Mendelian randomization-Egger Research Articles

Investigating the correlation between gut microbiota and prostate cancer through a two-sample Mendelian randomization analysis

Previous studies in observational epidemiology have suggested a potential correlation between the gastrointestinal tract microbiota and prostate cancer. However, the causal relationship between the 2 remains uncertain, our objective was to thoroughly examine the influence of the gut microbiome on the progression of prostate cancer. In this study, we focused on investigating the gut microbiome as an exposure factor, specifically analyzing data from the MiBioGen consortium, which had a substantial sample size of 18,340 participants. As our disease outcome, we utilized prostate cancer data from the FinnGen genome-wide association study, which involved 13,216 participants. To establish causal relationships, we conducted a comprehensive Mendelian randomization analysis employing multiple methods, including inverse variance-weighted, Mendelian randomization-Egger, maximum likelihood, and weighted median approaches. Additionally, we performed sensitivity analysis to address issues such as heterogeneity and horizontal pleiotropy, ensuring the robustness of our findings. The results obtained through inverse variance-weighted analysis revealed that certain microbial groups exhibited a protective effect on prostate cancer. Specifically, the phylum Verrucomicrobia, particularly the family Rikenellaceae, and the genera Anaerotruncus, Eisenbergiella, Olsenella, and Parabacteroides were found to have a beneficial impact. Conversely, the class Bacilli, class Erysipelotrichia, order Erysipelotrichales, order Lactobacillales, family Erysipelotrichaceae, and the genera Marvinbryantia, Romboutsia, Ruminococcaceae UCG002, and Sutterella had an adverse influence on prostate cancer. The sensitivity analysis did not reveal any such outliers, further strengthening the validity of our results. To summarize, a cause-and-effect connection was discovered between various types and prostate cancer. Nevertheless, additional randomized controlled experiments are required for validation.

The causal relationship between circulating inflammatory proteins and heart failure: A two-sample Mendelian randomization study

This study aims to explore the causal associations of 91 circulating inflammatory proteins with ischemic cardiomyopathy heart failure (ICM), dilated cardiomyopathy heart failure (DCM), and hypertrophic cardiomyopathy heart failure (HCM) to provide new ideas for the study of relevant heart failure mechanisms, adjunctive diagnosis and differentiation, and the clinical application of relevant drug targets. An analysis of the causal relationship between circulating inflammatory proteins and heart failure was conducted via inverse-variance weighted, weighted median estimator (WME), weighted mode (WM), and Mendelian randomization-Egger regression with Mendelian randomization. A Mendelian randomization analysis of 91 circulating inflammatory proteins revealed that natural killer cell receptor 2B4 levels, CXCL-6, fibroblast growth factor 5 levels, and interleukin-10 levels had positive causal relationships with ICM, whereas CX3CL-1, C-X-C motif chemokine 9 levels, interleukin-10 levels, leukemia inhibitory factor receptor levels, and signaling lymphocytic activation molecule levels had negative causal relationships; C-C motif chemokine 20 levels, C-X-C motif chemokine 5 levels, C-X-C motif chemokine 9 levels, fibroblast growth factor 5 levels, and oncostatin-M levels were positively correlated with DCM, whereas eukaryotic translation initiation factor 4E-binding protein 1 levels and Fms-related tyrosine kinase 3 ligand levels were negatively associated with DCM; and the CD40L receptor, Fms-related tyrosine kinase 3 ligand levels, hepatocyte growth factor levels, and sulfotransferase 1A1 levels were negatively associated with HCM. In this study, 9 of the 91 circulating inflammatory proteins were causally related to the ICM (4 positive, 5 negative), 7 were causally related to the DCM (5 positive, 2 negative), and 4 were causally related to the HCM (all negative). This study provides a theoretical foundation for the study of the relevant mechanisms of heart failure, clinical diagnosis, and treatment, as well as potential drug candidates closely related to heart failure.

Unlike common pneumonia, COVID-19 is a risk factor for multiple cardiovascular diseases: A two-sample Mendelian randomization study

This study investigates the differences between COVID-19 and past common forms of pneumonia and to determine if COVID-19 acts as a contributing factor in various cardiovascular diseases (CVDs). We retrieved large-sample genome-wide association study data from the Open GWAS database related to COVID-19, bacterial pneumonia (BP), viral pneumonia (VP), stable angina (SA), unstable angina (UA), heart failure (HF), ischemic heart disease (IHD), atrial fibrillation (AF), and myocardial infarction (MI). We selected single-nucleotide polymorphisms with strong correlations as instrumental variables (P < 5E-06), and set the threshold for the F-statistic to be over 10. Five statistical methods were used for analysis including inverse variance weighted, Mendelian randomization-Egger, weighted median, simple mode, and weighted mode, with inverse variance weighted as the primary method. We assessed the reliability of our results through heterogeneity, pleiotropy, and sensitivity testing; Our analysis probed the relationship between COVID-19, BP, VP, and 6 CVDs. COVID-19 infection was found to enhance the incidence of SA, UA, HF, and MI (SA: odds ratio [OR], 1.12; 95% confidence interval [CI], 1.04–1.20; P = .002; UA: OR, 1.14; 95% CI, 1.01–1.29; P = .041; HF: OR, 1.12; 95% CI, 1.03–1.23; P = .012; MI: OR, 1.11; 95% CI, 1.02–1.25; P = .032). There was no significant effect on the incidence of AF or IHD (P > .05), and no pleiotropy or sensitivity issues were found in the results. In contrast, neither past common BP nor VP was found to contribute to the progression of these 6 CVDs (P > .05). Unlike past common BP or VP, COVID-19 was found to increase the risks of SA, UA, HF, and MI, with no evidence supporting an increased risk for AF or IHD following COVID-19 infection.

The association between type 1 diabetes mellitus and the risk of immunoglobulin A nephropathy: a Mendelian randomization study.

To investigate the potential causal relationship between type 1 diabetes mellitus (T1DM) and IgA nephropathy (IgAN) to deepen understanding of the association between these two conditions and to provide a scientific basis for future preventive and therapeutic strategies. This study employed Mendelian randomization (MR) analysis, using single nucleotide polymorphisms (SNPs) derived from genome-wide association studies (GWAS) as genetic instrumental variables (IVs), to assess the association between T1DM and IgAN. The analytical approaches included univariable and multivariable MR, along with sensitivity analyses such as Mendelian randomization-Egger (MR-Egger) and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO), to evaluate the impact of heterogeneity and pleiotropy. Univariable MR analysis using the IVW method revealed an odds ratio (OR) of 1.009 [95% confidence interval (CI): 1.032-1.206] for the association between T1DM and IgAN. Adjusted results from multivariable MR analysis indicated a significant relationship between T1DM and increased risk of IgAN; for example, after adjusting for triglycerides (TG), the OR was 1.534 (CI: 1.213-1.543). After adjustment for HOMA-IR, the OR was 1.303 (CI: 1.149-1.198). Sensitivity analyses, including MR-Egger regression intercept testing (p = 0.476), suggested no pleiotropy, and MR-PRESSO did not detect any influence from outlier SNPs. The findings suggest that T1DM is a factor in increasing the risk of IgAN, enhancing our understanding of the potential relationship between T1DM and IgAN and providing possible biological pathways for future disease prevention and intervention.

Genetic association between autoimmune thyroiditis and microscopic polyangiitis: A two-sample Mendelian randomization study.

Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is a group of life-threatening autoimmune small vessel vasculitis and the prognosis depends heavily on whether a prompt diagnosis is achieved. Autoimmune thyroiditis is the most common autoimmune endocrine disease and could overlap with other autoimmune diseases. It remains elusive whether autoimmune thyroiditis affects the risk of AAV development. We performed a 2-sample Mendelian randomization analysis to explore the true association between autoimmune thyroiditis and microscopic polyangiitis (MPA), a subtype of AAV. Independent single-nucleotide polymorphisms associated with Hashimoto thyroiditis or Grave disease with genome-wide significance were selected as instrumental variables from large genome-wide association study. MPA genome-wide association study summary statistics were obtained from FinnGen consortium. The inverse-variance weighted method was conducted as the primary analysis for estimating the effect of the exposure on the outcome. Mendelian randomization-Egger and the weighted median method were used to confirm the results. We found a causal association between Hashimoto thyroiditis and MPA while no causal effect of Grave disease on MPA. This study contributed a genetic viewpoint to the understanding of the link between autoimmune thyroiditis and AAV.

The relationship between cereal intake and 3 common inflammatory joint diseases: A 2-sample Mendelian randomization study.

The association between cereal intake and inflammatory joint disease remains controversial. This study aims to use Mendelian randomization to comprehensively evaluate the causal relationship between cereal grain intake and Inflammatory joint diseases, including rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. This investigation used publicly available data from genome-wide association studies to aggregate statistics on the association between cereal intake and inflammatory joint disease. Several methods were employed to estimate 2-sample causality. The results of the random-effects inverse variance-weighted method analysis indicated that higher cereal intake reduced the risk of developing rheumatoid arthritis (odds ratio [OR] = 0.554; 95% confidence interval [CI]: 0.324-0. 948; P = .031) and psoriatic arthritis (OR = 0.336; 95% CI: 0.123-0.918; P = .033), and the results of the Mendelian randomization-Egger regression analysis showed no horizontal pleiotropy (P > .05) for the included single nucleotide polymorphisms. Using the leave-one-out method, no single nucleotide polymorphism was found to affect the overall effect estimate significantly, and there was no heterogeneity. Cereal intake had no causal effect on the risk of developing ankylosing spondylitis (OR = 0.636; 95% CI: 0.236-1.711; P = .370). There is genetic evidence that cereal consumption reduces the risk of developing Inflammatory joint diseases such as rheumatoid arthritis and psoriatic arthritis.

Genetic Association of Chronic Pains and Analgesics With Telomere Length: A Mendelian Randomization Study

Objective: The aim of this study was to explore the causal relationships between chronic pains (back pain, facial pain, general pain, headaches, knee pain, hip pain, neck/shoulder pain, stomach/abdominal pain) and analgesics (codeine, diclofenac, ibuprofen, morphine, paracetamol, tramadol) with telomere length using Mendelian randomization methods. Methods: In the study, various statistical methods including inverse variance weighted (IVW), Mendelian Randomization-Egger, weighted median, simple mode, and weighted mode were used to investigate the relationships between chronic pains, analgesics, and telomere length. Heterogeneity and pleiotropy tests were conducted to ensure the accuracy of the results. Results: The results of the IVW analysis revealed positive causal relationships between hip pain (odds ratio (OR): 1.145; 95% confidence interval (CI): 1.021–1.285; p = .020), and stomach/abdominal pain (OR: 1.100; 95% CI: 1.008–1.200; p = 0.033) with telomere length. Use of tramadol (OR: 0.074; 95% CI: 0.009–0.605; p = 0.015) had a negative causal relationships with telomere length. Conclusion: This study found positive associations between hip pain and stomach/abdominal pain with telomere length, and a negative association between tramadol and telomere length. However, no significant causal relationships were found with other types of chronic pains and analgesics. This could help develop healthier chronic pain treatments, avoiding the abuse of analgesics.

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.

Causal associations between telomere length and pulmonary arterial hypertension: A two-sample Mendelian randomization study.

Pulmonary arterial hypertension (PAH) is a life-threatening condition characterized by elevated pulmonary artery pressure, leading to right heart failure, and mortality. The role of telomere length, a marker of biological aging, in PAH remains unclear. We utilized summary-level data from genome-wide association studies for various measures of telomere length and PAH. Single nucleotide polymorphisms associated with telomere length at a genome-wide significance level were used as instrumental variables. The inverse variance weighted method was the primary analysis, with sensitivity analyses including the weighted median and Mendelian randomization-Egger regression. The odds ratios and 95% confidence intervals (CI) were calculated to estimate the causal effect of telomere length on PAH risk. The Mendelian randomization analyses revealed no significant causal association between overall telomere length and PAH (odds ratios per standard deviation increase = 1.229, 95% CI: 0.469-3.222, P = .676). Similar null findings were observed for granulocyte, lymphocyte, naive T-cell, memory T-cell, B-cell, and natural killer-cell telomere lengths. Sensitivity analyses confirmed the robustness of the results, with no evidence of horizontal pleiotropy or significant influence of individual single nucleotide polymorphisms on the overall estimates. This Mendelian randomization study didn't support a causal association between telomere length and PAH.

Causal effect of C-reaction protein and endometrial cancer: Genetic evidence of the role of inflammation in endometrial cancer.

Consensus remains elusive regarding the relationship between C-reactive protein (CRP) levels and endometrial cancer (EC). Our study sought to elucidate the causal association between CRP and EC, aiming to contribute to the understanding of this complex interplay. We primarily utilized the random-effects inverse variance-weighted method. This approach served as the foundation for our analysis, complemented by 3 additional techniques, including Mendelian randomization-Egger, weighted-median, and weighted mode. A series of sensitivity analyses were also conducted to affirm the stability and reliability of our results. Employing the inverse variance-weighted method, our findings indicated that a one-unit increment in log-transformed CRP concentrations (mg/L) was associated with a relatively 9.7% increased risk of overall EC (odds ratio [OR] = 1.097, 95% confidence interval [CI]: 0.996-1.208, P = .061), an 11% higher risk of endometrioid endometrial cancer (OR = 1.110, 95% CI: 1.000-1.231, P = .049) and a 25% increased risk of non-endometrioid cancers (OR = 1.250, 95% CI: 1.005-1.555, P = .045). Sensitivity analyses did not reveal evidence of horizontal pleiotropy in the analysis of CRP and overall EC, endometrioid endometrial cancer, or non-endometrioid cancers (P > .05). In the reverse analysis, our data demonstrated that EC exert no reverse effect on CRP levels. Our study suggested causal relationships between CRP and an elevated risk of EC and its subtypes, which contribute to the ongoing discourse on the role of inflammation, as indicated by CRP levels, in the etiology of EC and its variants.

Neutrophil count and reduced risk of venous thromboembolism: a Mendelian randomization study

ABSTRACT Background Venous thromboembolism (VTE) has a close relationship with the immune system, particularly neutrophils. This study aimed to investigate the association between blood cell traits and VTE using Mendelian randomization (MR). Method In this study, we discovered specific genetic variants associated with blood cell traits through genome-wide association studies (GWAS) conducted on 173,480 individuals of European ancestry. Additionally, we gathered summary level data on VTE from FinnGen consortium involving 377,277 individuals. To explore the connections between blood cell traits and VTE, we employed various methods, including inverse variance weighted (IVW), Mendelian Randomization-Egger (MR-Egger), weighted median, and weighted mode for comprehensive analysis, as well as Multivariable MR (MVMR) to adjust for potential confounders. Results The results of this study indicated that an elevated neutrophil count was a protective factor against VTE (odds ratio [OR] = 0.80, 95% confidence interval [CI] = 0.70–0.91, p = 1.19 × 10−3). The results were confirmed to be reliable through sensitivity analysis, which demonstrated the absence of horizontal pleiotropy, and random effects model of IVW eliminates the impact of heterogeneity. MVMR confirmed a stable causal link between neutrophil count and VTE (OR = 0.83, CI = 0.76–0.91, p = 9.97 × 10−5) after adjusting for type 2 diabetes and obesity. Conclusion According to our MR study, we found evidence suggesting that higher neutrophil count linked to a lower risk of VTE. These findings may provide potential therapeutic targets for the prevention and treatment of VTE.

Causal relationship between lymphocyte subsets and the risk of sepsis: A Mendelian randomization study.

Recent empirical research posits a link between lymphocyte subgroups and both the incidence and prognosis of sepsis. Nevertheless, the potential influence of multiple confounding variables obscures any clear causative correlation. Utilizing a 2-sample Mendelian randomization approach, we conducted a meta-analysis of lymphocyte subgroups. In a genome-wide association study, flow cytometry was applied to a lymphocyte subgroup comprising 3757 Sardinians to identify genes influenced by blood immune cells. The sepsis meta-analysis data were sourced from the UK Biobank database, including 11,643 treatment groups and 47,841 control groups. Inverse variance-weighted, Mendelian randomization-Egger regression, weighted median, simple mode, and weighted mode methods were deployed to ascertain the causative relationship between lymphocyte subgroup and sepsis. Cochran Q test, the Mendelian randomization-Egger intercept test, and funnel plots were leveraged to assess the robustness of study findings. The inverse variance-weighted analysis disclosed that the absolute count of CD4 regulatory T cells (CD4 Treg AC) within the lymphocyte subgroup has a causative link to an elevated risk of sepsis, with an odds ratio of 1.08 and a 95% confidence interval of 1.02 to 1.15 (P = .011). Compared to individuals not subjected to this factor, those exposed to CD4 Treg AC have a marginally elevated sepsis risk by approximately 0.08%. No causative relationships were observed between sepsis risk and the absolute counts of other lymphocyte subgroups such as CD8+ T cells, CD4+ CD8dim T cells, natural killer T cells, B cells (B cell absolute count), and HLA DR+ natural killer cells. The 2-sample Mendelian randomization study indicated a causal relationship between the level of CD4 Treg AC and the increased risk of sepsis. The elevation in circulating lymphocyte subgroups suggests higher susceptibility to sepsis, affirming the immune susceptibility inherent to this condition. The findings from our study may propose potential targets for diagnosis and intervention of sepsis.

Relationship between immune cells and diabetic nephropathy: a Mendelian randomization study.

Although previous studies have suggested potential correlations between immunocytes and diabetic nephropathy (DN), the causal correlations between them remain unclarified. In this study, we employed Mendelian randomization (MR) to analyze the potential causative correlations between immune 731 cells and DN. We used the Genome-Wide Association Studies (GWAS) database to aggregate signatures of immune cells and DN from European and East Asian populations. Single-nucleotide polymorphisms (SNPs) were used as instrumental variables. MR analysis was conducted using Mendelian randomization-Egger (MR-Egger) regression and the random-effects inverse-variance weighted (IVW) method. A total of 3,571 SNPs were included as instrumental variables. The MR-Egger regression model indicated no genetic pleiotropy (P = 0.6284). The results of the IVW method indicated a statistically significant causal relationship between immune cell HLA-DR on CD14-CD16- (P = 0.029), CD45RA-CD28-CD8 + T cell% T cells (P = 0.0278), CD11c on myeloid dendritic cells (P = 0.0352), HLA-DR on CD14+ monocytes (P < 0.001), CD27 on CD24 + CD27 + B cells (P = 0.0334), CD27 on IgD + CD24 + B cells (P = 0.0137), CD4 on CD39 + CD4 + T cells (P = 0.0347), CD28 on CD39 + CD4 + T cells (P = 0.0414), CD39 on CD39 + CD4 + T cells (P = 0.0426), and DN. Additionally, there was no heterogeneity in SNPs related HLA-DR on CD14-CD16-cells and DN(I2 = 32%, Cochran's Q = 2.9476, P = 0.2291). Moreover, leave-one-out analysis showed a causal correlation between HLA-DR on CD14-CD16- cells and DN. Higher expression of immune cell HLA-DR on CD14-CD16- cells may indicate a lower risk of DN.

Causal relationship between allergic rhinitis and otitis media: A Mendelian randomization study.

Otitis media and allergic rhinitis are prevalent conditions. Some data posit a significant association between the 2 ailments, proposing mechanisms such as allergic rhinitis-induced Eustachian tube dysfunction or concurrent allergic pathophysiology affecting both the nasal and aural cavities. Observational studies hint at an association between allergic rhinitis (AR) and nonsuppurative otitis media, yet definitive causality remains elusive. Thus, to elucidate the causal impact of AR on otitis media, a 2-sample Mendelian randomization study was undertaken. Data on AR, acute suppurative otitis media, chronic suppurative otitis media, and nonsuppurative otitis media were sourced from the Genome for Extensive Association Study, encompassing individuals of European ancestry. Single nucleotide polymorphisms linked with AR were utilized as instrumental variables. The inverse-variance weighting (IVW) method, alongside sensitivity analyses employing the weighted median and Mendelian randomization-Egger methods, was employed to assess causal effects. Our analysis revealed a significant causal effect of AR on nonsuppurative otitis media (IVW, odds ratio [OR] = 12.22, 95% confidence interval, 1.38-107.93, P = .024) and indicated an association with acute suppurative otitis media (IVW, OR = 6.95, 95% confidence interval, 0.80-60.35, P = .078). However, no causal effect of AR on chronic suppurative otitis media was discerned. Our findings delineate a measurable causal link between AR and nonsuppurative otitis media (OR = 12.22) and suggest an association with acute suppurative otitis media (OR = 6.95), though lacking evidence for a causal effect on chronic suppurative otitis media. These results underscore the propensity of AR to correlate with diverse forms of otitis media and furnish high-quality causal evidence pertinent to clinical management.

Causal relationship between fertility nutrients supplementation and PCOS risk: a Mendelian randomization study.

Polycystic ovary syndrome (PCOS), a prevalent endocrine disorder in women of reproductive age, is mainly ameliorated through drugs or lifestyle changes, with limited treatment options. To date, numerous researchers have found that fertility nutrient supplements may benefit female reproductive health, but their direct impact on polycystic ovary syndrome risk remains unclear. Our research employs Mendelian Randomization to assess how fertility nutrients affect PCOS risk. Initially, we reviewed 49 nutrients and focused on 10: omega-3 fatty acids, calcium, dehydroepiandrosterone, vitamin D, betaine, D-Inositol, berberine, curcumin, epigallocatechin gallate, and metformin. Using methodologies of Inverse Variance Weighting and Mendelian Randomization-Egger regression, we examined their potential causal relationships with PCOS risk. Our findings indicate omega-3 fatty acids reduced PCOS risk (OR=0.73, 95% CI: 0.57-0.94, P=0.016), whereas betaine increased it (OR=2.60, 95% CI: 1.09-6.17, P=0.031). No definitive causal relations were observed for calcium, dehydroepiandrosterone, vitamin D, D-Inositol, and metformin (P>0.05). Drug target Mendelian Randomization analysis suggested that increased expression of the berberine target gene BIRC5 in various tissues may raise PCOS risk (OR: 3.00-4.88; P: 0.014-0.018), while elevated expressions of curcumin target gene CBR1 in Stomach and epigallocatechin gallate target gene AHR in Adrenal Gland were associated with reduced PCOS risk (OR=0.48, P=0.048; OR=0.02, P=0.018, respectively). Our research reveals that specific fertility nutrients supplementation, such as omega-3 fatty acids, berberine, and curcumin, may reduce the risk of PCOS by improving metabolic and reproductive abnormalities associated with it.

The potential protective effect of 3-Hydroxybutyrate against aortic dissection: a mendelian randomization analysis

Background3-Hydroxybutyrate, also called β-hydroxybutyrate, is a significant constituent of ketone bodies. Previous observational and experimental studies have suggested that ketogenic diet, especially 3-hydroxybutyrate, may have a protective effect against cardiovascular disease. However, the relationship between ketone bodies, especially 3-hydroxybutyrate, and aortic dissection remains uncertain.Materials and methodsPublicly accessible data from genome-wide association study (GWAS) was utilized to obtain information on ketone bodies, including 3-hydroxybutyrate, acetoacetate and acetone as exposure respectively, while GWAS data on aortic dissection was used as outcome. Subsequently, two-sample Mendelian randomization (MR) analysis was conducted to examine the potential relationship between ketone bodies and aortic dissection. Then, reverse and multivariate Mendelian randomization analyses were performed. Additionally, sensitivity tests were conducted to assess the robustness of MR study.ResultsThe inverse-variance weighted (IVW) method of Mendelian randomization analysis of gene prediction observed a negative correlation between 3-hydroxybutyrate and risk of aortic dissection (OR 0.147, 95% CI 0.053–0.410). Furthermore, consistent findings were obtained through the implementation of the weighted median, simple mode, Mendelian randomization-Egger (MR-Egger), and weighted mode methods. After adjusting acetoacetate (OR 0.143, 95% CI 0.023-0.900) or acetone (OR 0.100, 95% CI 0.025–0.398), MR analysis of gene prediction still observed a negative correlation between 3-hydroxybutyrate and risk of aortic dissection. No indications of heterogeneity or pleiotropy among the SNPs were detected.ConclusionThe findings from the MR analysis demonstrated that genetically predicted 3-hydroxybutyrate exhibits a protective effect against aortic dissection.

Mendelian study on air pollution and membranous nephropathy outcomes associations.

Membranous nephropathy (MN) is an autoimmune disease of the kidney glomerulus, which mainly leads to nephrotic syndrome. This study investigates the associations between air pollution and MN risk and from an epigenomic perspective. In this study, we examine the associations between genetically predicted deoxyribonucleic acid methylation related to air pollution and MN risk. The data of air pollution included particulate matter (PM) with a diameter of 2.5 µm or less (PM2.5), PM with a diameter between 2.5 and 10 µm (PM2.5-10), PM with a diameter of 10 µm or less (PM10), nitrogen dioxide, and nitrogen oxides. Inverse variance weighted method was used as the main analysis method, and weighted median model and Mendelian randomization-Egger methods were selected for quality control. To assess the reliability of the results of the analyses, heterogeneity test, horizontal pleiotropy test, and the leave-one-out method were applied. There was a causal relationship between nitrogen oxides and MN risk (P = .010). Other types of air pollution were found no statistical association with MN disease (PM2.5: P = .378; PM2.5-10: P = .111; PM10: P = .035; nitrogen dioxide: P = .094). There was no heterogeneity or pleiotropy in the results. Our study suggests the association between nitrogen oxides and membrane nephropathy (MN) risk from the genetic perspective. This provides a theoretical basis for the prevention of MN disease.

Causal influence of plasma metabolites on age-related macular degeneration: A Mendelian randomization study.

Using genome-wide association study data from European populations, this research clarifies the causal relationship between plasma metabolites and age-related macular degeneration (AMD) and employs Metabo Analyst 5.0 for enrichment analysis to investigate their metabolic pathways. Employing Mendelian randomization analysis, this study leveraged single nucleotide polymorphisms significantly associated with plasma metabolites as instrumental variables. This approach established a causal link between metabolites and AMD. Analytical methods such as inverse-variance weighted, Mendelian randomization-Egger, and weighted median were applied to validate causality. Mendelian Randomization Pleiotropy Residual Sum and Outlier was utilized for outlier detection and correction, and Cochran's Q test was conducted to assess heterogeneity. To delve deeper into the metabolic characteristics of AMD, metabolic enrichment analysis was performed using Metabo Analyst 5.0. These combined methods provided a robust framework for elucidating the metabolic underpinnings of AMD. The 2-sample MR analysis, after meticulous screening, identified causal relationships between 88 metabolites and AMD. Of these, 16 metabolites showed a significant causal association. Following false discovery rate correction, 3 metabolites remained significantly associated, with androstenediol (3 beta, 17 beta) disulfate (2) exhibiting the most potent protective effect against AMD. Further exploration using Metabo Analyst 5.0 highlighted 4 metabolic pathways potentially implicated in AMD pathogenesis. This pioneering MR study has unraveled the causal connections between plasma metabolites and AMD. It identified several metabolites with a causal impact on AMD, with 3 maintaining significance after FDR correction. These insights offer robust causal evidence for future clinical applications and underscore the potential of these metabolites as clinical biomarkers in AMD screening, treatment, and prevention strategies.

Genetic Susceptibility of Thrombin Measurement Levels and the Risk of Colon Adenocarcinoma: A Mendelian Randomization Study.

Aims/Background: This investigation sought to establish a possible correlation between thrombin measurement levels and the risk of developing colon adenocarcinoma (COAD). Methods: Thrombin measurement levels were sourced from a study by Pietzner M (2020, PMID: 33328453) and integrated into the IEU database. Data on COAD were obtained from the FinnGen database (2021, C3_COLON_ADENO). Various analytical methods were used to assess the relationship, including inverse variance weighting (IVW), mendelian randomization-Egger (MR-Egger) regression, as well as weighted median and mode techniques. Sensitivity analyses were performed, including Cochran's Q test, MR-Egger intercept test, mendelian randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO), along with leave-one-out analysis, to ensure the robustness of the results. Results: The IVW analysis indicated a significant inverse association between elevated thrombin levels and the risk of COAD (odds ratio (OR) = 0.76, 95% CI = 0.66-0.88, p = 0.0003). These findings were supported by the weighted median analysis (OR = 0.78, 95% CI = 0.68-0.90, p = 0.0006) and the weighted mode analysis (OR = 0.78, 95% CI = 0.68-0.88, p = 0.0017). Conclusion: This research identified an inverse causal relationship between thrombin measurement levels and the incidence of COAD, suggesting that higher thrombin levels are associated with a reduced risk of developing COAD.

Revealing the link between gut microbiota and brain tumor risk: a new perspective from Mendelian randomization.

Recent studies have shown that gut microbiota may be related to the occurrence of brain tumors, but direct evidence is lacking. This study used the Mendelian randomization study (MR) method to explore the potential causal link between gut microbiota and brain tumors. We analyzed the genome-wide association data between 211 gut microbiota taxa and brain tumors, using the largest existing gut microbiota Genome-Wide Association Studies meta-analysis data (n=13266) and combining it with brain tumor data in the IEU OpenGWAS database. We use inverse-variance weighted analysis, supplemented by methods such as Mendelian randomization-Egger regression, weighted median estimator, simple mode, and weighted mode, to assess causality. In addition, we also conducted the Mendelian randomization-Egger intercept test, Cochran's Q test, and Mendelian randomization Steiger directionality test to ensure the accuracy of the analysis. Quality control includes sensitivity analysis, horizontal gene pleiotropy test, heterogeneity test, and MR Steiger directionality test. Our study found that specific gut microbial taxa, such as order Lactobacillales and family Clostridiaceae1, were positively correlated with the occurrence of brain tumors, while genus Defluviitaleaceae UCG011 and genus Flavonifractor were negatively correlated with the occurrence of brain tumors. The Mendelian randomization-Egger intercept test showed that our analysis was not affected by pleiotropy (P>0.05). This study reveals for the first time the potential causal relationship between gut microbiota and brain tumors, providing a new perspective for the prevention and treatment of early brain tumors. These findings may help develop new clinical intervention strategies and point the way for future research.