricicoccus appears to reduce the risk of LUSC, while Victivallis increases the risk. These findings highlight the role of the gut-lung axis in LUSC and open up new avenues for exploring gut microbiota as potential modulators of lung cancer risk. How this study might affect research, practice, or policy? The implications of this study may significantly influence future research into cancer prevention strategies by targeting gut microbiota. Additionally, it could inform clinical practices aimed at modulating gut microbiota to lower the risk of LUSC, potentially influencing dietary or probiotic interventions to reduce cancer susceptibility. Furthermore, these results might shape public health policies that focus on the gut-lung axis as a novel avenue for cancer prevention and management.

Association between thyroid dysfunction and diabetic retinopathy: a two-sample bidirectional Mendelian randomization study

ObjectivesTo assess the association between thyroid dysfunction and diabetic retinopathy (DR), a two-sample bidirectional Mendelian randomization (MR) study utilizing the Genome-wide Association Study (GWAS) database was conducted to investigate the causal relationship between these two variables.MethodsIn this study, GWAS of 48,328,151 single nucleotide polymorphisms(SNP) in the European population from the IEU open GWAS database were utilized as genetic tools for investigating thyroid dysfunction. The total sample size for the study on hyperthyroidism was 460,499 (case group: 3557; control group: 456,942). The total sample size for hypothyroidism was 410,141 (case group: 30,155; control group: 37,986). In addition, the data on DR were extracted from the FinnGen Biobank, comprising a total sample size of 319,046 individuals (10,413 cases and 308,633 controls). For the forward MR analysis, hyperthyroidism and hypothyroidism were considered as exposures with DR as the outcome. Reverse MR analysis was conducted using DR as exposure and hyperthyroidism and hypothyroidism as outcomes. Methods: The main analytical approach employed inverse variance weighting(IVW), supplemented by MR-Egger, Weighted mode method, weighted median, and Simple mode. Cochran's Q test, MR-PRESSO, MR-Egger and leave-one-out analysis were used to evaluate the sensitivity and pleiotropy.ResultsTwo-sample bidirectional MR analysis revealed a significant association between the presence of hyperthyroidism and hypothyroidism and an increased risk of DR in the forward MR analysis (IVW: OR = 1.29, 95% [CI] = 1.12–1.49, P < 0.001; OR = 1.17, 95% CI = 1.10–1.25, P < 0.001). In the reverse MR analysis, DR was found to be associated with an elevated risk of developing hyperthyroidism and hypothyroidism (IVW: OR = 1.56, 95% CI 1.38–1.76, P < 0.001; OR = 1.41, 95% CI 1.25–1.59, P < 0.001). Furthermore, most supplementary MR methods also demonstrated statistically significant differences and exhibited effect sizes consistent with those obtained from IVW. The sensitivity analysis confirmed the relative reliability of our causal findings.ConclusionsOur findings provide genetic evidence supporting a bidirectional causal relationship between thyroid function and DR.

Pyridoxal 5′-phosphate and risk of stroke: triangulation of evidence from a nationally representative cohort and bidirectional Mendelian randomization analysis

Pyridoxal 5′-phosphate and risk of stroke: triangulation of evidence from a nationally representative cohort and bidirectional Mendelian randomization analysis

Primary ovarian insufficiency consequence of autoimmune diseases: a bidirectional two-sample Mendelian randomization study

BackgroundObservational studies suggest the risk of primary ovarian insufficiency (POI) is increased in autoimmune disorders (AIDs), but it is unclear whether there is a causal relationship. Therefore, we aimed to investigate the bidirectional causality between 20 AIDs and POI using Mendelian randomization (MR) analysis.MethodsA bidirectional two-sample MR investigation was designed by using publicly accessible summary-level data from genome-wide association studies (GWAS). The inverse variance weighted (IVW) method was performed as the main analysis, supplemented by several sensitivity analyses. Cochran Q test was used to evaluate SNP estimate heterogeneity. MR-Egger and MR-PRESSO methods were utilized to detect horizontal pleiotropy.ResultsThe MR analyses revealed that genetically determined coeliac disease (CeD) (OR = 1.124, 95% CI 1.033-1.224, P = 0.007), vitiligo (OR = 1.092, 95% CI 1.003-1.188; P = 0.042), systemic lupus erythematosus (SLE) (OR = 1.122, 95% CI 1.030-1.223, P = 0.008), and selective immunoglobulin A deficiency (SIgAD) (OR = 0.866, 95% CI: 0.776-0.967, P = 0.011) exhibited significant causal relationships with POI. We also found suggestive evidence of positive effect of Addison’s disease (AD) towards POI (OR5e-6 = 1.076, 95% CI 1.002-1.154, P = 0.043).ConclusionThis comprehensive MR analysis indicated that SLE, CeD, vitiligo, and AD caused an increased risk of POI, SIgAD was associated with a decreased risk of POI. These insights carry profound clinical implications, particularly emphasizing the early intervention for women with AIDs/POI who wish to preserve their reproductive potential or plan for future pregnancies.

Skin Microbiota and Pathological Scars: A Bidirectional Two-Sample Mendelian Randomization Study.

Pathological scars (PSs), resulting from abnormal skin repair, chronic inflammation, and fibrosis, affect millions of people. Previous studies have demonstrated that skin microbiota (SM) plays a role in cutaneous inflammation and healing, but the interplay between PSs and SM remains unclear yet. To investigate the causal associations between SM and two specific PSs: hypertrophic scars (HSs) and keloids. A bidirectional two-sample mendelian randomization (MR) analysis using genetic data for SM, HS, and keloids was conducted. The random-effects inverse variance weighted (IVW) method was used as the primary approach, along with multiple MR methods. False discovery rate (FDR) correction was employed to address multiple testing. In forward analysis, the family Moraxellaceae and order Pseudomonadales exhibited the same significant protective effects on keloids (odds ratio [OR]: 0.849, 95% confidence interval [CI]: 0.770-0.935, q2 = 0.03626). The class Betaproteobacteria (OR: 0.938, 95% CI: 0.894-0.985, q1 = 0.01965) and genus Bacteroides (OR: 0.928, 95% CI: 0.884-0.973, q1 = 0.00889) each demonstrated a suggestive protective effect on HSs and keloids, respectively. Some limited evidence suggested that order Actinomycetales contributes to an increased risk of keloids. In reverse analysis, keloids were found to have negative effects on the class Gammaproteobacteria with limited evidence. There was no detectable evidence of horizontal pleiotropy or heterogeneity. This study provided evidence for the causalities between SM and PSs, which laid foundation for furthering clinical practice and research of microorganism-skin interaction.

Causal association between depression and constipation: A bidirectional two-sample Mendelian randomization study.

There is currently insufficient research on the causal relationship between depression and constipation. This study aims to provide clear evidence for the positive and negative causal relationship between depression and constipation through bidirectional two-sample Mendelian randomization (MR) analysis. MR is a statistical method used to evaluate the credible causal relationship between exposure and outcomes. In this study, we extracted corresponding genetic data from independent cohorts of patients with depression and constipation. Depression data was obtained from the Finngen database, while constipation data was obtained from the IEU OPEN genome-wide association study database. MR analysis was conducted using 5 methods: inverse variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode. In addition, we also used Cochran Q test, MR-Egger intercept test, and leave-one-out analysis to test for the existence of horizontal pleiotropy and evaluate the robustness of MR analysis results. In the analysis of the impact of depression on constipation, we identified 15 significant and statistically strong single nucleotide polymorphisms, and the IVW random effects analysis showed a causal relationship (OR = 1.005 [1.003, 1.007], P = 1.26 × 10-5). When analyzing the impact of constipation on depression, 10 significant and statistically strong single nucleotide polymorphisms were identified, but IVW analysis did not find a causal relationship (OR = 73.768 [0.004, 1.306 × 10-6], P = .389). There is no heterogeneity in the impact of depression on constipation in the bidirectional analysis results, and there is heterogeneity in the impact of constipation on depression, but there is no horizontal pleiotropy. Our bidirectional two-sample MR analysis identified a causal relationship between depression and constipation. This discovery may help clinical doctors to intervene in depression patients in a timely and effective manner when treating constipation patients, avoiding further deterioration of the condition.

The associations between oxidative stress and epilepsy: a bidirectional two-sample Mendelian randomization study

BackgroundStudies on the association between oxidative stress and epilepsy have yielded varied results. In this study, we aimed to investigate the causal relationship between oxidative stress markers and epilepsy.MethodsA bidirectional two-sample Mendelian randomization (MR) study was performed based on publicly available statistics from genome-wide association studies. To explore the causal effects, single nucleotide polymorphisms were selected as instrumental variables. Inverse-variance weighted method was performed for primary analysis, supplemented by weighted median, MR-Egger, simple mode, and weighted mode. Furthermore, sensitivity analyses were performed to detect heterogeneity and pleiotropy.ResultsOur results showed that part of the oxidative stress biomarkers are associated with epilepsy and its subtypes. Zinc is associated with increased risk of epilepsy and generalized epilepsy (odds ratio [OR] = 1.064 and 1.125, respectively). Glutathione transferase is associated with increased risk of generalized epilepsy (OR = 1.055), while albumin is associated with decreased risk of generalized epilepsy (OR = 0.723). Inverse MR analysis revealed that epilepsy is associated with increased levels of uric acid and total bilirubin (beta = 1.266 and 0.081, respectively), as well as decreased zinc level (beta = − 0.278). Furthermore, generalized epilepsy is associated with decreased ascorbate and retinol levels (beta = − 0.029 and − 0.038, respectively).ConclusionsOur study presented novel evidence of potential causal relationships between oxidative stress and epilepsy, suggesting potential therapeutic targets for epilepsy.

Unpicking Causal Relationships Between Grip Strength and Cardiorespiratory Fitness: A Bidirectional Mendelian Randomization Study.

Understanding the dominant direction of association between cardiorespiratory fitness (CRF) and grip strength could help refine physical activity recommendations. We performed a Mendelian Randomization (MR) analysis to elucidate the bidirectional relationship between CRF and grip strength (GS). Using an inverse-variance weighted (IVW) MR framework, we estimated the strength of the GS (exposure)-CRF (outcome) association using genome-wide association summary data. When examining the CRF (exposure)-GS (outcome) association, the CRF genetic instrument was related to individual-level GS phenotypic data in 367 693 UK Biobank participants. Several sensitivity analyses were performed (e.g., MR-Egger, MR-weighted median estimator and MR-PRESSO) and both measures were scaled by body weight (w). In the direction GS-to-CRF, a 1-unit increase in GSw (i.e., GS/weight) was associated with 1.70 mL/kg/min (95% confidence interval (CI): 1.14,2.27) higher CRFw (IVW model). This finding persisted across most sensitivity analyses. In the reverse direction, there was no evidence supporting an effect of CRFw on GSw, e.g., a 1-unit increase in CRFw led to a 0.00 kg/kg (95% CI: -0.01,0.02) higher GSw (IVW model). Our finding of a dominant direction of association from greater GS to higher CRF is relevant when considering how to promote physical activity guidelines. For example, placing too much emphasis on improving/maintaining CRF is unlikely to result in maximum benefits for other fundamental components of physical fitness, particularly muscle strength.

Investigating the Gene Relation Between Cervical Spondylosis and Depression: Bidirectional Mendelian Randomization Study

Investigating the Gene Relation Between Cervical Spondylosis and Depression: Bidirectional Mendelian Randomization Study

IL-20RA is Associated with the Risk of Diabetic Microangiopathy: A Bidirectional Mendelian Randomization Analysis and Clinical Validation

IL-20RA is Associated with the Risk of Diabetic Microangiopathy: A Bidirectional Mendelian Randomization Analysis and Clinical Validation

Human Papillomavirus Infection and Autoimmune Diseases: A Two-Sample Bidirectional Mendelian Randomization Study.

Although earlier observational studies have revealed a connection between human papillomavirus (HPV) infection and several autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), the exact causative mechanism underlying this association is still unknown. This two-sample bidirectional MR study was conducted based on publicly released data from genome-wide association studies (GWAS). Our results were mainly derived from the inverse variance weighted (IVW) model, with the remaining three models also being calculated. The MR Steiger test was used to examine the correctness of our causal direction. Sensitivity analysis was performed using Mendelian randomized pleiotropy residual sum and outlier (MR-PRESSO), MR-Egger regression. The IVW results showed that there was a positive causal association between HPV16 E7 protein and SLE (odds ratio (OR) = 1.075, 95% confidence interval (CI), 1.003-1.151, FDR-p = 0.04), however, there was a negative causal association between HPV18 E7 protein and SLE (OR = 0.884, 95% CI, 0.804-0.972, FDR-p = 0.02). No causal associations of HPV16 E7 protein and HPV18 E7 protein with RA, IBD was observed including its subtypes Ulcerative colitis (UC) and Crohn's disease (CD). Sensitivity analysis showed that there was no significant heterogeneity (p > 0.05) or genetic pleiotropy (p > 0.05). Our two-sample bidirectional Mendelian randomization study identifies a causal association between HPV infection and SLE, but no causal association between HPV infection and RA and IBD.

The mitochondrial DNA copy number and ovary-related reproductive disorders: A bidirectional two-sample Mendelian randomization study.

In the present study, a bidirectional two-sample Mendelian randomization approach was utilized to explore potential causal relationships between mitochondrial DNA copy number (mtDNA-CN) and ovary-related reproductive disorders (ORRDs), including ovarian dysfunction, ovarian cyst, polycystic ovary syndrome (PCOS), premature ovarian failure (POF) and ovarian endometriosis. Genetic associations with mtDNA-CN were obtained from three genome-wide association study (GWAS) summary statistics from the UK Biobank, and ORRD data were investigated using summary statistics from the FinnGen cohort. Single nucleotide polymorphisms (SNPs) correlated with mtDNA-CN were selected as genetic instrumental variables (IVs) to estimate the causal effect of mtDNA-CN on ORRDs using the inverse-variance weighted (IVW) method with heterogeneity and pleiotropy analysis, and we repeated this in the opposite direction using instruments for ORRDs. We found that the genetically predicted mtDNA was indicative of increased levels of PCOS (OR = 1.16; P < 0.001) and ovarian endometriosis (OR = 1.25; P = 0.007) in the IVW analysis and was not associated with the risk of other ORRDs. In the reverse direction, genetically predicted ORRDs were not associated with mtDNA-CN levels in the IVW analysis. Sensitivity and replication analyses showed the results to be stable. We found that mtDNA-CN may increase the risk of PCOS and ovarian endometriosis. This may have implications for mtDNA-CN as a biomarker for these conditions in clinical practice.

Causal association of serum vitamin D levels with urolithiasis: a bidirectional two-sample Mendelian randomization study.

In light of inconsistent evidence from previous observational studies regarding the correlation between serum vitamin D levels and urolithiasis, this study aimed to investigate the genome-wide causal association between genetically predicted serum 25(OH)D levels and urolithiasis using the Mendelian randomization (MR) approach. In this study, we utilized genome-wide association studies (GWAS) summary statistics from the UK Biobank and SUNLIGHT consortium for serum vitamin D levels, as well as urolithiasis data from FinnGen. We employed bidirectional two-sample MR analysis to evaluate potential causal relationships. The primary MR analysis relied on the inverse variance weighted (IVW) method, supplemented by MR-Egger, weighted median, and weighted mode approaches. Sensitivity analyses were conducted to ensure result robustness, including Cochran's Q test, MR-Egger intercept test, leave-one-out tests, and MR pleiotropy residual sum and outlier (MR-PRESSO) test. The MR analysis indicated no significant causal effects of serum 25(OH)D levels on urolithiasis [IVW method: (kidney and ureteral stones: OR = 1.134;95% CI, 0.953 to 1.350, p = 0.155; lower urinary tract stones: OR = 1.158; 95% CI, 0.806 to 1.666, p = 0.428)]. However, according to the IVW results, genetically predicted kidney and ureteral stones were associated with decreased serum 25(OH)D levels (beta = -0.025; 95% CI, -0.048 to -0.003; p = 0.028), while they did not indicate a causal effect of lower urinary tract stones on serum 25(OH)D levels (beta = -0.002; 95% CI, -0.013 to -0.008; p = 0.662). A sensitivity analysis suggested the robustness of these causal associations. Our MR study did not provide evidence supporting a causal association between serum 25(OH)D levels and urolithiasis among individuals of European descent. However, there might exist a negative causal association between kidney and ureteral stones and serum 25(OH)D levels.

Association between 25(OH) vitamin D and multiple sclerosis: cohort, shared genetics, and Causality

BackgroundMultiple Sclerosis (MS), an autoimmune disorder causing demyelination and neurological damage, has been linked to 25-hydroxyvitamin D (25OHD) levels, suggesting its role in immune response and MS onset. This study used GWAS datasets to investigate genetic associations between 25OHD and MS.MethodsWe utilized a large-scale prospective cohort to evaluate serum 25OHD levels and MS risk. Linkage Disequilibrium Score Regression (LDSC) assessed genetic correlations between 25OHD levels and MS. Cross-trait genome-wide pleiotropy analysis revealed shared genetic loci. MAGMA analysis identified pleiotropic genes, enriched tissues, and gene sets. Stratified LDSC estimated tissue-specific and cell-specific heritability enrichment, and multi-trait co-localization analysis identified shared immune cell subsets. Bidirectional Mendelian Randomization (MR) assessed the causal association between 25OHD and MS risk.ResultsThe observational study found a nonlinear relationship between 25OHD levels and MS risk, with the lowest quartile showing significant risk elevation. Our findings revealed shared genetic structure between 25OHD levels and MS, suggesting a common biological pathway involving immune function and CNS integrity. We found 24 independent loci shared between 25OHD levels and MS risk, enriched in brain tissues and involved in pathways like LDL, HDL, and TG metabolism. Four loci (6p24.3, 6p22.2, 12q14.1, and 19p13.2) had strong co-localization evidence, with mapped genes as potential drug targets. Bidirectional MR analysis supported a causal effect of 25OHD levels on MS risk, suggesting 25OHD supplementation could modulate MS risk.ConclusionThis study reveals the complex relationship between 25OHD levels and MS, indicating that higher levels are not always advantageous and recommending moderation in supplementation. We identified SMARCA4 as a potential therapeutic target and detailed key pathways influencing this interaction.Graphical

Causal relationship between serum uric acid levels and male infertility: a bidirectional two-sample Mendelian randomization study.

Uric acid is the final metabolic product of purines in the human body and has been implicated in the pathogenesis of various diseases. Nevertheless, the relationship between serum uric acid levels and male infertility remains inconclusive. This Mendelian randomization (MR) study aims to elucidate the potential impact of serum uric acid levels on the risk of male infertility. We conducted the bidirectional MR analysis utilizing summary data from genome-wide association studies (GWAS) on serum uric acid levels and male infertility. The inverse variance weighted (IVW) method was employed to evaluate the primary outcomes, and multivariate MR analyses were conducted to combine estimates of the causal effects of multiple risk factors. Additionally, sensitivity analyses were performed to confirm the robustness of the results. In the univariable MR analysis, serum uric acid levels did not exhibit a significant association with the risk of male infertility [IVW odds ratio (OR) 0.92, 95% confidence interval (CI): 0.614-1.390, P=0.70]. Similar conclusions were drawn from the reverse MR analysis (IVW OR 1.000, 95% CI: 0.997-1.003, P=0.96). In the multivariable MR (MVMR) analysis, after adjusting for confounding factors such as body mass index (BMI), type 2 diabetes, alcohol consumption, and smoking, serum uric acid levels remained unassociated with male infertility (IVW OR 0.839, 95% CI: 0.613-1.148, P=0.27). Consistent results were observed in the reverse analysis (IVW OR 1.003, 95% CI: 0.994-1.012, P=0.49). Our study provides genetic evidence indicating no significant causal relationship between serum uric acid levels and male infertility in the general population, suggesting that serum uric acid is not a potential risk factor for male infertility.

Genetic Evidence of Causal Effect between C1q/TNF-Related Protein-1 and Atherosclerosis: a Bidirectional and Multivariate Mendelian Randomization Study.

To investigate the causal relationship between C1q/TNF-related protein-1 (CTRP1) and atherosclerosis across various vascular sites, informed by studies connecting CTRP1 to coronary artery disease. Summary statistics of CTRP1 from the available genome-wide association studies and atherosclerosis in classic vascular sites (including cerebral, coronary, and other arteries) from the FinnGen biobank were extracted for a primary MR analysis, and the analysis was replicated using Ischemic Stroke cohort (large artery atherosclerosis) for validation. The inverse variance-weighted method was used for primary assessment. Sensitivity analysis was performed by Cochrane's Q test and leave-one-out analysis. Potential pleiotropic effects were assessed by MR-Egger intercept and MR-PRESSO global test. Additionally, multivariable MR (MVMR) analysis was performed to investigate the independent effect of CTRP1 on atherosclerosis after removing confounding factors. Reliable causal evidence was found for CTRP1 involvement in three atherosclerosis endpoints: causal effects of CTRP1 on cerebral atherosclerosis (OR=1.31, CI:1.04-1.66; FDR_P=0.0222)], coronary atherosclerosis (OR=1.13, CI: 1.08-1.19; FDR_P=2.86e-07), and atherosclerosis at other sites (OR=1.06, CI:1.02-1.11; FDR_P=0.0125). The validation cohort further confirmed its causal effect on large-artery atherosclerosis (OR=1.10, CI:1.03-1.18; FDR_P=0.0115). The reverse MR analysis did not support the causal effect of atherosclerosis on CTRP1. Moreover, the MVMR analysis, adjusting for confounders (CTRP3, CTRP5, and CTRP9A), highlighted a significant independent causal effect of CTRP1 remaining on atherosclerosis. CTRP1 may represent a promising target for preventing and treating systemic atherosclerosis.

The role of 1400 plasma metabolites in gastric cancer: A bidirectional Mendelian randomization study and metabolic pathway analysis.

While observational studies have illustrated correlations between plasma metabolites and gastric cancer (GC), the causal association between the 2 is still unclear. Our study aims to delineate the bidirectional relationship between plasma metabolites and GC and find potential metabolic pathways. We undertook a bidirectional 2-sample Mendelian randomization (MR) analysis to investigate the causal relationship, specificity, and direction of association between 1400 plasma metabolites and GC. The GWAS data for metabolites was obtained from a cohort of 8299 European individuals. And the GC's GWAS data was from FinnGen Consortium with 2384 European individuals, and the GWAS catalog with 1029 European ancestry cases for validation. Causal estimates were primarily calculated by the inverse-variance weighted (IVW) method. To ensure robustness, we performed comprehensive sensitivity analyses to assess heterogeneity and address concerns regarding horizontal pleiotropy. We validated the forward relationship between metabolites and GC from another database and implemented meta-analysis. Furthermore, we conducted metabolic enrichment and pathway analysis of these causal metabolites using MetaboAnalyst5.0/6.0 with the database of Kyoto Encyclopedia of Genes and Genomes. All statistical analysis was carried out using R software. Metabolites like 2s, 3R-dihydroxybutyrate, 4-acetamidobutanoate, ferulic acid 4-sulfate and methyl indole-3-acetate was proven positively linked with the development of GC. Asparagine, glucose to maltose ratio, glycohyocholate, Gulonate levels, linoleoyl ethanolamide and Spermidine to (N(1) + N(8))-acetylspermidine ratio was proven to be negatively associated with GC. Moreover, linoleic acid, histidine, glutamine, bilirubin, Succinate to proline ratio were found to be potentially linked to the development of GC. Furthermore, our analysis identified 18 significant metabolic pathways, including Arginine and proline metabolism (P < .009) and Valine, leucine, and isoleucine biosynthesis (P < .031). Our findings offer evidence supporting potential casual relations between multiple plasma metabolites and GC. These findings may offer great potential for future application of these biomarkers in GC screening and clinical prevention strategies.

Gut microbiota and epigenetic age acceleration: a bi-directional Mendelian randomization study

BackgroundThe gut microbiota is closely related to aging, but the genetic relationship between gut microbiota and aging has not been well investigated. The aim of the study was to explore the association of microbiota with epigenetic age acceleration (EAA) using the Mendelian randomization.MethodThe independent genetic instruments of gut microbiota were obtained from MiBioGen consortium and the Dutch Microbiome Project. EAA data were derived from genome-wide association study. To assess the causal relationship between gut microbiota and EAA, we applied four different methods of Mendelian Randomization (MR) analysis: the inverse variance weighted method (IVW), the MR-Egger regression, the weighted median analysis (WMA), and the weighted mode. Furthermore, sensitivity analyses were conducted to evaluate heterogeneity and horizontal pleiotropy.ResultsWe identified potential causal associations between 12 bacterial taxa and EAA (PIVW and PWMA < 0.05). Among them, species Holdemania_unclassified (OR: 1.31, 95% CI: 1.13–1.52, P = 0.0004) retained a strong positive association with GrimAge acceleration. Family Acidaminococcaceae (OR: 0.64, 95% CI: 0.44–0.93, P = 0.019) and family Clostridiaceae1 (OR: 0.69, 95% CI: 0.49–0.97 P = 0.031) were negative association with GrimAge acceleration. Reverse MR analyses indicated that EAA was associated with 6 bacterial taxa in IVW and WMA. Among them, a strong inverse association was found between Phenoage acceleration and genus Turicibacter (OR: 0.928, 95%CI: 0.888–0.971, PIVW and PWMA < 0.001).ConclusionOur study implicates the potential causal effects of specific microbiota on EAA, potentially providing novel insights into the prevention aging through specific gut microbiota.

Causal association between epigenetic age acceleration and two pulmonary vascular diseases: pulmonary arterial hypertension and pulmonary embolism—a bidirectional Mendelian study

BackgroundPulmonary arterial hypertension (PAH) is a relatively rare but severe disease with a poor prognosis. Pulmonary embolism (PE) is a serious condition that can cause sudden death. Epigenetic age acceleration (EAA) is a robust indicator derived from the DNA methylation-based epigenetic clock, which can predict the extent of aging. It has been proved that the epigenetic clock and EAA are associated with many cardiovascular diseases, while their associations with PAH and PE remain inconclusive. Our study aims to investigate the associations among these factors.MethodBy harnessing summary-level data from large-scale genome-wide association studies (GWAS), we designed a two-sample bidirectional Mendelian randomization (MR) analysis to assess the causal associations between measures of three epigenetic clocks, including GrimAge acceleration (n = 34,467), Hannum Age acceleration (n = 34,449) and PhenoAge acceleration (n = 34,463) and PAH (including 125 cases and 162,837 controls), as well as PE (including 3940 cases and 480,658 controls). The inverse variance-weighted (IVW) method was used as the primary method for MR analysis. Other methods, such as MR egger and weighted mode, served as complements to the IVW approach, were also applied in the analyses. Then, the MR pleiotropy test and MR-PRESSO test, which are effective tools for quality control of MR analysis, were subsequently used to ensure the accuracy of the study.ResultsThe forward MR analysis indicated that all three epigenetic clocks had no significant effects on PAH or PE. The reverse analysis indicated that the onset and progression of PAH and PE had insignificant effects on three epigenetic clocks. The results of the quality control assessment confirmed that our findings were reliable.ConclusionOur two-sample bidirectional MR analysis suggested that there is no significant association between epigenetic clocks and these two pulmonary vascular diseases.