Gut microbiota metabolic pathways: Key players in knee osteoarthritis development.

OBJECTIVE: To confirm the causality of gut microbiota pathway abundance and knee osteoarthritis (KOA). METHODS: Microbial metabolic pathways were taken as exposures, with data from the Dutch Microbiome Project (DMP). Data on KOA from the UK Biobank were utilized as endpoints. In addition, we extracted significant and independent single nucleotide polymorphisms as instrumental variables. Two-sample Mendelian randomization (MR) analysis was applied to explore the causal relationship between gut microbiota pathway abundance and KOA, and MR-Egger and weighted median were used as additional validation of the MR results. Meanwhile, Cochran Q, MR-Egger intercept, MR-PRESSO, and leave-one-out were used to perform sensitivity analyses on the MR results. RESULTS: MR results showed that enterobactin biosynthesis, diacylglycerol biosynthesis I, Clostridium acetobutylicum acidogenic fermentation, glyoxylate bypass and tricarboxylic acid cycle were the risk factors for KOA. (OR = 1.13,95%CI = 1.04-1.23;OR = 1.12,95%CI = 1.04-1.20;OR = 1.14,95%CI = 1.04-1.26; OR = 1.06,95%CI = 1.00-1.12) However, adenosylcobalamin salvage from cobinamide I, hexitol fermentation to lactate formate ethanol and acetate, purine nucleotides degradation II aerobic, L tryptophan biosynthesis and inosine 5 phosphate biosynthesis III pathway showed significant protection against KOA. (OR = 0.93,95%CI = 0.86-1.00;OR = 0.94,95%CI = 0.88-1.00;OR = 0.91,95%CI = 0.86-0.97;OR = 0.95,95%CI = 0.92-0.99; OR = 0.91, 95%CI = 0.85-0.98) Further multiplicity and sensitivity analyses demonstrated the robustness of the results. CONCLUSION: Our study identified specific metabolic pathways in gut microbiota that promote or inhibit KOA, which provides the most substantial evidence-based medical evidence for the pathogenesis and prevention of KOA.

Genetic evidence supporting potential causal roles of EIF4 family in breast cancer: a two-sample randomized Mendelian study.

Translational control plays a crucial role in the regulation of apoptosis, with the EIF4 family serving as one of the mRNA translation factors that modulate the process of mRNA translation based on mRNA characteristics. To address this potential causal role of EIF4 family proteins and breast cancer, Mendelian randomization was employed. The study incorporated four sets of genetics instrumental variables, namely EIF4E, EIF4B, EIF4A, and EIF4EBP2. The outcome variables selected for analysis were the BCAC consortium, which included estrogen receptor positive (ER+) and estrogen receptor negative (ER-) samples. To assess the potential violations of the MR assumption, the primary MR analysis employed inverse variance weighted (IVW), and several sensitivity analyses were conducted. The findings of the two-sample MR analysis indicate that EIF4E has an adverse effect on breast cancer risk (p = 0.028). However, the evidence for the relationship between EIF4E and ER status of breast cancer suggests a weak association with ER+ breast cancer (p = 0.054), but not with ER- breast cancer (p > 0.05). The study findings indicate that EIF4A is not causally linked to the risk of ER+ breast cancer, but is significantly associated with an elevated risk of ER- breast cancer (p = 0.028). However, the evidence is inadequate to support the effects of EIF4B and EIF4EBP2 on breast cancer (p > 0.05). Our results suggest that EIF4 may be a potential factor in the occurrence and development of breast cancer, which may lead to a better understanding of its causes and prevention.

Higher genetically predicted triglyceride level increases the bladder cancer risk independent of LDL and HDL levels.

The causal relationship between lipid levels and bladder cancer is still inconclusive currently. We aimed to reveal the causal relationship between triglycerides, HDL, and LDL and the risk of bladder cancer by univariable and multivariable Mendelian randomization (MR) analysis. The single nucleotide polymorphisms (SNPs) of exposure (triglycerides: 441,016 samples; HDL: 403,943 samples; LDL: 440,546 samples) were obtained from UK Biobank. The Genetic variation related to bladder cancer included 1554 cases and 359,640 controls. Univariable and multivariable MR methods were conducted with subsequent analysis, and smoking was regarded as a confounder. The inverse-variance weighted (IVW), MR-Egger, weighted-median method, Cochran's Q test, and MR-PRESSO were considered the main MR analysis and sensitivity analysis methods. Univariable MR analysis results suggested the triglycerides level (P = 0.011, OR = 1.001, 95% CI = 1.000-1.002) was causally associated with increased risk of bladder cancer. Multivariable MR results indicated that higher triglyceride levels could still increase the risk of bladder cancer after adjusting the effects of HDL, LDL, and smoking (P = 0.042, OR = 1.001, 95% CI = 1.000-1.002). Our findings supported that triglyceride level is causally associated with an increased risk of bladder cancer independent of LDL and HDL at the genetic level. Timely attention to changes in blood lipid levels might reduce the risk of bladder cancer.

Prescription glucocorticoid medication and iridocyclitis are associated with an increased risk of senile cataract occurrence: a Mendelian randomization study.

Iridocyclitis and the use of glucocorticoid medication have been widely studied as susceptibility factors for cataracts. However, the causal relationship between them remains unclear. This study aimed to investigate the causal relationship between the development of iridocyclitis and the genetic liability of glucocorticoid medication use on the risk of senile cataracts occurrence by performing Two-sample Mendelian randomization (MR) analyses. Instrumental variables (IVs) significantly associated with exposure factors (P < 5 × 10-8) were identified using published genome-wide association data from the FinnGen database and UK Biobank. Reliability analyses were conducted using five approaches, including inverse-variance weighted (IVW), MR-Egger regression, simple median, weighted median, and weighted mode. A sensitivity analysis using the leave-one-out method was also performed. Genetic susceptibility to glucocorticoid use was associated with an increased risk of developing senile cataracts (OR, 1.10; 95% CI, 1.02-1.17; P < 0.05). Moreover, iridocyclitis was significantly associated with a higher risk of developing senile cataracts (OR, 1.03; 95% CI, 1.01-1.05; P < 0.05). Nonetheless, some heterogeneity in the IVs was observed, but the MR results remained consistent after penalizing for outliers. The estimates were consistent in multivariate analyses by adjusting for body mass index (BMI) and diabetes mellitus type 2 (T2DM). This study provides new insights into the prevention and management of senile cataracts by highlighting the increased risk associated with iridocyclitis and the use of glucocorticoids.

Ferroptosis biomarkers predict tumor mutation burden's impact on prognosis in HER2-positive breast cancer.

BACKGROUND: Ferroptosis has recently been associated with multiple degenerative diseases. Ferroptosis induction in cancer cells is a feasible method for treating neoplastic diseases. However, the association of iron proliferation-related genes with prognosis in HER2+ breast cancer (BC) patients is unclear. AIM: To identify and evaluate fresh ferroptosis-related biomarkers for HER2+ BC. METHODS: First, we obtained the mRNA expression profiles and clinical information of HER2+ BC patients from the TCGA and METABRIC public databases. A four-gene prediction model comprising PROM2, SLC7A11, FANCD2, and FH was subsequently developed in the TCGA cohort and confirmed in the METABRIC cohort. Patients were stratified into high-risk and low-risk groups based on their median risk score, an independent predictor of overall survival (OS). Based on these findings, immune infiltration, mutations, and medication sensitivity were analyzed in various risk groupings. Additionally, we assessed patient prognosis by combining the tumor mutation burden (TMB) with risk score. Finally, we evaluated the expression of critical genes by analyzing single-cell RNA sequencing (scRNA-seq) data from malignant vs normal epithelial cells. RESULTS: We found that the higher the risk score was, the worse the prognosis was (P < 0.05). We also found that the immune cell infiltration, mutation, and drug sensitivity were different between the different risk groups. The high-risk subgroup was associated with lower immune scores and high TMB. Moreover, we found that the combination of the TMB and risk score could stratify patients into three groups with distinct prognoses. HRisk-HTMB patients had the worst prognosis, whereas LRisk-LTMB patients had the best prognosis (P < 0.0001). Analysis of the scRNA-seq data showed that PROM2, SLC7A11, and FANCD2 were significantly differentially expressed, whereas FH was not, suggesting that these genes are expressed mainly in cancer epithelial cells (P < 0.01). CONCLUSION: Our model helps guide the prognosis of HER2+ breast cancer patients, and its combination with the TMB can aid in more accurate assessment of patient prognosis and provide new ideas for further diagnosis and treatment.

Genetic prediction of modifiable lifestyle factors for erectile dysfunction.

Background: The causal relationship between certain lifestyle factors and erectile dysfunction (ED) is still uncertain. Aim: The study sought to investigate the causal effect of 9 life factors on ED through 2-sample single-variable Mendelian randomization (SVMR) and multivariable Mendelian randomization (MVMR). Methods: Genetic instruments to proxy 9 risk factors were identified by genome-wide association studies. The genome-wide association studies estimated the connection of these genetic variants with ED risk (n = 223 805). We conducted SVMR, inverse variance-weighting, Cochran's Q, weighted median, MR-Egger, MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier), and MVMR analyses to explore the total and direct relationship between life factors and ED. Outcomes: The primary outcome was defined as self or physician-reported ED, or using oral ED medication, or a history of surgery related to ED. Results: In SVMR analyses, suggestive associations with increased the risk of ED were noted for ever smoked (odds ratio [OR], 5.894; 95% confidence interval [CI], 0.469 to 3.079; P = .008), alcohol consumption (OR, 1.495; 95% CI, 0.044 to 0.760; P = .028) and body mass index (BMI) (OR, 1.177; 95% CI, 0.057 to 0.268; P = .003). Earlier age at first intercourse was significantly related to reduced ED risk (OR, 0.659; 95% CI, -0.592 to -0.244; P = 2.5 × 10-6). No strong evidence was found for the effect of coffee intake, time spent driving, physical activity, and leisure sedentary behaviors on the incidence of ED (All P > .05). The result of MVMR analysis for BMI (OR, 1.13; 95% CI, 1.01 to 1.25; P = .045) and earlier age at first intercourse (OR, 0.77; 95% CI, 0.56 to 0.99; P = .018) provided suggestive evidence for the direct impact on ED, while no causal factor was detected for alcoholic drinks per week and ever smoked. Clinical implications: This study provides evidence for the impact of certain modifiable lifestyle factors on the development of ED. Strengths and limitations: We performed both SVMR and MVMR to strengthen the causal relationship between exposures and outcomes. However, the population in this study was limited to European ancestry. Conclusion: Ever smoked, alcoholic drinks per week, BMI, and age first had sexual intercourse were causally related to ED, while the potential connection between coffee intake, physical activity, recreational sedentary habits, and increased risk of ED needs to be further confirmed.

Exploring a Potential Causal Link Between Dietary Intake and Chronic Obstructive Pulmonary Disease: A Two-Sample Mendelian Randomization Study.

Background: Chronic Obstructive Pulmonary Disease (COPD), the most prevalent chronic respiratory condition, significantly impairs patients' quality of life. The pivotal element in disease management lies in prevention, underscoring the paramount importance of employing a scientific approach to investigate early prevention strategies for COPD. Methods: This study delved into the causal link between 28 dietary intakes and COPD employing two-sample Mendelian randomization. We primarily utilized the Inverse Variance Weighted (IVW) method as the main outcome, complemented by Weighted Median (WM), MR-Egger method, along with several sensitivity analysis techniques, all accompanied by visual representations. Results: We identified higher odds of COPD following exposure to green beans (OR=1.381, 95% CI=1.119-1.704, P=0.003) and pork intake (OR=2.657, 95% CI=1.203-5.868, P=0.016). In contrast, the odds of developing COPD were lower following exposure to dried fruit (OR=0.481, 95% CI=0.283-0.819, P=0.007), cereal (OR=0.560, 95% CI=0.356-0.880, P=0.012), and whole egg consumption (OR=0.700, 95% CI=0.504-0.972, P=0.033). Conclusion: In light of our study's findings, we anticipate that strategically modifying dietary choices may offer an avenue for early COPD prevention in the future.

Genetic association analysis of dietary intake and idiopathic pulmonary fibrosis: a two-sample mendelian randomization study.

BACKGROUND: IPF is a complex lung disease whose aetiology is not fully understood, but diet may have an impact on its development and progression. Therefore, we investigated the potential causal connection between dietary intake and IPF through TSMR to offer insights for early disease prevention recommendations. METHODS: The study incorporated 29 dietary exposure factors, oily fish intake, bacon intake, processed meat intake, poultry intake, beef intake, pork intake, lamb/mutton intake, non-oily fish intake, fresh fruit intake, cooked vegetable intake, baked bean intake, fresh tomato intake, tinned tomato intake, salad/raw vegetable intake, Fresh fruit intake, coffee intake, tea intake, water intake, red wine intake, average weekly beer plus cider intake, alcoholic drinks per week, cereal intake, bread intake, whole-wheat intake, whole-wheat cereal intake, cheese intake, yogurt intake, salt added to food and whole egg intake. The study explored the causal link between diet and IPF using TSMR analysis, predominantly the IVW method, and performed sensitivity analyses to validate the results. RESULT: The study revealed that consuming oily fish, yogurt, and dried fruits had a protective effect against IPF, whereas the consumption of alcoholic beverages and beef was linked to an increased risk of IPF. CONCLUSION: In this MR study, it was discovered that the consumption of oily fish, yogurt, and dried fruits exhibited a protective effect against IPF, whereas the intake of alcoholic beverages and beef was associated with an elevated risk of IPF. These findings underscore the significance of making informed and timely dietary decisions in IPF prevention.

Causal effects between gut microbiota and pulmonary arterial hypertension: A bidirectional Mendelian randomization study.

BACKGROUND: Multiple studies have highlighted a potential link between gut microbes and the onset of Pulmonary Arterial Hypertension (PAH). Nonetheless, the precise cause-and-effect relationship remains uncertain. OBJECTIVES: In this investigation, we utilized a two-sample Mendelian randomization (TSMR) approach to probe the presence of a causal connection between gut microbiota and PAH. METHODS: Genome-wide association (GWAS) data for gut microbiota and PAH were sourced from MiBioGen and FinnGen research, respectively. Inverse variance weighting (IVW) was used as the primary method to explore the causal effect between gut flora and PAH, supplemented by MR-Egger, weighted median (WM). Sensitivity analyses examined the robustness of the MR results. Reverse MR analysis was used to rule out the effect of reverse causality on the results. RESULTS: The results indicate that Genus Ruminococcaceae UCG004 (OR = 0.407, P = 0.031) and Family Alcaligenaceae (OR = 0.244, P = 0.014) were protective factors for PAH. Meanwhile Genus Lactobacillus (OR = 2.446, P = 0.013), Class Melainabacteria (OR = 2.061, P = 0.034), Phylum Actinobacteria (OR = 3.406, P = 0.010), Genus Victivallis (OR = 1.980, P = 0.010), Genus Dorea (OR = 3.834, P = 0.024) and Genus Slackia (OR = 2.622, P = 0.039) were associated with an increased Prevalence of PAH. Heterogeneity and pleiotropy were not detected by sensitivity analyses, while there was no reverse causality for these nine specific gut microorganisms. CONCLUSIONS: This study explores the causal effects of eight gut microbial taxa on PAH and provides new ideas for early prevention of PAH.

Genetically predicted cardiovascular diseases could increase the risk of erectile dysfunction: a bidirectional Mendelian randomization.

PURPOSE: Erectile dysfunction (ED) often appears concomitantly with cardiovascular diseases (CVDs). However, the causal relationship between ED and CVDs is still unclear. This study aimed to investigate the causal effects between CVDs and ED using bidirectional Mendelian randomization (MR). METHODS: ED data (6175 cases and 217,630 controls) were obtained from the IEU OpenGWAS project. Seven types of CVDs were acquired in our study, including stroke (Sample size = 440,328), myocardial infection (Sample size = 184,305), coronary heart disease (Sample size = 86,995), hypertension (Sample size = 36,683), heart failure (Sample size = 208,178), atrial fibrillation (Sample size = 1,030,836), and coronary artery disease (Sample size = 141,217). Inverse variance weighted (IVW) was selected as the primary method for MR analysis. RESULTS: IVW results indicated that stroke (OR = 1.14, 95% CI = 1.02-1.29, P = 0.025), coronary artery disease (OR = 1.09, 95% CI = 1.02-1.16, P = 0.013), coronary heart disease (OR = 1.07, 95% CI = 1.01-1.13, P = 0.017), myocardial infection (OR = 1.09, 95% CI = 1.02-1.17, P = 0.011), and atrial fibrillation (OR = 1.06, 95% CI = 1.00-1.12, P = 0.04) were causally associated with ED. The reverse MR analysis suggested that ED did not influence the prevalence of CVDs. CONCLUSION: These findings highlighted CVDs as causal risk factors for ED, but ED did not directly result in the development of CVDs. Regular monitoring of the erectile function of individuals with CVDs, along with implementing appropriate preventive measures, might help reduce the incidence of ED and enhance the sexual well-being of patients with CVDs.