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Background: Observational studies and experimental evidence have shown that chemokines play important roles in lung cancer development, progression, and treatment. However, few studies have examined the causal association between them. Methods: Summary data of chemokines and lung cancer were obtained from genome-wide association studies. Mendelian randomization (MR) analyses were performed by five methods, Inverse variance weighted (IVW), Weighted median estimation, MR-Egger, Simple mode and Weighted, with IVW as the primary analysis method. Sensitivity analysis was used to assess the reliability of the MR results. Multivariate Mendelian randomization studies were used to infer whether causality was influenced by potential mediators. The expression levels of CCL21 were analyzed by quantitative real-time PCR. Results: We found that CCL21 was negatively associated with lung adenocarcinoma risk. CCL25 was positively associated with lung squamous cell carcinoma risk. CCL5 was negatively associated with small cell lung cancer risk. CCL21, CCL24, CCL27, and CCL28 was positively associated with small cell lung cancer risk. After multivariate Mendelian randomization adjustment for smoking behavior, it was found that the effect of CCL25 on lung squamous cell cancer disappeared, and the effect of CCL21 on small cell lung cancer was quite opposite to the univariate. The receiver operating characteristic curve indicated that chemokines had high accuracy in the diagnosis of lung cancer. CCL21 expression levels showed large differences in lung adenocarcinoma cells. Conclusion: These results highlighted the causal effects of chemokines on lung cancer and suggested a mediating role of smoking behavior in the association between chemokines and lung cancer. [ABSTRACT FROM AUTHOR]

Background: Mitochondrial DNA (mtDNA) plays an important role in autoimmune diseases (AD), yet the relationship between mitochondria and autoimmune disease is controversial. This study employed bidirectional Mendelian randomization (MR) to explore the causal relationship between mtDNA copy number and 13 ADs (including ankylosing spondylitis [AS], Crohn's disease [CD], juvenile rheumatoid arthritis [JRA], polymyalgia rheumatica [PMR], psoriasis [PSO], rheumatoid arthritis [RA], Sjogren's syndrome [SS], systemic lupus erythematosus [SLE], thyrotoxicosis, type 1 diabetes mellitus [T1DM], ulcerative colitis [UC], and vitiligo). Methods: A two-sample MR analysis was performed to assess the causal relationship between mtDNA copy number and AD. Genome-wide association study (GWAS) for mtDNA copy number were obtained from the UK Biobank (UKBB), while those associated with AD were sourced from the FinnGen Biobank. Inverse variance weighting (IVW) was the primary analysis method, complemented by three sensitivity analyses (MR-Egger, weighted median, weighted mode) to validate the results. Results: IVW MR analysis identified significant associations between mtDNA copy number and CD (OR=2.51, 95% CI 1.56-4.22, P<0.001), JRA (OR=1.87, 95% CI 1.17-7.65, P=0.022), RA (OR=1.71, 95%CI 1.18-2.47, P=0.004), thyrotoxicosis (OR=0.51, 95% CI0.27-0.96, P=0.038), and T1DM (OR=0.51, 95% CI 0.27-0.96, P=0.038). Sensitivity analyses indicated no horizontal pleiotropy. Conclusions: Our study revealed a potential causal relationship between mtDNA copy number and ADs, indicating that these markers may be relevant in exploring new therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background: Coffee is a widely consumed beverage with potential benefits for various chronic diseases. Its effect on reducing erectile dysfunction (ED) risk is unclear. This Mendelian randomization (MR) study investigates the impact of coffee/caffeine consumption on ED. Methods: Two sets of coffee consumption-associated genetic variants at the genome-wide significance level were obtained from recent studies of coffee consumption. Taking into account other sources of caffeine, genetic variants associated with caffeine consumption from tea were also obtained. The inverse variance weighted (IVW) method was utilized as the primary analysis. Sensitivity analysis methods and meta-analysis methods were performed to confirm the robustness of the results, while the genetic variants associated with confounders, e.g., diabetes and hypertension, were excluded. Results: Genetically predicted coffee/caffeine consumption was unlikely to be associated with the risk of ED in the Bovijn datasets, with similar directional associations observed in the FinnGen datasets. The combined odds ratio for ED was 1.011 (95% CI 0.841-1.216, p=0.906) for coffee consumption from the genome-wide meta-analysis, 1.049 (95% CI 0.487-2.260, p=0.903) for coffee consumption from the genome-wide association study, and 1.061 (95% CI 0.682-1.651, p=0.793) for caffeine from tea. Conclusion: Using genetic data, this study found no association between coffee/caffeine consumption and the risk of ED. [ABSTRACT FROM AUTHOR]

Although observational clinical studies have established an association between Intestinal Diseases (IDS) and Anal Diseases (ADS), the causal relationship is still not fully understood due to the limitations of observational studies. Genome-wide association study (GWAS) statistical data for IDS and ADS were obtained from publicly available databases. To assess the causal effects of IDS on ADS, we conducted Mendelian randomization analysis. The inverse variance weighted method indicated that Inflammatory bowel disease (IBD) had a significant causal relationship with three kinds of ADS: Anorectal abscess (ARB), Haemorrhoidal disease (HEM), and Fissure and fistula of anal and rectal regions (FISSANAL). Crohn's disease (CD) and Ulcerative colitis (UC) also showed significant causal effects with three ADS: ARB, HEM, and FISSANAL. Furthermore, a potential link between CD and BNA(Benign neoplasm of anus and anal canal), Irritable bowel syndrome (IBS) and HEM, Colorectal cancer (CRC) and BNA, and Celiac disease and MNA (Malignant neoplasm of anus and anal canal) was observed. This comprehensive MR analysis highlight the significant and increased risk of common Anal Diseases (ARB, FISSANAL, and HEM) in patients with IBD, CD, and UC. Additionally, potential positive causal associations emerged between IBS and HEM, CRC and BNA, as well as between celiac disease and MNA. [ABSTRACT FROM AUTHOR]

Researchers have conducted extensive research on the correlation between brain resting-state functional activities (RSFA) and migraine. However, we still do not fully understand the exact nature of the causal relationship between these RSFA and migraine. We conducted a bidirectional two-sample Mendelian randomization (MR) study to investigate the causal association between migraine and RSFA. We gathered summary statistics from genome-wide association studies for 191 resting-state functional magnetic resonance imaging phenotypes. We employed various analytical methods for bidirectional two-sample MR analyses. This included inverse variance weighted, weighted median, MR Egger, and the constrained maximum likelihood approaches. We also conducted pleiotropy and heterogeneity analyses to evaluate the robustness and reliability. We found the functional connectivity between the default mode and the central executive network (OR = 1.39, p = 4.77 × 10−4, FDR corrected p value = 0.040) and the intensity of spontaneous brain activity in the calcarine or lingual gyrus within the visual network (OR = 0.74, p = 5.94 × 10−4, FDR corrected p value = 0.040) having a causal effect on the risk of migraine. Our MR analysis provided genetic support for these networks, which may play an important role in influencing migraine susceptibility. [ABSTRACT FROM AUTHOR]

Asthma and lung cancer are both significant public health concerns worldwide. Previous observational studies have indicated a potential link between asthma and an increased risk of lung cancer, whereas the causal relationship remains uncertain. We aimed to investigate the potential causal relationship between asthma and lung cancer risk utilizing Mendelian randomization (MR) design.The present study employed a two-sample MR analysis utilizing summary statistics from genome-wide association studies (GWAS) with European descent of asthma and lung cancer. The MR analysis was performed using inverse variance weighting (IVW), supplemented with MR-Egger regression and weighted median method to investigate the potential causality between asthma and lung cancer. Furthermore, Sensitivity analyses were also conducted to ensure the reliability of the findings. The MR analysis showed that genetically predicted asthma had suggestive causal association with the elevated risk of lung cancer [odds ratio (OR), 1.05 (95%Cl,1.01–1.09), P = 0.01]. The consistent direction of effects observed in the three methods further supported this finding. In addition, sensitivity analyses demonstrated the reliability of the results. This study provided potential evidence supporting a causal association between asthma and lung cancer. These findings highlighted the importance of early detection and prevention strategies for lung cancer in individuals with asthma. Further research was needed to elucidate the underlying mechanisms linking asthma and lung cancer. [ABSTRACT FROM AUTHOR]

Background: Cohort studies have increasingly shown associations between inflammatory markers and myocardial infarction (MI); however, the specific causal relationships between inflammatory markers and the development of MI remain unclear. Methods and results: By utilizing publicly accessible genome-wide association studies, we performed a two-sample Mendelian randomization (MR) analysis to explore the causal associations between inflammatory markers and myocardial infarction (MI). A random-effects inverse-variance weighted method was used to calculate effect estimates. The study included a total of 395,795 European participants for MI analysis and various sample sizes for inflammatory factors, ranging from 3,301 to 563,946 participants.Neutrophil count was found to increase the risk of MI (odds ratio [OR] = 1.08; 95% confidence interval [CI], 1.00–1.17; p = 0.04). C-reactive protein levels correlated positively with MI. No associations were observed with IL-1 beta, IL-6, IL-18, procalcitonin, TNF-α, total white cell count, or neutrophil percentage of white cells. Neutrophil count and C-reactive protein were inversely associated with lactate dehydrogenase: neutrophil cell count (OR 0.95; 95% CI, 0.93–0.98; p < 0.01) and C-reactive protein (OR 0.96; 95% CI, 0.92–1.00; p = 0.02). No associations of MI with myoglobin, troponin I, and creatine kinase-MB levels were found. Conclusions: This two-sample MR analysis revealed a causal positive association of MI with neutrophil count, C-reactive protein level, and the myocardial injury marker lactate dehydrogenase. These results indicate that monitoring C-reactive protein and neutrophil counts may be useful in management of MI patients. [ABSTRACT FROM AUTHOR]

Objectives: Epilepsy and amyotrophic lateral sclerosis (ALS) are common neurological disorders. The association between the two disorders has been raised in observational studies. However, it is uncertain to what extent they have mutual causal effects. In this study, we aimed to investigate their causal association using a two‐sample Mendelian randomization (MR) method. Methods: We performed a two‐sample bidirectional MR analysis to evaluate the causal association of epilepsy with the risk of ALS. Publicly published genome‐wide association study statistics for epilepsy and ALS were used in the study. The primary analysis included genetic variants with a p value of less than 1 × 10–5 as instrumental variables. We applied several alternative methods, including inverse variance weighting, weighted median, simple mode, weighted mode, MR‐Egger regression and MR pleiotropy residual sum and outlier, and statistical graphs to assess the associations of epilepsy and its subtype with the risk of ALS. Reverse MR analyses were also performed to examine the association of ALS with the risk of epilepsy. Results: The primary MR analysis found no causal effect of epilepsy on risk of ALS (odds ration [OR]: 1.133, 95% confidence interval [CI]: 0.964–1.332, p =.130). Among subtypes of epilepsy, it also failed to observe any causal association between general epilepsy and ALS (OR: 1.036, 95% CI: 0.969–1.108, P =.300). However, focal epilepsy contributed to an increase in the risk of ALS (OR: 1.177, 95% CI: 1.027–1.348, p =.019). Moreover, the investigation of reverse causalities did not reveal significant results. Conclusions: The current study supports a causal influence of focal epilepsy on ALS risk. Future studies are needed to explore its potential role in ALS. [ABSTRACT FROM AUTHOR]

Purpose: Studies have demonstrated that hormonal imbalance, such as elevated level of estrogen or reduced level of progesterone, was the main inducing factor of uterine leiomyoma (UL) development and some cancers. UL has been reported to be associated with several cancers in observational studies. However, the causal associations between UL and cancers remain unclear. Methods: A two-sample Mendelian randomization (MR) analysis was conducted to investigate the causal associations between UL and 16 site-specific cancers using the public databases. Four methods, namely, the inverse variance weighting (IVW), MR-Egger, weighted median, and weighted mode, were applied in our MR analysis. Sensitivity tests were also performed to evaluate the robustness of these causal associations. Results: The IVW analysis indicated that genetically predicted UL increased the risk of low malignant potential ovarian cancer [odds ratio (OR) = 1.22, 95% confidence interval (CI): 1.06-1.40, p = 0.004], serous ovarian cancer (OR = 1.29, 95% CI: 1.10-1.52, p = 0.002), invasive mucinous ovarian cancer (OR = 1.24, 95% CI: 1.08-1.44, p = 0.003), clear cell ovarian cancer (OR = 1.25, 95% CI: 1.03-1.51, p = 0.023), breast cancer (OR = 1.07, 95% CI: 1.02-1.11, p = 0.002), and brain tumor (OR = 1.23, 95% CI: 1.06-1.42, p = 0.007). Conversely, genetically predicted UL reduced the risk of gastric cancer (OR = 0.91, 95% CI: 0.85-0.98, p = 0.008). The causal effects were consistent in the sensitivity analysis. Conclusions: Our results demonstrated that UL exhibits a causal relationship with high risk of several cancers. We suggest reinforcing the cancer screening in UL patients to enable the early detection of cancers. [ABSTRACT FROM AUTHOR]

Background: Evidence suggests a connection between DNA methylation (DNAm) aging and reproductive aging. However, the causal relationship between DNAm and age at menopause remains uncertain. Methods: Employing established DNAm epigenetic clocks, such as DNAm Hannum age acceleration (Hannum), Intrinsic epigenetic age acceleration (IEAA), DNAm-estimated granulocyte proportions (Gran), DNAm GrimAge acceleration (GrimAgeAccel), DNAm PhenoAge acceleration (PhenoAgeAccel), and DNAm-estimated plasminogen activator inhibitor-1 levels (DNAmPAIadjAge), a bidirectional Mendelian randomization (MR) study was carried out to explore the potential causality between DNAm and menopausal age. The primary analytical method used was the inverse variance weighted (IVW) estimation model, supplemented by various other estimation techniques. Results: DNAm aging acceleration or deceleration, as indicated by Hannum, IEAA, Gran, GrimAgeAccel, PhenoAgeAccel, and DNAmPAIadjAge, did not exhibit a statistically significant causal effect on menopausal age according to forward MR analysis. However, there was a suggestive positive causal association between age at menopause and Gran (Beta = 0.0010; 95% confidence interval (CI): 0.0004, 0.0020) in reverse MR analysis. Conclusion: The observed increase in granulocyte DNAm levels in relation to menopausal age could potentially serve as a valuable indicator for evaluating the physiological status at the onset of menopause. [ABSTRACT FROM AUTHOR]

Background: The genetic association between urticaria and mental disorders and whether inflammatory cytokines mediate this process remains unclear. Materials and methods: A Mendelian randomization (MR) approaches to elucidate the causal relationship between urticaria and mental disorders and to validate the mediation of inflammatory cytokines. Genome‐wide association study (GWAS) databases used were obtained from Psychiatric Genomics Cooperation (PGC), GWAS Catalog, and FinnGen Consortium. Our study was conducted using inverse variance weighted (IVW) and Bayesian weighted MR (BWMR) methods for joint analysis. Results: The MR results showed that urticaria increased the risk of attention deficit hyperactivity disorder (ADHD) (odds ratio [OR] =$ = $ 1.088, 95% confidence interval [CI]: 1.026–1.154, p=$ = $ 0.0051); cholinergic urticaria increased the risk of bipolar disorder (BD) (OR =$ = $ 1.012, 95% CI: 1.001–1.022, p=$ = $ 0.0274); dermatographic urticaria increased the risk of ADHD (OR =$ = $ 1.057, 95% CI: 1.005–1.112, p=$ = $ 0.0323); idiopathic urticaria increased the risk of schizophrenia (SCZ) (OR =$ = $ 1.057, 95% CI: 1.005–1.112, p=$ = $ 0.0323); other unspecified urticaria increased the risk of ADHD (OR =$ = $ 1.085, 95% CI: 1.023–1.151, p=$ = $ 0.0063). We found that eight inflammatory cytokines were negatively associated with mental disorders and seven inflammatory cytokines were positively associated with mental disorders. Finally, our results suggested that inflammatory cytokines do not act as mediators between urticaria and mental disorders. Conclusions: Our study reveals a causal relationship between urticaria and the increased risk of mental disorders. We suggest that the treatment of urticaria could incorporate psychiatric interventions and mental health assessment of patients. [ABSTRACT FROM AUTHOR]

Abstract Background Observational studies and experimental evidence have shown that chemokines play important roles in lung cancer development, progression, and treatment. However, few studies have examined the causal association between them. Methods Summary data of chemokines and lung cancer were obtained from genome-wide association studies. Mendelian randomization (MR) analyses were performed by five methods, Inverse variance weighted (IVW), Weighted median estimation, MR-Egger, Simple mode and Weighted, with IVW as the primary analysis method. Sensitivity analysis was used to assess the reliability of the MR results. Multivariate Mendelian randomization studies were used to infer whether causality was influenced by potential mediators. The expression levels of CCL21 were analyzed by quantitative real-time PCR. Results We found that CCL21 was negatively associated with lung adenocarcinoma risk. CCL25 was positively associated with lung squamous cell carcinoma risk. CCL5 was negatively associated with small cell lung cancer risk. CCL21, CCL24, CCL27, and CCL28 was positively associated with small cell lung cancer risk. After multivariate Mendelian randomization adjustment for smoking behavior, it was found that the effect of CCL25 on lung squamous cell cancer disappeared, and the effect of CCL21 on small cell lung cancer was quite opposite to the univariate. The receiver operating characteristic curve indicated that chemokines had high accuracy in the diagnosis of lung cancer. CCL21 expression levels showed large differences in lung adenocarcinoma cells. Conclusion These results highlighted the causal effects of chemokines on lung cancer and suggested a mediating role of smoking behavior in the association between chemokines and lung cancer.

Abstract Walking pace is a simple and functional form of exercise and a strong predictor of health, but little is known about its causal association with rheumatoid arthritis. This study aimed to investigate the causal effect of WP on the developing RA using Mendelian randomization analysis. The genetic variation associated with WP was selected as an instrumental variable from the latest genome-wide association studies. Summary-level data for the outcomes were obtained from the corresponding GWAS. The inverse-variance weighted method was used as the primary MR analysis. The results were further tested using a multivariable MR approach based on Bayesian model averaging. Confounders (BMI, SMK, HBP, TD) with close associations with RA were included in the analysis. An observational study with individual data from UK Biobank was performed to reinforce our findings. The MR results indicated the significant inverse associations of WP with the risk of RA (odds ratio (OR), 0.31; 95% confidence interval (CI), 0.15, 0.62; p = 1.05 × 10 −3). After adjusting for the risk factors, the associations for WP and RA did not change substantially. Observational study results demonstrated the same effect of WP on reducing the risk of RA. The Mendelian randomization analysis and observational study provide evidence suggesting that walking pace is a protective factor for rheumatoid arthritis. Given its simple measurement, walking pace may be a pragmatic target for interventions.

Abstract Observational studies and clinical trials have suggested the relationship between the gut microbiome and respiratory diseases, but the causality between them remains unclear. Firstly, we selected eight respiratory diseases Genome-wide association study (GWAS) datasets mainly from the FinnGen collaboration as outcomes. The exposure was based on GWAS statistics about the gut microbiome, sourced from the MiBioGen consortium, including gut microbial taxa. The causal link between the gut microbiome and respiratory illnesses was then estimated using a Two-sample Mendelian randomization (MR) analysis, including the inverse-variance weighted (IVW), weighted median, MR-Egger, simple mode, and weighted mode. To ensure reliability, F-statistics and sensitivity tests were conducted. Furthermore, we performed a reverse MR analysis of the pre-Mendelian positive findings to possible reverse causality. For the 196 gut microbe taxa, the IVW analysis suggested 88 potential associations with eight clinically prevalent respiratory diseases. Among them, 30 causal associations were found in more than one MR method. Multiple statistical corrections have confirmed three causal associations: genus Holdemanella was a risk factor for chronic obstructive pulmonary disease (COPD) (P = 1.3 × 10−4, OR = 1.18), family FamilyXIII was a protective factor for COPD (P = 1.3 × 10−3, OR = 0.75), and genus Oxalobacter was a risk factor for asthma (P = 2.1 × 10−4, OR = 1.09). Our MR analysis results indicate that there would be a causal relationship between the gut microbiome and respiratory diseases, contributing to the gut-lung axis. This finding offers new insights into the gut microbiome’s roles in respiratory diseases’ clinical prevention, pathogenesis, and improvement of clinical symptoms. Further randomized controlled trials are necessary to clarify the protective effect of probiotics and fecal microbial transplantation on respiratory health.

Abstract Although observational clinical studies have established an association between Intestinal Diseases (IDS) and Anal Diseases (ADS), the causal relationship is still not fully understood due to the limitations of observational studies. Genome-wide association study (GWAS) statistical data for IDS and ADS were obtained from publicly available databases. To assess the causal effects of IDS on ADS, we conducted Mendelian randomization analysis. The inverse variance weighted method indicated that Inflammatory bowel disease (IBD) had a significant causal relationship with three kinds of ADS: Anorectal abscess (ARB), Haemorrhoidal disease (HEM), and Fissure and fistula of anal and rectal regions (FISSANAL). Crohn’s disease (CD) and Ulcerative colitis (UC) also showed significant causal effects with three ADS: ARB, HEM, and FISSANAL. Furthermore, a potential link between CD and BNA(Benign neoplasm of anus and anal canal), Irritable bowel syndrome (IBS) and HEM, Colorectal cancer (CRC) and BNA, and Celiac disease and MNA (Malignant neoplasm of anus and anal canal) was observed. This comprehensive MR analysis highlight the significant and increased risk of common Anal Diseases (ARB, FISSANAL, and HEM) in patients with IBD, CD, and UC. Additionally, potential positive causal associations emerged between IBS and HEM, CRC and BNA, as well as between celiac disease and MNA.

Abstract Background Cohort studies have increasingly shown associations between inflammatory markers and myocardial infarction (MI); however, the specific causal relationships between inflammatory markers and the development of MI remain unclear. Methods and results By utilizing publicly accessible genome-wide association studies, we performed a two-sample Mendelian randomization (MR) analysis to explore the causal associations between inflammatory markers and myocardial infarction (MI). A random-effects inverse-variance weighted method was used to calculate effect estimates. The study included a total of 395,795 European participants for MI analysis and various sample sizes for inflammatory factors, ranging from 3,301 to 563,946 participants.Neutrophil count was found to increase the risk of MI (odds ratio [OR] = 1.08; 95% confidence interval [CI], 1.00–1.17; p = 0.04). C-reactive protein levels correlated positively with MI. No associations were observed with IL-1 beta, IL-6, IL-18, procalcitonin, TNF-α, total white cell count, or neutrophil percentage of white cells. Neutrophil count and C-reactive protein were inversely associated with lactate dehydrogenase: neutrophil cell count (OR 0.95; 95% CI, 0.93–0.98; p

Abstract Researchers have conducted extensive research on the correlation between brain resting-state functional activities (RSFA) and migraine. However, we still do not fully understand the exact nature of the causal relationship between these RSFA and migraine. We conducted a bidirectional two-sample Mendelian randomization (MR) study to investigate the causal association between migraine and RSFA. We gathered summary statistics from genome-wide association studies for 191 resting-state functional magnetic resonance imaging phenotypes. We employed various analytical methods for bidirectional two-sample MR analyses. This included inverse variance weighted, weighted median, MR Egger, and the constrained maximum likelihood approaches. We also conducted pleiotropy and heterogeneity analyses to evaluate the robustness and reliability. We found the functional connectivity between the default mode and the central executive network (OR = 1.39, p = 4.77 × 10−4, FDR corrected p value = 0.040) and the intensity of spontaneous brain activity in the calcarine or lingual gyrus within the visual network (OR = 0.74, p = 5.94 × 10−4, FDR corrected p value = 0.040) having a causal effect on the risk of migraine. Our MR analysis provided genetic support for these networks, which may play an important role in influencing migraine susceptibility.

Wei Zu,1,&ast; Shaojiong Zhou,2,&ast; Tao Du,1 Chenyanwen Zhu,3 Siyue Nie,4 Hongwei Zhu1 1Department of Functional Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Neurology & Innovation Center for Neurological Disorders, Xuanwu Hospital, Capital Medical University, National Center for Neurological Disorders, Beijing, People’s Republic of China; 3 4+4 Medical Doctor Program, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China; 4Chinese PLA Medical School; Department of Oncology, Chinese PLA General Hospital, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongwei Zhu, Department of Functional Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, People’s Republic of China, Email zhuhongwei@xwh.ccmu.edu.cnIntroduction: This study aims to investigate the potential causal effects of modifiable risk factors on Fibromyalgia (FM).Methods: Genetic variants associated with 34 exposure factors were obtained from Genome-wide association studies (GWAS). Summary statistics for FM were acquired from the FinnGen consortium. Bidirectional Mendelian randomization (MR) analysis was conducted between all exposures and outcomes. The inverse-variance weighted (IVW) method was employed as the primary estimation technique. Heterogeneity and pleiotropy were assessed using MR-PRESSO global test, the weighted median, Cochran’s Q statistic and MR-Egger.Results: Depression (OR=2.087, 95% CI: 1.466– 2.971), alcohol consumption (OR=1.489, 95% CI: 1.094– 2.028), body fat percentage (OR=1.524, 95% CI: 1.153– 2.013) and body mass index (BMI) (OR=1.542, 95% CI: 1.271– 1.872) were associated with an increased risk of FM among genetically susceptible individuals. Conversely, higher education level (OR=0.404, 95% CI: 0.297– 0.549), longer years of education (OR=0.489, 95% CI: 0.290– 0.825) and higher household income (OR=0.328, 95% CI: 0.215– 0.502) were protective against FM. Additionally, rheumatoid arthritis (OR=1.138, 95% CI: 1.061– 1.221) and ankylosing spondylitis (OR=1.079, 95% CI: 1.021– 1.140) were identified as important risk factors for FM.Conclusion: This MR study unveiled a complex causal relationship between modifiable risk factors and FM. Psychosocial factors significantly increase the odds of FM, while obesity and some autoimmune diseases that frequently coexist with FM demonstrate causal associations. Additionally, lifestyle habits such as alcohol consumption are causally related to FM. Further investigation is needed to determine whether risk factors contribute to the pathogenesis of FM through mechanisms involving central sensitization, inflammatory, and hyperalgesia. This study enhances our understanding of the factors that drive FM onset and progression, offering valuable insights for future targeted prevention and treatment strategies.Keywords: fibromyalgia, modifiable risk factors, causal association, Mendelian randomization

Abstract Asthma and lung cancer are both significant public health concerns worldwide. Previous observational studies have indicated a potential link between asthma and an increased risk of lung cancer, whereas the causal relationship remains uncertain. We aimed to investigate the potential causal relationship between asthma and lung cancer risk utilizing Mendelian randomization (MR) design.The present study employed a two-sample MR analysis utilizing summary statistics from genome-wide association studies (GWAS) with European descent of asthma and lung cancer. The MR analysis was performed using inverse variance weighting (IVW), supplemented with MR-Egger regression and weighted median method to investigate the potential causality between asthma and lung cancer. Furthermore, Sensitivity analyses were also conducted to ensure the reliability of the findings. The MR analysis showed that genetically predicted asthma had suggestive causal association with the elevated risk of lung cancer [odds ratio (OR), 1.05 (95%Cl,1.01–1.09), P = 0.01]. The consistent direction of effects observed in the three methods further supported this finding. In addition, sensitivity analyses demonstrated the reliability of the results. This study provided potential evidence supporting a causal association between asthma and lung cancer. These findings highlighted the importance of early detection and prevention strategies for lung cancer in individuals with asthma. Further research was needed to elucidate the underlying mechanisms linking asthma and lung cancer.

Background and Objectives: The precise impact of tea consumption on the risk of depression remains unclear. This study aimed to explore the relationship between the consumption patterns of tea and the likelihood of depression onset, utilizing a two-sample Mendelian randomization (MR) methodology. Methods and Study Design: We utilized available genome-wide association study (GWAS) datasets on tea intake and depressive disorders. To investigate the causal relationship between tea consumption and depression, we employed a set of two-sample Mendelian Randomization (MR) methods. These included the inverse-variance weighted (IVW) analysis, weighted median approach, and MR-Egger regression. Additionally, we utilized MR-PRESSO and the MR-Egger intercept test for the detection of pleiotropic effects. To ensure the robustness and consistency of our findings, a sensitivity analysis was carried out, applying the 'leave-one-out' strategy. The Bayesian weighted Mendelian randomization (BWMR) was employed to conduct additional testing on the obtained results. Results: The study's outcomes revealed a causal association between increased tea intake and an increased risk of depression (Inverse-Variance Weighted Analysis: Odds Ratio [OR] = 1.029, 95% Confidence Interval [CI]: 1.003-1.055, p = 0.027). This was observed despite variations in instrumental variables and the nonexistence of horizontal pleiotropy. Furthermore, the robustness of our Mendelian Randomization investigation was affirmed through the implementation of the 'leave-one-out' method in our sensitivity analysis. The findings from BWMR were in line with those obtained from IVW (BWMR: OR=1.030, 95% CI: 1.003-1.057, p = 0.029). Conclusions: The results from this study indicate a substantial and positive causal link between the regularity of tea drinking and the risk of depression onset. [ABSTRACT FROM AUTHOR]

Abstract Background The relationship between periodontitis and cardiovascular disease (CVD) has been extensively studied, but the role of biological aging in this relationship remains poorly understood. This study is dedicated to investigating the effect of periodontitis on the incidence of CVD and to elucidating the potential mediating role of biological aging. Furthermore, this study will seek to elucidate the causal association between periodontitis, CVD, and biological aging. Methods We included 3269 participants from the National Health and Nutrition Examination Survey (2009–2014) with diagnostic information on periodontitis and composite CVD events. Biological aging was evaluated by utilizing both the Klemera–Doubal method’s calculated biological age (KDMAge) and phenotypic age (PhenoAge). Logistic regression, restricted cubic spline (RCS) analysis, and subgroup analysis were used for data analysis. Mediation analysis was employed to explore the mediating role of biological aging. Subsequently, Mendelian randomization (MR) analyses were performed using genome-wide association study databases to explore potential causal relationships between periodontitis, CVD, and biological aging. Results Periodontitis was associated with a higher risk of CVD. Participants with periodontitis were found to have increased levels of biological aging, and elevated levels of biological aging were associated with increased CVD risk. Mediation analyses showed a partial mediating effect of biological aging (PhenoAge: 44.6%; KDMAge: 22.9%) between periodontitis and CVD risk. MR analysis showed that periodontitis played a causal role in increasing the risk of small vessel stroke, while myocardial infarction was found to increase the risk of periodontitis. In addition, reverse MR analysis showed that phenotypic aging can increase the risk of periodontitis, and there is a two-way causal relationship between CVD and biological aging. Conclusions Periodontitis is associated with an increased CVD risk, partially mediated by biological aging, with a complex causal interrelationship. Targeted interventions for periodontal health may slow the biological aging processes and reduce CVD risk.

Abstract Background While growing evidence suggests a relationship between migraine and cardiovascular disease, the genetic evidence for a causal relationship between migraine and cardiovascular disease is still scarce. Investigating the causal association between migraine and cardiovascular disease is vital. Methods We carried out a bidirectional Mendelian randomization (MR) study including discovery samples and replication samples using publicly available genome-wide association study (GWAS) summary datasets and stringent screening instrumental variables. Four different MR techniques—Inverse variance weighted (IVW), MR ‒Egger, weighted median, and weighted mode—as well as various sensitivity analyses—Cochran’s Q, IVW radial, leave-one-out (LOO), and MR-PRESSO—were utilized to investigate the causal relationship between cardiovascular disease and migraine. Results The protective causal effects of genetically predicted migraine on coronary artery disease (OR, 0.881; 95% CI 0.790–0.982; p = 0.023) and ischemic stroke (OR, 0.912; 95% CI 0.854–0.974; p = 0.006) were detected in forward MR analysis but not in any other cardiovascular disease. Consistently, we also discovered protective causal effects of coronary atherosclerosis (OR, 0.865; 95% CI 0.797–0.940; p = 0.001) and myocardial infarction (OR, 0.798; 95% CI 0.668–0.952; p = 0.012) on migraine in reverse MR analysis. Conclusion We found a potential protective effect of migraine on coronary artery disease and ischemic stroke and a potential protective effect of coronary atherosclerosis and myocardial infarction on migraine. We emphasised epidemiological and genetic differences and the need for long-term safety monitoring of migraine medications and future research to improve cardiovascular outcomes in migraine patients.

Objective To explore the bidirectional causal relationships between periodontitis and asthma using the two-sample Mendelian randomization (MR) method to provide a basis for exploring the etiology and formulating preventive and therapeutic measures of periodontitis and asthma. Methods We performed two-sample bidirectional Mendelian randomization analysis using publicly released European genome-wide association studies (GWAS) statistics for periodontitis (n = 34 615) and asthma (n = 408 422). The inverse variance weighted (IVW) method was employed as the main approach to estimate the bidirectional causal relationships between periodontitis and asthma. In addition, weighted median (WM), MR-Egger regression, maximum likelihood, and Mendelian randomization robust adjusted profile score (MR-RAPS) were used as supplementary analyses. Sensitivity analyses were conducted using Cochran's Q test, Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO), and leave-one-out analysis. Results A total of 12 and 43 single-nucleotide polymorphisms (SNPs) were included as instrumental variables for periodontitis and asthma, respectively. The results of IVW, WM, MR-Egger regression, maximum likelihood, and MR-RAPS showed that periodontitis was not causally related to the risk of asthma (IVW: OR: 1.003, 95% CI: 0.973-1.035, P = 0.828, WM: OR: 0.990, 95% CI: 0.951-1.031, P = 0.641; MR-Egger regression: OR: 0.988, 95% CI: 0.960-1.028, P = 0.573; maximum likelihood: OR: 1.003, 95% CI: 0.972-1.035, P = 0.834; MR-RAPS: OR: 1.002, 95% CI: 0.970-1.036, P = 0.890) among the European population, and no causal effect of asthma on periodontitis was found (IVW: OR: 1.021, 95% CI: 0.938-1.111, P = 0.633, WM: OR: 1.011, 95% CI: 0.894-1.142, P = 0.866; MR-Egger regression: OR: 1.042, 95% CI: 0.824-1.319, P = 0.731; maximum likelihood: OR: 1.021, 95% CI: 0.938-1.112, P = 0.631; MR-RAPS: OR: 1.017, 95% CI: 0.931-1.110, P = 0.713) among the European population. Cochran's Q test showed no heterogeneity among the included instrumental variables, MR-PRESSO test found no horizontal pleiotropy, and the leave-one-out method did not identify outlier SNPs. Conclusion The results of this study, based on European genetic data, do not support a bidirectional causal association between periodontitis and asthma in the European population.

Abstract Background Evidence suggests that coronavirus disease 2019 (COVID-19) is associated with the risk of cardiovascular diseases (CVDs). However, the results are inconsistent, and the causality remains to be established. We aimed to investigate the potential causal relationship between COVID-19 and CVDs by using two-sample Mendelian randomization (MR) analysis. Methods Summary‐level data for COVID-19 and CVDs including myocarditis, heart failure (HF), acute myocardial infarction (AMI), arrhythmia and venous thromboembolism (VTE) were obtained from the IEU OpenGWAS project, a public genome-wide association study (GWAS). Single nucleotide polymorphisms (SNPs) were used as instrumental variables. Five complementary MR methods were performed, including inverse variance weighted (IVW), MR-Egger, weighted median, weighted mode and simple mode methods. IVW method was considered as the primary approach. Besides, sensitivity analyses, including Cochran’s Q test, MR-Egger intercept test, and leave-one-out analysis, were performed to evaluate the robustness of the results. Results According to the IVW results, our MR study indicated that genetically predicted COVID-19 was not causally connected with the risk of CVDs [myocarditis: odds ratio (OR) = 1.407, 95% confidence interval (CI) = 0.761-2.602, p-value = 0.277; HF: OR = 1.180, 95% CI = 0.980-1.420, p-value = 0.080; AMI: OR = 1.002, 95% CI = 0.998-1.005, p-value = 0.241; arrhythmia: OR = 0.865, 95% CI = 0.717-1.044, p-value = 0.132; VTE: OR = 1.013, 95% CI = 0.997-1.028, p-value = 0.115]. The supplementary MR methods showed similar results. Sensitivity analyses suggested that the causal estimates were robust. Conclusion This two-sample MR analysis did not provide sufficient evidence for a causal relationship between COVID-19 and the risk of acute CVDs, which may provide new insights into the prevention of acute CVDs in COVID-19 patients.

Abstract Long-term mortality effects of particulate air pollution have been investigated in a causal analytic frame, while causal evidence for associations with gaseous air pollutants remains extensively lacking, especially for carbon monoxide (CO) and sulfur dioxide (SO2). In this study, we estimated the causal relationship of long-term exposure to nitrogen dioxide (NO2), CO, SO2, and ozone (O3) with mortality. Utilizing the data from National Morbidity, Mortality, and Air Pollution Study, we applied a variant of difference-in-differences (DID) method with conditional Poisson regression and generalized weighted quantile sum regression (gWQS) to investigate the independent and joint effects. Independent exposures to NO2, CO, and SO2 were causally associated with increased risks of total, nonaccidental, and cardiovascular mortality, while no evident associations with O3 were identified in the entire population. In gWQS analyses, an interquartile range-equivalent increase in mixture exposure was associated with a relative risk of 1.067 (95% confidence interval: 1.010–1.126) for total mortality, 1.067 (1.009–1.128) for nonaccidental mortality, and 1.125 (1.060–1.193) for cardiovascular mortality, where NO2 was identified as the most significant contributor to the overall effect. This nationwide DID analysis provided causal evidence for independent and combined effects of NO2, CO, SO2, and O3 on increased mortality risks among the US general population.

Abstract Background Neuropsychiatric disorders and cervical cancer exert substantial influences on women’s health. Furthermore, neuropsychiatric disorders frequently manifest as common symptoms in cancer patients, potentially increasing the risk of malignant neoplasms. This study aimed to identify neuropsychiatric disorders that are genetically and causally related to cervical cancer and to investigate the molecular mechanisms underlying these associations. Methods GWAS data related to nine neuropsychiatric disorders, namely, schizophrenia, bipolar disorder, autism spectrum disorder, Parkinson’s disease, anxiety, Alzheimer’s disease, mood disorders, depression, and alcohol dependence, were obtained to calculate heritability (h 2) and genetic correlation (rg) with cervical cancer using linkage disequilibrium score regression (LDSC). Mendelian randomization (MR) analysis of the two cohorts was employed to assess the causal effects. Shared gene expression pattern analysis was subsequently conducted to investigate the molecular mechanism underlying these significant associations. Results Anxiety, mood disorders, depression, and alcohol dependence were genetically correlated with cervical cancer (all adjusted P

Abstract Accumulating evidence from observational studies have suggested an association between gastroesophageal reflux disease (GERD) and non-alcoholic fatty liver disease (NAFLD). However, due to that such studies are prone to biases, we imported Mendelian randomization (MR) to explore whether the causal association between two diseases exsit. Hence, we aimed to analysis the potential association with MR. The single nucleotide polymorphisms (SNPs) of GERD were retrieved from the genome-wide association study dataset as the exposure. The SNPs of NAFLD were taken from the FinnGen dataset as the outcome. The relationship was analyzed with the assistance of inverse variance weighted, MR-Egger, and weighted median. We also uitilized the MR-Egger intercept, Cochran’s Q test, leave-one-out analysis, MR-PRESSO, and Steiger directionality test to evaluate the robustness of the causal association. The meta-analysis were also implemented to give an overall evaluation. Finally, our analysis showed a causal relationship between GERD and NAFLD with aid of MR and meta-analysis (OR 1.71 95% CI 1.40–2.09; P

Background: The understanding of the immunological mechanisms underlying bipolar disorder (BD) has enhanced in recent years due to the extensive use of high-density genetic markers for genotyping and advancements in genome-wide association studies (GWAS). However, studies on the relationship between immune cells and the risk of BD remain limited, necessitating further investigation. Methods: Bidirectional two-sample Mendelian Randomization (MR) analysis was employed to investigate the causal association between immune cell morphologies and bipolar disorder. Immune cell traits were collected from a research cohort in Sardinia, whereas the GWAS summary statistics for BD were obtained from the Psychiatric Genomics Consortium. Sensitivity analyses were conducted, and the combination of MR-Egger and MR-Presso was used to assess horizontal pleiotropy. Cochran’s Q test was employed to evaluate heterogeneity, and the results were adjusted for false discovery rate (FDR). Results: The study identified six immune cell phenotypes significantly associated with BD incidence (P< 0.01). These phenotypes include IgD- CD27- % lymphocyte, CD33br HLA DR+ CD14- AC, CD8 on CD28+ CD45RA+ CD8br, CD33br HLA DR+ AC, CD14 on CD14+ CD16+ monocyte, and HVEM on CD45RA- CD4+. After adjusting the FDR to 0.2, two immune cell phenotypes remained statistically significant: IgD-CD27-% lymphocyte (OR=1.099, 95% CI: 1.051-1.149, P = 3.51E-05, FDR=0.026) and CD33br HLA DR+ CD14-AC (OR=0.981, 95% CI: 0.971-0.991, P = 2.17E-04, FDR=0.079). In the reverse MR analysis, BD significantly impacted the phenotypes of four monocytes (P< 0.01), including CD64 on CD14+ CD16+ monocyte, CD64 on monocyte, CX3CR1 on CD14- CD16-, CD64 on CD14+ CD16- monocyte. However, after applying the FDR correction (FDR < 0.2), no statistically significant results were observed. Conclusions: This MR investigation reveals associations between immune cell phenotypes, bipolar disorder, and genetics, providing novel perspectives on prospective therapeutic targets for bipolar disorder. [ABSTRACT FROM AUTHOR]

Introduction: A growing body of research has shown a strong connection between circulating inflammatory proteins and Peripheral artery disease (PAD). However, the causal relationship between circulating inflammatory proteins and PAD is still not fully understood. To investigate this association, we conducted a bidirectional Mendelian randomization study. Materials and methods: Our study utilized genetic variation data obtained from genome-wide association studies (GWAS) datasets. Specifically, the GWAS dataset related to PAD (identifier: finn-b-I9&lowbar;PAD) included 7,098 cases and 206,541 controls. Additionally, we extracted data on 91 inflammatory proteins from another GWAS dataset (identifiers: GCST90274758-GCST90274848), involving 14,824 participants. To assess the causal relationship between circulating inflammatory proteins and PAD development, we employed methodologies such as inverse variance weighting (IVW), MR Egger regression, and the weighted median approach. Furthermore, sensitivity analyses were conducted to ensure the reliability and robustness of our findings. Results: Two inflammatory proteins were found to be significantly associated with PAD risk: Natural killer cell receptor 2B4 levels (OR, 1.219; 95% CI,1.019~1.457; P=0.03), Fractalkine levels (OR, 0.755; 95% CI=0.591~0.965; P=0.025). PAD had statistically significant effects on 12 inflammatory proteins: C-C motif chemokine 19 levels (OR, 0.714; 95% CI, 0.585 to 0.872; P=0.001), T-cell surface glycoprotein CD5 levels (OR, 0.818; 95% CI, 0.713 to 0.938; P=0.004), CUB domain-containing protein 1 levels (OR, 0.889; 95% CI, 0.809 to 0.977; P=0.015), Fibroblast growth factor 23 levels (OR, 1.129; 95% CI, 1.009 to 1.264; P=0.034), Interferon gamma levels (OR, 1.124; 95% CI, (1.011 to 1.250); P=0.031),Interleukin-15 receptor subunit alpha levels (OR, 1.183; 95% CI,(1.005 to 1.392); P=0.044), Interleukin-17C levels (OR,1.186; 95% CI, (1.048 to 1.342); P=0.007), Interleukin-1-alpha levels (OR, 1.349; 95% CI, (1.032 to 1.765); P=0.029), Interleukin-5 levels (OR, 1.119; 95% CI,(1.003 to 1.248); P=0.043), Latency-associated peptide transforming growth factor beta 1 levels (OR,1.123; 95% CI, (1.020 to 1.236); P=0.018), Matrix metalloproteinase-10 levels (OR, 1.119; 95% CI,(1.015 to 1.233); P=0.024), Signaling lymphocytic activation molecule levels (OR, 0.823; 95% CI, (0.693 to 0.978); P=0.027). Conclusion: Our research expands on genetic studies exploring the strong association between circulating inflammatory proteins and PAD. This discovery has the potential to inform and shape future clinical and basic research endeavors in this area. [ABSTRACT FROM AUTHOR]

Background: The relationship between periodontitis and cardiovascular disease (CVD) has been extensively studied, but the role of biological aging in this relationship remains poorly understood. This study is dedicated to investigating the effect of periodontitis on the incidence of CVD and to elucidating the potential mediating role of biological aging. Furthermore, this study will seek to elucidate the causal association between periodontitis, CVD, and biological aging. Methods: We included 3269 participants from the National Health and Nutrition Examination Survey (2009–2014) with diagnostic information on periodontitis and composite CVD events. Biological aging was evaluated by utilizing both the Klemera–Doubal method's calculated biological age (KDMAge) and phenotypic age (PhenoAge). Logistic regression, restricted cubic spline (RCS) analysis, and subgroup analysis were used for data analysis. Mediation analysis was employed to explore the mediating role of biological aging. Subsequently, Mendelian randomization (MR) analyses were performed using genome-wide association study databases to explore potential causal relationships between periodontitis, CVD, and biological aging. Results: Periodontitis was associated with a higher risk of CVD. Participants with periodontitis were found to have increased levels of biological aging, and elevated levels of biological aging were associated with increased CVD risk. Mediation analyses showed a partial mediating effect of biological aging (PhenoAge: 44.6%; KDMAge: 22.9%) between periodontitis and CVD risk. MR analysis showed that periodontitis played a causal role in increasing the risk of small vessel stroke, while myocardial infarction was found to increase the risk of periodontitis. In addition, reverse MR analysis showed that phenotypic aging can increase the risk of periodontitis, and there is a two-way causal relationship between CVD and biological aging. Conclusions: Periodontitis is associated with an increased CVD risk, partially mediated by biological aging, with a complex causal interrelationship. Targeted interventions for periodontal health may slow the biological aging processes and reduce CVD risk. [ABSTRACT FROM AUTHOR]

Objective: Emerging evidence suggests alterations in gut microbiota (GM) composition following thyroid nodules (TNs) development, yet the causal relationship remains unclear. Utilizing Mendelian Randomization (MR), this study aims to elucidate the causal dynamics between GM and TNs. Methods: Employing summary statistics from the MiBioGen consortium (n=18,340) and FinnGen consortium (1,634 TNs cases, 263,704 controls), we conducted univariable and multivariable MR analyses to explore the GM-TNs association. Techniques including inverse variance weighted, MR-Egger regression, weighted median, and MR-PRESSO were utilized for causal inference. Instrumental variable heterogeneity was assessed through Cochran's Q statistic and leave-one-out analysis. Reverse MR was applied for taxa showing significant forward MR associations, with multivariate adjustments for confounders. Results: Our findings suggest that certain microbiota, identified as Ruminococcaceae&lowbar;NK4A214&lowbar;group (OR, 1.89; 95%CI, 0.47-7.64; p = 0.040), Senegalimassilia (OR, 1.72; 95%CI, 1.03-2.87; p =0.037), Lachnospiraceae (OR,0.64; 95%CI,0.41-0.99; p =0.045), exhibit a protective influence against TNs' development, indicated by negative causal associations. In contrast, microbiota categorized as Desulfovibrionales (OR, 0.63; 95%CI, 0.41-0.95; p =0.028), Prevotella&lowbar;7 (OR, 0.79; 95%CI, 0.63-1.00; p =0.049), Faecalibacterium (OR, 0.66; 95%CI, 0.44-1.00; p =0.050), Desulfovibrionaceae (OR, 0.55; 95%CI, 0.35-0.86; p =0.008), Deltaproteobacteria (OR, 0.65; 95%CI, 0.43-0.97; p =0.036) are have a positive correlation with with TNs, suggesting they may serve as risk factors. Reverse MR analyses did not establish significant causal links. After comprehensive adjustment for confounders, taxa Desulfovibrionales (Order), Desulfovibrionaceae (Family), Deltaproteobacteria (Class) remain implicated as potential contributors to TNs' risk. Discussion: This study substantiates a significant causal link between GM composition and TNs development, underscoring the thyroid-gut axis's relevance. The findings advocate for the integration of GM profiles in TNs' prevention and management, offering a foundation for future research in this domain. [ABSTRACT FROM AUTHOR]

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Background: Growing evidence indicates a potential association between the gut microbiome and psoriasis. Nevertheless, the precise nature of these associations and whether they constitute causal relationships remain unclear. Methods: A rigorous bidirectional two-sample Mendelian randomization study was undertaken to establish a putative causal link between gut microbiota and psoriasis. We drew upon publicly available datasets containing summary statistics from GWAS to accomplish this. Utilizing various analytical techniques, including inverse variance weighting, MR-Egger, weighted median, weighted model, and MR-PRESSO, we sought to validate the putative causal association between gut microbiota and psoriasis. A reverse Mendelian randomization analysis was conducted to further investigate the relationship. Results: After conducting a forward Mendelian randomization analysis, a causal relationship was established between 19 gut microbiota and psoriasis. Furthermore, the reverse MR study revealed causality between psoriasis and 13 gut microbiota. Notably, no substantial heterogeneity of instrumental variables or horizontal pleiotropy was observed. Conclusion: This research suggests a potential genetic association and causal nexus between gut microorganisms and psoriasis, indicating potential implications for the clinical management and therapy of psoriasis. Additional observational studies with a larger population sample size and animal model experiments are imperative to fully elucidate this association's underlying mechanisms. [ABSTRACT FROM AUTHOR]

Background: While growing evidence suggests a relationship between migraine and cardiovascular disease, the genetic evidence for a causal relationship between migraine and cardiovascular disease is still scarce. Investigating the causal association between migraine and cardiovascular disease is vital. Methods: We carried out a bidirectional Mendelian randomization (MR) study including discovery samples and replication samples using publicly available genome-wide association study (GWAS) summary datasets and stringent screening instrumental variables. Four different MR techniques—Inverse variance weighted (IVW), MR ‒Egger, weighted median, and weighted mode—as well as various sensitivity analyses—Cochran's Q, IVW radial, leave-one-out (LOO), and MR-PRESSO—were utilized to investigate the causal relationship between cardiovascular disease and migraine. Results: The protective causal effects of genetically predicted migraine on coronary artery disease (OR, 0.881; 95% CI 0.790–0.982; p = 0.023) and ischemic stroke (OR, 0.912; 95% CI 0.854–0.974; p = 0.006) were detected in forward MR analysis but not in any other cardiovascular disease. Consistently, we also discovered protective causal effects of coronary atherosclerosis (OR, 0.865; 95% CI 0.797–0.940; p = 0.001) and myocardial infarction (OR, 0.798; 95% CI 0.668–0.952; p = 0.012) on migraine in reverse MR analysis. Conclusion: We found a potential protective effect of migraine on coronary artery disease and ischemic stroke and a potential protective effect of coronary atherosclerosis and myocardial infarction on migraine. We emphasised epidemiological and genetic differences and the need for long-term safety monitoring of migraine medications and future research to improve cardiovascular outcomes in migraine patients. [ABSTRACT FROM AUTHOR]

Background: Previous observational studies have revealed the strong relationship between fatty acids (FA) and inflammatory bowel disease (IBD). Nonetheless, due to the inherent limitations of retrospective research, the causality between the two has not been clearly established. Methods: Genetic variants associated with the 17 FA indicators were derived from genome-wide association studies. Summary statistics for the discovery cohort and testing cohort for IBD, including ulcerative colitis (UC) and Crohn's disease (CD), were available from IIBDGC and FinnGen, respectively. Bidirectional MR analysis and sensitivity analysis with multiple measures were applied to comprehensively investigate the causal link between FA and IBD. Results: Combining the results of various MR methods, the validation of testing cohort, and the merging of meta-analysis, we demonstrated that genetically predicted Omega-3 FA levels, Ratio of Omega-3 FA to total FA, Docosahexaenoic acid (DHA) levels, and Ratio of DHA to total FA reduced the risk of IBD, UC, and CD. Meanwhile, multivariate MR suggested that the risk effects of Omega-3 FA and DHA for UC and CD were mainly affected by Saturated FA and Monounsaturated fatty acid (MUFA). Furthermore, although there was the causal association between Ratio of MUFA to total FA as well as Ratio of Polyunsaturated fatty acid (PUFA) to MUFA and CD, sensitivity analysis prompted that the findings were not robust. None of the above results had a reverse causal effect. Conclusion: This MR investigation provided evidence of causality between diverse FA and IBD. These findings offered new insights into the treatment and prevention of IBD. [ABSTRACT FROM AUTHOR]

Background and purpose: The causal association between inflammatory cytokines and the development of intracranial aneurysm (IA), unruptured IA (uIA) and subarachnoid hemorrhage (SAH) lacks clarity. Methods: The summary‐level datasets for inflammatory cytokines were extracted from a genome‐wide association study of the Finnish Cardiovascular Risk in Young Adults Study and the FINRISK survey. The summary statistics datasets related to IA, uIA and SAH were obtained from the genome‐wide association study meta‐analysis of the International Stroke Genetics Consortium and FinnGen Consortium. The primary method employed for analysis was inverse variance weighting (false discovery rate), supplemented by sensitivity analyses to address pleiotropy and enhance robustness. Results: In the International Stroke Genetics Consortium, 10, six and eight inflammatory cytokines exhibited a causal association with IA, uIA and SAH, respectively (false discovery rate, p < 0.05). In FinnGen datasets, macrophage Inflammatory Protein‐1 Alpha (MIP_1A), MIP_1A and interferon γ‐induced protein 10 (IP_10) were verified for IA, uIA and SAH, respectively. In the reverse Mendelian randomization analysis, the common cytokines altered by uIA and SAH were vascular endothelial growth factor (VEGF), MIP_1A, IL_9, IL_10 and IL_17, respectively. The meta‐analysis results show that MIP_1A and IP_10 could be associated with the decreased risk of IA, and MIP_1A and IP_10 were associated with the decreased risk of uIA and SAH, respectively. Notably, the levels of VEGF, MIP_1A, IL_9, IL_10 and TNF_A were increased with uIA. Comprehensive heterogeneity and pleiotropy analyses confirmed the robustness of these results. Conclusion: Our study unveils a bidirectional association between inflammatory cytokines and IA, uIA and SAH. Further investigations are essential to validate their relationship and elucidate the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Background: Observational research suggests that hypotension is a potential hazard factor of delirium. Nevertheless, previous observational articles are limited in their ability to establish causality between hypotension and delirium. The present study was sought to explore the genetic causal relationship between these two conditions using two-sample Mendelian randomization (MR). Methods: Genome-wide association study (GWAS) summarized data for hypotension and delirium were obtained from the FinnGen Consortium. The researchers utilized several statistical methods, such as inverse-variance weighted (IVW), weighted median, MR Egger, weighted mode, and simple mode in conducting the MR statistical analysis. In order to identify heterogeneity among the MR outcomes, we employed the Cochrane's Q test. Furthermore, we used the MR-Egger intercept test and MR pleiotropy residual sum and outliers (MR-PRESSO) test to examine horizontal pleiotropy. Results: The findings revealed that hypotension was identified as an independent hazard variable for delirium (p = 0.010, odds ratio [OR] [95% confidence interval (CI)] = 1.302 [1.066-1.592]) using the IVW method. The presence of horizontal pleiotropy was found to have minimal impact on establishing causal relationship (p = 0.999), and there was no evidence to suggest heterogeneity between genetic variations (p = 0.379). Additionally, the leave-one-out method demonstrated the stability and robustness of this association. Conclusion: We performed two-sample MR analyses and found evidence of a genetic causal relationship between hypotension and delirium. Our findings suggest that individuals with a genetic predisposition for hypotension may have a higher risk of developing delirium. This suggests that interventions aimed at improving perioperative hypotension could aid in limiting the incidence of delirium. [ABSTRACT FROM AUTHOR]

Background: Cerebral aneurysm is a high-risk cerebrovascular disease with a poor prognosis, potentially linked to multiple factors. This study aims to explore the association between mitochondrial-associated proteins and the risk of cerebral aneurysms using Mendelian randomization (MR) methods. Methods: We used GWAS summary statistics from the IEU Open GWAS project for mitochondrial-associated proteins and from the Finnish database for cerebral aneurysms (uIA, aSAH). The association between mitochondrial-associated exposures and cerebral aneurysms was evaluated using MR-Egger, weighted mode, IVW, simple mode and weighted median methods. Reverse MR assessed reverse causal relationship, while sensitivity analyses examined heterogeneity and pleiotropy in the instrumental variables. Significant causal relationship with cerebral aneurysms were confirmed using FDR correction. Results: Through MR analysis, we identified six mitochondrial proteins associated with an increased risk of aSAH: AIF1 (OR: 1.394, 95% CI: 1.109-1.752, p = 0.0044), CCDC90B (OR: 1.318, 95% CI: 1.132-1.535, p = 0.0004), TIM14 (OR: 1.272, 95% CI: 1.041-1.553, p = 0.0186), NAGS (OR: 1.219, 95% CI: 1.008-1.475, p = 0.041), tRNA PusA (OR: 1.311, 95% CI: 1.096-1.569, p = 0.003), and MRM3 (OR: 1.097, 95% CI: 1.016-1.185, p = 0.0175). Among these, CCDC90B, tRNA PusA, and AIF1 demonstrated a significant causal relationship with an increased risk of aSAH (FDR q < 0.1). Three mitochondrial proteins were associated with an increased risk of uIA: CCDC90B (OR: 1.309, 95% CI: 1.05-1.632, p = 0.0165), tRNA PusA (OR: 1.306, 95% CI: 1.007-1.694, p = 0.0438), and MRM3 (OR: 1.13, 95% CI: 1.012-1.263, p = 0.0303). In the reverse MR study, only one mitochondrial protein, TIM14 (OR: 1.087, 95% CI: 1.004-1.177, p = 0.04), showed a causal relationship with aSAH. Sensitivity analysis did not reveal heterogeneity or pleiotropy. The results suggest that CCDC90B, tRNA PusA, and MRM3 may be common risk factors for cerebral aneurysms (ruptured and unruptured), while AIF1 and NAGS are specifically associated with an increased risk of aSAH, unrelated to uIA. TIM14 may interact with aSAH. Conclusion: Our findings confirm a causal relationship between mitochondrialassociated proteins and cerebral aneurysms, offering new insights for future research into the pathogenesis and treatment of this condition. [ABSTRACT FROM AUTHOR]

Background: Micronutrient levels play a critical role in epilepsy. This study investigates the impact of micronutrient levels on epilepsy via Mendelian randomization (MR). Methods: A two-sample MR framework evaluated the genetic association between 15 serum micronutrients and epilepsy phenotypes. The analysis included calcium, iron, zinc, selenium, copper, magnesium, potassium, folate, vitamins B6, B12, C, D, E, retinol, and carotene against all epilepsy, generalized epilepsy, childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), generalized tonic-clonic seizures alone and with spike-wave electroencephalography (GTCS), and various focal epilepsy phenotypes [with hippocampal sclerosis (HS), lesions other than HS, lesionnegative]. The random-effects inverse-variance weighted (IVW) model was the primary method used, supported by heterogeneity and pleiotropy assessments. Multivariable Mendelian randomization analyses (MVMR) were used to identify micronutrients that are significantly causally associated with different epilepsy subtypes and to confirm the most potential causal risk factors for these subtypes. Results: Zinc conferred an increased risk of focal epilepsy with HS (OR = 1.01; p = 0.045). Carotene was similarly linked to higher risks of lesion-negative cases (OR = 1.129; p = 0.037). Conversely, vitamin B6 was associated with reduced risks of focal epilepsy with HS (OR = 0.949; p = 0.020), and vitamin D was linked to decreased risks of both CAE (OR = 0.976, 95% CI: 0.959-0.993, p = 0.006) and JAE (OR = 0.986, 95% CI: 0.973-0.999, p = 0.032). These associations were robust, showing minimal heterogeneity and no evidence of pleiotropy across various sensitivity analyses. After adjustment using MVMR, significant causal relationships between vitamin D and both CAE and JAE remained. Furthermore, the causal relationship between zinc and vitamin B6 on focal epilepsy with HS became non-significant, while carotene shifted from a risk factor to a protective factor for focal epilepsy lesion-negative after adjusting for vitamin D. Conclusion: MR estimates provide robust evidence for the causal effects of vitamin D on reducing the risk of CAE, and JAE, which might provide alternative treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence suggests a robust correlation between the gut microbiome and alopecia areata. In light of the extensive diversity of gut microbiota, this study aims to utilize state-of-the-art and comprehensive data to explore the causative association between gut microbiota and alopecia areata. Objective: We conducted a Mendelian randomization (MR)-based two-sample study to elucidate the causal relationship between gut microbiota and alopecia areata. Method: Summary information on Ncase = 767 and Ncontrol = 394,105 cases of alopecia areata was obtained from the FinnGen study. A total of 473 gut microbial taxa were summarized from the genome-wide association study (GWAS) catalog. The study comprised a forward Mendelian randomization (MR) analysis with the gut microbiome as the exposure factor and alopecia areata as the outcome, as well as a reverse MR analysis with alopecia areata as the exposure factor and the gut microbiome as the outcome. Various analytical methods including inverse variance weighting (IVW), Weighted Median, MR-Egger, Weighted Mode, and Simple Mode were employed. Subsequently, sensitivity analysis was conducted to ensure the robustness of our research findings. Result: This study has established a causal relationship between gut microbiota and alopecia areata. Forward causal analysis revealed causality relationships between 16 gut microbial taxa and alopecia areata, while reverse causal analysis found that there may be a causal relationship between alopecia areata and 16 gut microbial taxa (not statistically significant). Conclusion: Our study findings suggest a causal relationship between gut microbiota and alopecia areata, providing potential guidance for future clinical trials. [ABSTRACT FROM AUTHOR]

Background: Evidence suggests that coronavirus disease 2019 (COVID-19) is associated with the risk of cardiovascular diseases (CVDs). However, the results are inconsistent, and the causality remains to be established. We aimed to investigate the potential causal relationship between COVID-19 and CVDs by using two-sample Mendelian randomization (MR) analysis. Methods: Summary‐level data for COVID-19 and CVDs including myocarditis, heart failure (HF), acute myocardial infarction (AMI), arrhythmia and venous thromboembolism (VTE) were obtained from the IEU OpenGWAS project, a public genome-wide association study (GWAS). Single nucleotide polymorphisms (SNPs) were used as instrumental variables. Five complementary MR methods were performed, including inverse variance weighted (IVW), MR-Egger, weighted median, weighted mode and simple mode methods. IVW method was considered as the primary approach. Besides, sensitivity analyses, including Cochran's Q test, MR-Egger intercept test, and leave-one-out analysis, were performed to evaluate the robustness of the results. Results: According to the IVW results, our MR study indicated that genetically predicted COVID-19 was not causally connected with the risk of CVDs [myocarditis: odds ratio (OR) = 1.407, 95% confidence interval (CI) = 0.761-2.602, p-value = 0.277; HF: OR = 1.180, 95% CI = 0.980-1.420, p-value = 0.080; AMI: OR = 1.002, 95% CI = 0.998-1.005, p-value = 0.241; arrhythmia: OR = 0.865, 95% CI = 0.717-1.044, p-value = 0.132; VTE: OR = 1.013, 95% CI = 0.997-1.028, p-value = 0.115]. The supplementary MR methods showed similar results. Sensitivity analyses suggested that the causal estimates were robust. Conclusion: This two-sample MR analysis did not provide sufficient evidence for a causal relationship between COVID-19 and the risk of acute CVDs, which may provide new insights into the prevention of acute CVDs in COVID-19 patients. [ABSTRACT FROM AUTHOR]

Background: Uveitis, characterized by inflammation of the iris, ciliary body, and choroid, presents a significant global clinical challenge, contributing substantially to visual impairment. Risk factors include autoimmune diseases and immune cell dysfunctions, yet many remain unidentified. Immune cells, notably T cells, B cells, and monocytes, play pivotal roles in uveitis pathogenesis. While biologic agents show promise, comprehensive studies on immune cell types in ocular diseases are lacking. Genome-wide association studies (GWAS) and Mendelian randomization MR) present promising avenues to elucidate genetic susceptibilities and causal relationships between immune cell traits and uveitis risk. Methods: Two-sample MR analysis was used to evaluate the causal relationship between 731 immune cells and uveitis, and genome-wide significance analysis was performed for genetic variation in 731 immune cells traits (P < 5 x 10-8). Immune characteristics include median fluorescence intensity (MFI), relative cell counts (RC), absolute cell counts (AC), and morphological parameters (MP), which were determined by published GWAS, and public data from the IEU Open GWAS database. The main analysis method of MR is inverse variance weighting IVW). Heterogeneity and horizontal pleiotropy were also assessed. Results: 5 immunophenotypes, including CD62L-DC %DC, IgD+ CD38dim %B cell, CD3 on CM CD4+T cell, CD3 on CD45RA-CD4 +T cell, and CD3 on CD39+ CD4+ Treg may increase the risk of uveitis. 5 immunophenotypes, including CD11b on CD33dim HLA DR-Myeloid cell, HLA DR on CD33dim HLA DR+ CD11b-myeloid cell, CD14-CD16 + %monocyte, HLA DR on CD14-CD16 + monocyte and PDL-1 on CD14-CD16 + monocyte was negatively associated with the risk of uveitis. Among them, HLA DR on CD14-CD16 + monocyte (OR=0.921, 95%CI =0.875-0.970, P=0.001) and HLA DR on CD33dim HLA DR+ CD11b- (OR=0.879, 95%CI = 0.833- 0.927, P=0.00) were negatively associated with the risk of uveitis in bi-direction. Conclusion: These results indicate that 10 immune cells traits are significantly associated with the risk of developing uveitis and 2 of them were strongly associated with uveitis bi-directionally, after excluding the effects of confounding factors such as some immune diseases, which provided new ideas and therapeutic targets for the study of immune mechanism of uveitis. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to explore the potential causal associations between serum uric acid (SUA) and the risk of colorectal cancer, colon cancer and rectal cancer. Methods: Twenty-six SUA-related single nucleotide polymorphisms which were identified by a large meta-analysis of genome-wide association studies (GWASs) were used as instrumental variables in the two-sample Mendelian randomization (MR) study. Meta-analyses were used to synthesize the results of multiple GWASs which were extracted from the MRC Integrative Epidemiology Unit GWAS database for each type of cancer. The inverse variance weighted (IVW) method was used as the primary MR method to analyze the association between SUA and colorectal cancer risk. Several sensitivity analyses were performed to test the robustness of results. Results: The IVW method showed that there were no causal relationships between SUA and the risk of colorectal cancer [odds ratio (OR): 1.0015; 95% confidence interval (CI): 0.9975-1.0056] and colon cancer (OR: 1.0015; 95% CI: 0.9974-1.0055). The SUA levels were negative correlated with rectal cancer risk (OR: 0.9984; 95% CI: 0.9971-0.9998). The similar results were observed in both males (OR: 0.9987; 95% CI: 0.9975-0.9998) and females (OR: 0.9985; 95% CI: 0.9971-0.9999). The sensitivity analyses suggested no evidence of heterogeneity or horizontal pleiotropy. The leave-one-out analyses showed that one SNP (rs1471633) significantly drove the causal effect of SUA on rectal cancer risk. The MR-Egger regression and weighted median both showed that there were no causal relationships between SUA and the risk of colorectal cancer and its subtypes. Conclusion: Overall, there was no linear causal association between SUA and the risk of colorectal cancer. However, further research is needed to investigate the role of higher SUA levels such as hyperuricemia or gout in the occurrence of colorectal cancer. [ABSTRACT FROM AUTHOR]

Long-term mortality effects of particulate air pollution have been investigated in a causal analytic frame, while causal evidence for associations with gaseous air pollutants remains extensively lacking, especially for carbon monoxide (CO) and sulfur dioxide (SO2). In this study, we estimated the causal relationship of long-term exposure to nitrogen dioxide (NO2), CO, SO2, and ozone (O3) with mortality. Utilizing the data from National Morbidity, Mortality, and Air Pollution Study, we applied a variant of difference-in-differences (DID) method with conditional Poisson regression and generalized weighted quantile sum regression (gWQS) to investigate the independent and joint effects. Independent exposures to NO2, CO, and SO2 were causally associated with increased risks of total, nonaccidental, and cardiovascular mortality, while no evident associations with O3 were identified in the entire population. In gWQS analyses, an interquartile range-equivalent increase in mixture exposure was associated with a relative risk of 1.067 (95% confidence interval: 1.010–1.126) for total mortality, 1.067 (1.009–1.128) for nonaccidental mortality, and 1.125 (1.060–1.193) for cardiovascular mortality, where NO2 was identified as the most significant contributor to the overall effect. This nationwide DID analysis provided causal evidence for independent and combined effects of NO2, CO, SO2, and O3 on increased mortality risks among the US general population. [ABSTRACT FROM AUTHOR]

Background: Neuropsychiatric disorders and cervical cancer exert substantial influences on women's health. Furthermore, neuropsychiatric disorders frequently manifest as common symptoms in cancer patients, potentially increasing the risk of malignant neoplasms. This study aimed to identify neuropsychiatric disorders that are genetically and causally related to cervical cancer and to investigate the molecular mechanisms underlying these associations. Methods: GWAS data related to nine neuropsychiatric disorders, namely, schizophrenia, bipolar disorder, autism spectrum disorder, Parkinson's disease, anxiety, Alzheimer's disease, mood disorders, depression, and alcohol dependence, were obtained to calculate heritability (h2) and genetic correlation (rg) with cervical cancer using linkage disequilibrium score regression (LDSC). Mendelian randomization (MR) analysis of the two cohorts was employed to assess the causal effects. Shared gene expression pattern analysis was subsequently conducted to investigate the molecular mechanism underlying these significant associations. Results: Anxiety, mood disorders, depression, and alcohol dependence were genetically correlated with cervical cancer (all adjusted P < 0.05). Only depression was causally related to cervical cancer in both the discovery (ORIVW: 1.41, PIVW = 0.02) and replication cohorts (ORIVW: 1.80, PIVW = 0.03) in the MR analysis. Gene expression pattern analysis revealed that 270 genes related to depression and cervical cancer, including tumour necrosis factor (TNF), were significantly upregulated in cervical cancer patients, while vascular endothelial growth factor A (VEGFA), transcription factor AP-1 (JUN), and insulin-like growth factor I (IGF-I) were associated with prognosis in cervical cancer patients (all P < 0.05). These overlapping genes implicated the involvement of multiple biological mechanisms, such as neuron death, the PI3K-Akt signalling pathway, and human papillomavirus infection. Conclusions: Genetic, causal and molecular evidence indicates that depression increases the risk of cervical cancer. The TNF, VEGFA, JUN, and IGF-1 genes and the neuron death, PI3K-Akt, and human papillomavirus infection signalling pathways may possibly explain this association. [ABSTRACT FROM AUTHOR]

Background: Former research has emphasized a correlation between lung cancer (LC) and sepsis, but the causative link remains unclear. Method: This study used univariate Mendelian Randomization (MR) to explore the causal relationship between LC, its subtypes, and sepsis. Linkage Disequilibrium Score (LDSC) regression was used to calculate genetic correlations. Multivariate MR was applied to investigate the role of seven confounding factors. The primary method utilized was inverse-variance-weighted (IVW), supplemented by sensitivity analyses to assess directionality, heterogeneity, and result robustness. Results: LDSC analysis revealed a significant genetic correlation between LC and sepsis (genetic correlation = 0.325, p = 0.014). Following false discovery rate (FDR) correction, strong evidence suggested that genetically predicted LC (OR = 1.172, 95% CI 1.083-1.269, p = 8.29 × 10-5, Pfdr = 2.49 × 10-4), squamous cell lung carcinoma (OR = 1.098, 95% CI 1.021-1.181, p = 0.012, Pfdr = 0.012), and lung adenocarcinoma (OR = 1.098, 95% CI 1.024-1.178, p = 0.009, Pfdr = 0.012) are linked to an increased incidence of sepsis. Suggestive evidence was also found for small cell lung carcinoma (Wald ratio: OR = 1.156, 95% CI 1.047-1.277, p = 0.004) in relation to sepsis. The multivariate MR suggested that the partial impact of all LC subtypes on sepsis might be mediated through body mass index. Reverse analysis did not find a causal relationship (p > 0.05 and Pfdr > 0.05). Conclusion: The study suggests a causative link between LC and increased sepsis risk, underscoring the need for integrated sepsis management in LC patients. [ABSTRACT FROM AUTHOR]

Background: The relationship between blood lipids, lipid-modifying medications, and cancer risk has been under investigation for some time. Recent studies suggest that lipid-lowering medications might influence melanoma outcomes, though findings remain controversial. Our study aims to clarify the potential causal relationship between lipid-lowering drugs commonly used and melanoma incidence through a comprehensive Mendelian randomization (MR) analysis. Methods: Genetic variations within an LDL-related drug target gene (LDLcholesterol from a genome-wide association study) served as proxies for exposure to lipid-lowering drugs. We conducted a two-sample Mendelian randomization analysis using inverse variance weighting (IVW), MR-Egger, and weighted median approaches. The MR-PRESSO test and pleiotropy_test were utilized to identify and adjust for horizontal pleiotropy. Stability and reliability of the Mendelian randomization findings were assessed using the leave-one-out method, Cochran's Q test, and funnel plot analysis. Odds ratios (OR) were employed to evaluate the causal relationship between genetic proxies of lipidlowering drugs and melanoma risk. Results: IVW analysis revealed that HMGCR gene expression is linked to a decreased risk of melanoma [OR: 0.624(0.439-0.888); p = 0.008]. Conversely, PCSK9 gene expression is tied to an elevated risk of melanoma [OR: 1.233(1.026-1.484); p = 0.025]. No significant association was observed between NPC1L1 and melanoma. Conclusions: HMGCR inhibitors (statins) may increase melanoma risk, while PCSK9 inhibitors (evolocumab, alirocumab) could potentially decrease melanoma risk. [ABSTRACT FROM AUTHOR]

Prior studies suggested that vitamin E might be beneficial in alleviating atopic dermatitis, but confirming a causal link was hindered by limitations such as sample sizes and unaccounted confounders. The present study aimed to clarify this through Mendelian randomization (MR) analysis. GWAS summary statistics was obtained from public databases encompassing a study on vitamin E and two studies related to atopic dermatitis. Two sets of instrumental variables (IVs) were selected using lenient (p < 1e‐5) and strict (p < 5e‐6) thresholds for separate MR analyses. Inverse variance weighted (IVW) was used as the primary MR method, supplemented by six additional MR methods, and followed by a meta‐analysis to consolidate the impact of vitamin E on atopic dermatitis from two independent studies. Furthermore, various sensitivity tests were performed to assess the reliability of the MR results. A meta‐analysis of IVW analyses deriving from two different atopic dermatitis cohorts under lenient IV selection thresholds demonstrated that vitamin E exhibited a significant lowering risk of atopic dermatitis effect (OR = 0.817, 95% CI: 0.673–0.991, p =.041), which was validated under strict IV selection thresholds (OR = 0.822, 95% CI: 0.709–0.954, p =.010). In addition, six other MR methods remained parallel to IVW (OR > 1). Multiple sensitivity tests showed that MR analyses were not affected by heterogeneity and horizontal pleiotropy. Overall, this MR study supported vitamin E reducing the risk of atopic dermatitis. Consequently, maintaining an adequate intake of vitamin E could potentially serve as an effective preventive measure against atopic dermatitis. [ABSTRACT FROM AUTHOR]

The goal was to explore the effect of interleukin-6 (IL6) and C reactive protein (CRP) on malignant melanoma (MM) using two-sample Mendelian randomization. Methods: Data for this study were obtained from the IEU Open GWAS project website for genome-wide association study data (GWAS) on interleukin-6, C reactive protein levels and malignant melanoma. Inverse variance weighted (IVW) method was mainly used and supplemented with MR-Egger regression and weighted median. Finally, horizontal multivariate validity and heterogeneity tests were performed to assess the stability and reliability of the results. Results: The results of univariate two-sample MR analyses showed no significant effect of CRP on MM: inverse variance weighting method (OR=0.999, 95% CI: 0.998-1.001, P=0.343), MR-Egger regression (OR= 1.000, 95% CI: 0.998-1.001, P= 0.180), and weighted median method (OR= 0.999, 95% CI: 0.997 to 1.000, P= 0.583), and weighted model (OR= 0.999, 95% CI: 0.998 to 1.001, P= 0.328). Also, IL-6 had no significant effect on MM: inverse variance weighting method (OR= 1.001, 95% CI: 0.999 to 1.002, P=0.461), MR-Egger regression (OR= 1.000, 95% CI: 0.997 to 1.004, P= 0.910), weighted median method (OR= 1.000, 95% CI: 0.998 to 1.002, P= 0.749), and weighted mode (OR= 1.000, 95% CI: 0.998 to 1.002, P= 0.820). Conclusion: There was no causal relationship between C-reactive protein and IL-6 on the risk of malignant melanoma. [ABSTRACT FROM AUTHOR]

Aim: Diabetes mellitus (DM) may promote the occurrence of epilepsy through mechanisms, such as inflammation, immune imbalance, and cerebrovascular injury, caused by metabolic abnormalities. However, evidence for the effects of DM and blood glucose (BG) on the risk of epilepsy is limited. Herein, this study used the Mendelian randomization (MR) method to investigate the potential causal associations of DM and BG-related indexes with epilepsy. Methods: In this two-sample MR study, summary statistics data of the genome-wide association studies (GWASs) on exposures, including type 1 diabetes mellitus (T1DM), T2DM, fasting glucose, and glycated hemoglobin (HbAlc), were extracted from the MRC-Integrative Epidemiology Unit (MRC-IEU). The GWAS data on study outcomes, including epilepsy, focal epilepsy, and generalized epilepsy, were obtained from the FinnGen consortium. MR-Egger regression was used to examine horizontal pleiotropism of instrumental variables (IVs), and Cochran's Q statistics was used to quantify the heterogeneity. MR analysis methods including inverse variance weighted (IVW) tests, weighted median, and MR-Egger were utilized to investigate the causal associations between DM and BG-related indexes with epilepsy. The evaluation indexes were odds ratios (ORs) and 95% confidence intervals (CIs). Reverse causal association analyses were also performed. In addition, IVW-radial and leave-one-out tests were utilized for sensitivity analyses. Results: IVW estimates suggested that T1DM has potential causal associations with epilepsy (OR = 1.057, 95% CI: 1.031-1.084) and generalized epilepsy (OR = 1.066, 95% CI: 1.018-1.116). No significant reverse causal associations of T1DM with epilepsy or generalized epilepsy were found (all P > 0.05). In addition, sensitivity analysis results identified no outlier, indicating that the associations of T1DM with epilepsy and generalized epilepsy were relatively robust. Conclusion: Patients with T1DM had a potential risk of developing epilepsy, and prompt treatment of DM and dynamic monitoring may be beneficial to prevent epilepsy in this high-risk population. However, the causal associations of DM and BG with epilepsy may warrant further verification. [ABSTRACT FROM AUTHOR]