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Increased left atrial volume and decreased left atrial function have long been associated with atrial fibrillation. The availability of large-scale cardiac magnetic resonance imaging data paired with genetic data provides a unique opportunity to assess the genetic contributions to left atrial structure and function, and understand their relationship with risk for atrial fibrillation. Here, we use deep learning and surface reconstruction models to measure left atrial minimum volume, maximum volume, stroke volume, and emptying fraction in 40,558 UK Biobank participants. In a genome-wide association study of 35,049 participants without pre-existing cardiovascular disease, we identify 20 common genetic loci associated with left atrial structure and function. We find that polygenic contributions to increased left atrial volume are associated with atrial fibrillation and its downstream consequences, including stroke. Through Mendelian randomization, we find evidence supporting a causal role for left atrial enlargement and dysfunction on atrial fibrillation risk.

Previous research has found that milk is associated with a decreased risk of colorectal cancer (CRC). However, it is unclear whether the milk digestion by the enzyme lactase-phlorizin hydrolase (LPH) plays a role in CRC susceptibility. Our study aims to investigate the direct causal relationship of CRC risk with LPH levels by applying a two-sample Mendelian Randomization (MR) strategy. Genetic instruments for LPH were derived from the Fenland Study, and CRC-associated summary statistics for these instruments were extracted from the FinnGen Study, PLCO Atlas Project, and Pan-UK Biobank. Primary MR analyses focused on a cis-variant (rs4988235) for LPH levels, with results integrated via meta-analysis. MR analyses using all variants were also undertaken. This analytical approach was further extended to assess CRC subtypes (colon and rectal). Meta-analysis across the three datasets illustrated an inverse association between genetically predicted LPH levels and CRC risk (OR: 0.92 [95% CI, 0.89-0.95]). Subtype analyses revealed associations of elevated LPH levels with reduced risks for both colon (OR: 0.92 [95% CI, 0.89-0.96]) and rectal cancer (OR: 0.92 [95% CI, 0.87, 0.98]). Consistency was observed across varied analytical methods and datasets. Further exploration is warranted to unveil the underlying mechanisms and validate LPHs potential role in CRC prevention.

We assessed the causal relation of four glycemic traits and type 2 diabetes liability with 167 metabolites using Mendelian randomization with various sensitivity analyses and a reverse Mendelian randomization analysis. We extracted instruments for fasting glucose, 2-h glucose, fasting insulin, and glycated hemoglobin from the Meta-Analyses of Glucose and Insulin-related traits Consortium (n = 200,622), and those for type 2 diabetes liability from a meta-analysis of multiple cohorts (148,726 cases, 965,732 controls) in Europeans. Outcome data were from summary statistics of 167 metabolites from the UK Biobank (n = 115,078). Fasting glucose and 2-h glucose were not associated with any metabolite. Higher glycated hemoglobin was associated with higher free cholesterol in small low-density lipoprotein. Type 2 diabetes liability and fasting insulin were inversely associated with apolipoprotein A1, total cholines, lipoprotein subfractions in high-density-lipoprotein and intermediate-density lipoproteins, and positively associated with aromatic amino acids. These findings indicate hyperglycemia-independent patterns and highlight the role of insulin in type 2 diabetes development. Further studies should evaluate these glycemic traits in type 2 diabetes diagnosis and clinical management.

Major depressive disorder (MDD) and bipolar disorder (BD) are prevalent psychiatric conditions linked to inflammatory processes. However, it is unclear whether associations of immune cells with these disorders are likely to be causal. We used two-sample Mendelian randomization (MR) approach to investigate the relationship between 731 immune cells and the risk of MDD and BD. Rigorous sensitivity analyses are conducted to assess the reliability, heterogeneity, and horizontal pleiotropy of the findings. Genetically-predicted CD27 on IgD+ CD38− unswitched memory B cell (inverse variance weighting (IVW): odds ratio (OR) [95 %]: 1.017 [1.007 to 1.027], p = 0.001), CD27 on IgD+ CD24+ B cell (IVW: OR [95 %]: 1.021 [1.011 to 1.031], p = 4.821E−05) and other 12 immune cells were associated with increased risk of MDD in MR, while HLA DR++ monocyte %leukocyte (IVW: OR [95 %]: 0.973 [0.948 to 0.998], p = 0.038), CD4 on Central Memory CD4+ T cell (IVW: OR [95 %]: 0.979 [0.963 to 0.995], p = 0.011) and other 13 immune cells were associated with decreased risk of MDD in MR. Additionally, CD33+ HLA DR+ Absolute Count (IVW: OR [95 %]: 1.022[1.007 to 1.036], p = 0.007), CD28+ CD45RA− CD8+ T cell %T cell (IVW: OR [95 %]: 1.024 [1.008 to 1.041], p = 0.004) and other 18 immune cells were associated with increased risk of BD in MR, while CD62L on CD62L+ myeloid Dendritic Cell (IVW: OR [95 %]: 0.926 [0.871 to 0.985], p = 0.014), IgD− CD27− B cell %lymphocyte (IVW: OR [95 %]: 0.918 [0.880 to 0.956], p = 4.654E−05) and other 13 immune cells were associated with decreased risk of BD in MR. This MR study provides robust evidence supporting a causal relationship between immune cells and the susceptibility to MDD and BD, offering valuable insights for future clinical investigations. Experimental studies are also required to further examine causality, mechanisms, and treatment potential for these immune cells for MDD and BD. • Early life infection is linked with autoimmune disease and subsequent psychiatric disorders in adults. • Complex immune-brain interactions may have causal and therapeutic implications for MDD and BD. • MR can control residual factors including limited sample size and flawed study design. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a complex neurodegenerative condition characterized by metabolic imbalances and neuroinflammation, posing a formidable challenge in medicine due to the lack of effective treatments. Despite considerable research efforts, a cure for AD remains elusive, with current therapies primarily focused on symptom management rather than addressing the disease's underlying causes. This study initially discerned, through Mendelian randomization analysis that elevating pantothenate levels significantly contributes to the prophylaxis of Alzheimer's disease. We explore the therapeutic potential of pantothenate encapsulated in liposomes (Pan@TRF@Liposome NPs), targeting the modulation of CRM1-mediated PKM2 nuclear translocation, a critical mechanism in AD pathology. Additionally, we investigate the synergistic effects of exercise, proposing a combined approach to AD treatment. Exercise-induced metabolic alterations share significant similarities with those associated with dementia, suggesting a potential complementary effect. The Pan@TRF@Liposome NPs exhibit notable biocompatibility, showing no liver or kidney toxicity in vivo, while demonstrating stability and effectiveness in modulating CRM1-mediated PKM2 nuclear translocation, thereby reducing neuroinflammation and neuronal apoptosis. The combined treatment of exercise and Pan@TRF@Liposome NP administration in an AD animal model leads to improved neurofunctional outcomes and cognitive performance. These findings highlight the nanoparticles' role as effective modulators of CRM1-mediated PKM2 nuclear translocation, with significant implications for mitigating neuroinflammation and neuronal apoptosis. Together with exercise, this dual-modality approach could offer new avenues for enhancing cognitive performance and neurofunctional outcomes in AD, marking a promising step forward in developing treatment strategies for this challenging disorder. The administration of Pan@TRF@Liposome nanoparticles (NPs) combined with physical exercise results in a significant reduction in neuroinflammation and neuronal apoptosis, improved neurofunctional outcomes, and enhanced cognitive performance in an Alzheimer's disease (AD) animal model. This treatment also demonstrates notable biocompatibility, stability, and effectiveness in modulating CRM1-mediated PKM2 nuclear translocation. The graphical abstract illustrates the therapeutic potential of Pan@TRF@Liposome NPs and exercise in improving AD outcomes. The injection of lipid nanoparticles shows Pan@TRF@Liposomes crossing the blood-brain barrier. The mechanism of action details the modification of PKM2 by SUMO1 and its nuclear translocation via CRM1. The combined treatment highlights the synergistic benefits of nanoparticle administration and physical exercise, leading to M2 polarization of microglia and reduction in amyloid-beta (Aβ) plaques. Overall, this combined approach results in a marked improvement in AD symptoms and cognitive function. [Display omitted] • Elevating pantothenate levels significantly contributes to preventing Alzheimer's disease. • Pan@TRF@Liposome nanoparticles reduced neuroinflammation and neuronal apoptosis. • Pan@TRF@Liposome nanoparticles exerted effects through targeting the regulation of CRM1-mediated PKM2 nuclear translocation. • The combined treatment of exercise and Pan@TRF@Liposome nanoparticles in AD animal model improved neurofunctional outcomes. [ABSTRACT FROM AUTHOR]

Preterm birth is the leading cause of neonatal mortality worldwide, and dyslipidemia is associated with preterm birth in observational studies. We use Mendelian randomization (MR) analyses to uncover the causal association between blood lipid levels and preterm birth. We extracted uncorrelated (R2 < 0.001) single-nucleotide polymorphisms strongly associated (p < 5 × 10–8) with blood lipids from genome wide association studies of FinnGen database and UK Biobank participants. Inverse variance weighted method was the main MR analysis. Sensitivity analyses including genetic pleiotropy, heterogeneity, and directionality of causality were conducted. The study included 115,082 participants with lipid measurements, 8,507 patients with preterm birth. Increasing apolipoprotein B (odds ratio (OR), 1.12[95 % CI, 1.02–1.23]; p = 0.019), low-density lipoprotein cholesterol (OR, 1.11[95 % CI, 1.00–1.22]; p = 0.040), non-high-density lipoprotein cholesterol (OR, 1.12[95 % CI, 1.01–1.24]; p = 0.026), remnant cholesterol (OR, 1.11[95 % CI, 1.00–1.23]; p = 0.047) and total free cholesterol (OR, 1.11[95 % CI, 1.01–1.23]; p = 0.037) were associated with increased risk of preterm delivery. Moreover, triglycerides in low-density lipoprotein were causally associated with the risk of PTB. Our sensitivity analysis yielded robust results, uncovering no evidence of horizontal pleiotropy or reverse causal relationships. Our investigation unveils the adverse impact of dyslipidemia on preterm birth, with a particular emphasis on the detrimental effect of elevated low-density lipoprotein cholesterol. [ABSTRACT FROM AUTHOR]

The objective of the study was to explore the relationship and potential mechanism between Parkinson's disease (PD) and diabetic retinopathy (DR) using bioinformatics methods. We first examined the causal relationship between PD and DR by Mendelian randomization (MR) analysis. The datasets of PD and DR patients from the Gene Expression Omnibus database were used to identify differentially expressed genes (DEGs). Then, we performed the Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and immune infiltration analysis. We also constructed a protein–protein interaction network and receiver operating characteristic (ROC) curve. Finally, an online website was used for drug prediction. The MR analysis demonstrated a causal relationship between DR and PD (odds ratio [OR] = 0.86; 95% confidence interval [CI] 0.79–0.93; p = 3.24E − 04), in which DR acted as a protective factor against PD. There were 81 DEGs identified from the PD and DR datasets, of which 29 genes had protein interaction relationships, and enrichment analysis showed that these genes were mainly related to immune pathways. As indicated by immune cell infiltration analysis, the expression of immune cells between PD and the control group was significantly different. ROC curve results showed five genes had diagnostic value, and several potential chemical compounds were predicted to target the genes. Our findings demonstrate a reduced risk of PD in patients with DR. We also found that PD and DR are closely related in terms of inflammation, which provides clues for further exploring the common mechanisms and interaction of these two diseases. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to elucidate the causal relationship between Obstructive Sleep Apnea (OSA) and Chronic Respiratory Diseases (CRDs), employing Mendelian Randomization (MR) to overcome limitations inherent in observational studies. Methods: Utilizing a two-sample MR approach, this study analyzed genetic variants as instrumental variables to investigate the causal link between OSA and various CRDs, including chronic obstructive pulmonary disease (COPD), asthma, bronchiectasis, and idiopathic pulmonary fibrosis (IPF). Data were sourced from the FinnGen Consortium (OSA, n = 375,657) and UK Biobank, focusing on genome-wide associations between single-nucleotide polymorphisms (SNPs) and the diseases. Instrumental variables were selected based on strict criteria, and analyses included a random-effects inverse-variance weighted method supplemented by several sensitivity analyses. Results: The study suggests a protective effect of OSA against COPD (OR = 0.819, 95% CI 0.722–0.929, P-value = 0.002), which becomes non-significant after adjusting for BMI, indicating a potential mediating role of BMI in the OSA-COPD nexus. No significant causal links were found between OSA and other CRDs (asthma, IPF, bronchiectasis) or between COPD, asthma, and OSA. Conclusions: Our findings reveal a BMI-mediated protective effect of OSA on COPD, with no causal connections identified between OSA and other CRDs. These results emphasize the complex relationship between OSA, BMI, and COPD, guiding future clinical strategies and research directions, particularly in light of the study's genetic analysis limitations. [ABSTRACT FROM AUTHOR]

Background: Hyperthyroidism is an endocrine disorder with a relatively low global prevalence but significantly higher incidence among females compared to males. The onset age primarily ranges from 30 to 50, although it is not limited to this age group. Challenges in the treatment of hyperthyroidism include individualized treatment plan formulation, management of side effects, and prediction of disease progression, necessitating comprehensive consideration to achieve more effective therapy and management. Mendelian randomization studies can reveal more precise therapeutic targets between blood and urine biomarkers and hyperthyroidism, providing more decadent treatment options for the condition. Methods: The study will build upon the omics Mendelian randomization (MR) framework by conducting MR analysis using 35 blood and urine biomarkers separately for two distinct databases of hyperthyroidism. Subsequently, the results will undergo meta-analysis and multiple corrections to ensure accuracy and reliability. Finally, positive findings will undergo reverse MR validation to verify causal relationships with hyperthyroidism. Results: In the British database, the MR analysis of Total bilirubin levels about hyperthyroidism yielded an odds ratio (OR) of 1.097 (95% CI: 0.951-1.265, P = 0.205). Conversely, in the Thyroid Omics Association database, the MR analysis revealed an OR of 1.283 (95% CI: 1.122-1.467, P = 0.0002) for the same relationship. Meta-analysis of the MR analysis results from both databases, following multiple corrections, resulted in an OR of 1.192 (95% CI: 1.081-1.314, P = 0.015). Additionally, the direction of beta values in the MR analysis results from both databases was consistent. Conclusion: The urine biomarker total bilirubin levels may contribute to an increased risk of hyperthyroidism and accelerate its progression, thus representing a risk factor for the condition. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the causal relationship between gut microbiota characteristics (207 taxa and 205 pathways) and Alzheimer's disease and determine and quantify the role of immune cells as potential mediators. Methods: Gut microbiota characteristics (207 taxa and 205 pathways) were obtained from the NHGRI-EBI GWAS Catalog project, while Alzheimer's disease data and 731 immune cell characteristics were obtained from the IEU Open GWAS project. Two-sample Mendelian randomization (MR) was conducted to determine whether gut microbiota characteristics (207 taxa and 205 pathways) were causally related to Alzheimer's disease. Furthermore, two-step MR was employed to quantify the proportion of the effect of immune cell characteristics mediated by gut microbiota characteristics (207 taxa and 205 pathways) on Alzheimer's disease. Results: A total of 17 immune cell characteristics were identified as potential mediators for 13 gut microbiota influencing Alzheimer's disease, with Effector Memory CD4+ T-cell Absolute Count accounted for 8.99% of the causal relationship between genus Oscillibacter and Alzheimer's disease. Conclusion: In summary, our research confirms a causal relationship between gut microbiota and Alzheimer's disease, with immune cells contributing to a significant portion of the effect. However, the full mediators of gut microbiota's impact on Alzheimer's disease remain unclear. Further investigation is warranted to explore additional potential risk factors acting as mediators. [ABSTRACT FROM AUTHOR]

Background: Numerous observational studies have identified associations between both psoriasis (PsO) and psoriatic arthritis (PsA), and autoimmune diseases (AIDs); however, the causality of these associations remains undetermined. Methods: We conducted a bidirectional two-sample Mendelian Randomization study to identify causal associations and directions between both PsO and PsA and AIDs, such as systemic lupus erythematosus (SLE), Crohn's disease (CD), ulcerative colitis (UC), multiple sclerosis (MS), uveitis, bullous pemphigoid (BP), Hashimoto's thyroiditis (HT), rheumatoid arthritis (RA), vitiligo, and ankylosing spondylitis (AS). The causal inferences were drawn by integrating results from four regression models: Inverse Variance Weighting (IVW), MR-Egger, Weighted Median, and Maximum Likelihood. Furthermore, we performed sensitivity analyses to confirm the reliability of our findings. Results: The results showed that CD [IVW odds ratio (ORIVW), 1.11; 95% confidence interval (CI), 1.06-1.17; P = 8.40E-06], vitiligo (ORIVW, 1.16; 95% CI, 1.05-1.28; P = 2.45E-03) were risk factors for PsO, while BP may reduce the incidence of PsO (ORIVW, 0.91; 95% CI, 0.87-0.96; P = 1.26E-04). CD (ORIVW, 1.07; 95% CI, 1.02-1.12; P = 0.01), HT (ORIVW, 1.23; 95% CI, 1.08-1.40; P = 1.43E-03), RA (ORIVW, 1.11; 95% CI, 1.02-1.21, P = 2.05E-02), AS (ORIVW, 2.18; 95% CI, 1.46-3.27; P = 1.55E-04), SLE (ORIVW, 1.04; 95% CI, 1.01-1.08; P = 1.07E-02) and vitiligo (ORIVW, 1.27; 95% CI, 1.14-1.42; P = 2.67E-05) were risk factors for PsA. Sensitivity analyses had validated the reliability of the results. Conclusions: Our study provides evidence for potential causal relationships between certain AIDs and both PsO and PsA. Specifically, CD and vitiligo may increase the risk of developing PsO, while CD, HT, SLE, RA, AS, and vitiligo may elevate the risk for PsA. Additionally, it is crucial to closely monitor the condition of PsO patients with specific AIDs, as they have a higher likelihood of developing PsA than those without AIDs. Moving forward, greater attention should be paid to PsA and further exploration of other PsO subtypes is warranted. [ABSTRACT FROM AUTHOR]

BACKGROUND: We investigated the potential impact of antihypertensive drugs for atrial fibrillation (AF) prevention through a drug target Mendelian randomization study to avoid the potential limitations of clinical studies. METHODS: Validated published single-nucleotide polymorphisms (SNPs) that mimic the action of 12 antihypertensive drug classes, including alpha-adrenoceptor blockers, adrenergic neuron blockers, angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, beta-adrenoceptor blockers, centrally acting antihypertensive drugs, calcium channel blockers, loop diuretics, potassium-sparing diuretics and mineralocorticoid receptor antagonists, renin inhibitors, thiazides and related diuretic agents, and vasodilators were used. We estimated, via their corresponding gene and protein targets, the downstream effect of these drug classes to prevent AF via systolic blood pressure using 2-sample Mendelian randomization analyses. The SNPs were extracted from 2 European genome-wide association studies for the drug classes (n=317 754; n=757 601) and 1 European genome-wide association study for AF (n=1 030 836). RESULTS: Drug target Mendelian randomization analyses supported the significant preventive causal effects of lowering systolic blood pressure per 10 mm Hg via alpha-adrenoceptor blockers (n=11 SNPs; odds ratio [OR], 0.34 [95% CI, 0.21-0.56]; P=2.74×10-05), beta-adrenoceptor blockers (n=17 SNPs; OR, 0.52 [95% CI, 0.35-0.78]; P=1.62×10-03), calcium channel blockers (n=49 SNPs; OR, 0.50 [95% CI, 0.36-0.70]; P=4.51×10-05), vasodilators (n=19 SNPs; OR, 0.53 [95% CI, 0.34-0.84]; P=7.03×10-03), and all 12 antihypertensive drug classes combined (n=158 SNPs; OR, 0.64 [95% CI, 0.54-0.77]; P=8.50×10-07) on AF risk. CONCLUSIONS: Our results indicated that lowering systolic blood pressure via protein targets of various antihypertensive drugs seems promising for AF prevention. Our findings inform future clinical trials and have implications for repurposing antihypertensive drugs for AF prevention. [ABSTRACT FROM AUTHOR]

Objectives: Osteosarcoma (OS) is the primary bone tumor originating from transformed mesenchymal cells. It is unclear whether associations between specific circulating immune cells and OS are causal or due to bias. To clarify whether predicted genetically altered circulating immune cells are associated with OS development, we performed a two-sample Mendelian randomization (MR) analysis. Methods: The genetic variants strongly associated with immune cell traits as instrumental variables (IVs) were used to perform MR analyses. The effect of specific immune cells on OS risk was measured using the summary statistics from the genome-wide association studies (GWAS). Results: Our findings indicate that CD80 on CD62L+ myeloid dendritic cell and CD28-CD4-CD8-T-cell absolute count are positively associated with OS (CD80 on CD62L+ myeloid dendritic cell, OR: 3.41 [95% CI: 1.40 to 8.31], p = 0.007; CD28-CD4-CD8-T-cell absolute count, OR: 4.49 [95% CI: 1.29 to 15.62], p = 0.018). It is also found that CD20 has a negative effect on CD24+CD27+ B cell on OS (OR: 0.32 [95% CI: 0.14 to 0.72], p = 0.006) and a similar impact on IgD+ CD38-B cell on OS (OR: 0.19 [95% CI: 0.05 to 0.68], p = 0.011). Conclusions: These findings illustrate that the genetic predisposition to specific immune cells can exert a causal effect on OS risk, which confirms the crucial role played by immunity in OS development. Particularly, the causal association between immune cells and OS underscores the evidence for exploring the new treatment strategy for OS in the future. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to explore the genetic effects of hormones modulated through the pituitary-thyroid/adrenal/gonadal axis on the risk of developing venous thromboembolism (VTE) and to investigate the potentially causal relationships between them. Methods: A two-sample Mendelian randomization (MR) design was used. The single-nucleotide polymorphisms (SNPs) used as instrumental variables for various hormones and hormone-mediated diseases were derived from published genome-wide association studies (GWASs). Summary statistics for the risk of developing VTE (including deep venous thrombosis [DVT] and pulmonary embolism [PE]) were obtained from the UK Biobank and the FinnGen consortium. Inverse-variance weighting (IVW) was applied as the primary method to analyse causal associations. Other MR methods were used for supplementary estimates and sensitivity analysis. Results: A genetic predisposition to greater free thyroxine (FT4) concentrations was associated with a greater risk of developing DVT (OR = 1.0007, 95%CI [1.0001–1.0013], p = 0.0174) and VTE (OR = 1.0008, 95%CI [1.0002–1.0013], p = 0.0123). Genetically predicted hyperthyroidism was significantly associated with an increased risk of developing DVT (OR = 1.0685, 95%CI [1.0139–1.1261], p = 0.0134) and VTE (OR = 1.0740, 95%CI [1.0165–1.1348], p = 0.0110). According to the initial MR analysis, testosterone concentrations were positively associated with the risk of developing VTE (OR = 1.0038, 95%CI [1.004–1.0072], p = 0.0285). After sex stratification, estradiol concentrations were positively associated with the risk of developing DVT (OR = 1.0143, 95%CI [1.0020–1.0267], p = 0.0226) and VTE (OR = 1.0156, 95%CI [1.0029–1.0285], p = 0.0158) in females, while the significant relationship between testosterone and VTE did not persist. SHBG rs858518 was identified as the only SNP that was associated with an increased risk of developing VTE, mediated by estradiol, in females. Conclusions: Genetically predicted hyperthyroidism and increased FT4 concentrations were positively associated with the risk of developing VTE. The effects of genetically predicted sex hormones on the risk of developing VTE differed between males and females. Greater genetically predicted estradiol concentrations were associated with an increased risk of developing VTE in females, while the SHBG rs858518 variant may become a potential prevention and treatment target for female VTE. [ABSTRACT FROM AUTHOR]

Background: The role of autoimmune diseases (ADs) in temporomandibular disorders (TMDs) has been emphasized in observational studies. However, whether the causation exists is unclear, and controversy remains about which specific disorder is destructive in TMDs. This Mendelian randomization (MR) study aims to estimate the causal effect of common ADs on TMDs. Methods: Genetic data from published genome-wide association studies for fourteen common ADs, specifically multiple sclerosis (MS, N = 15,283), ankylosing spondylitis (AS, N = 22,647), asthma (N = 408,422), celiac disease (N = 15,283), Graves' disease (N = 458,620), Hashimoto thyroiditis (N = 395,640), primary biliary cirrhosis (PBC, N = 11,375), primary sclerosing cholangitis (PSC, N = 14,890), psoriasis vulgaris (N = 483,174), rheumatoid arthritis (RA, N = 417,256), systemic lupus erythematosus (SLE, N = 23,210), Type 1 diabetes (T1D, N = 520,580), inflammatory bowel disease (IBD, N = 34,652), and Sjogren's syndrome (SS, N = 407,746) were collected. Additionally, the latest summary-level data for TMDs (N = 228,812) were extracted from the FinnGen database. The overall effects of each immune traits were assessed via inverse-variance weighted (IVW), weighted median, and MR-Egger methods, and performed extensive sensitivity analyses. Finally, 731 immune cell phenotypes (N = 3,757) were analyzed for their mediating role in the significant causality. Results: Univariable MR analyses revealed that genetically predicted RA (IVW OR: 1.12, 95% CI: 1.05-1.19, p < 0.001) and MS (IVW OR: 1.06, 95% CI: 1.03-1.10, p = 0.001) were associated with increased risk of TMDs. Two out of 731 immune cell phenotypes were identified as causal mediators in the associations of RA with TMDs, including "CD25++ CD8+ T cell % CD8+ T cell" (mediation proportion: 6.2%) and "CD3 on activated CD4 regulatory T cell" (5.4%). Additionally, "CD127 on granulocyte" mediated 10.6% of the total effect of MS on TMDs. No reverse directions, heterogeneity, and pleiotropy were detected in the analyses (p > 0.05). Conclusion: This MR study provides new evidence regarding the causal impact of genetic predisposition to RA or MS on the increased risk of TMDs, potentially mediated by the modulation of immune cells. These findings highlight the importance for clinicians to pay more attention to patients with RA or MS when consulting for temporomandibular discomfort. The mediating role of specific immune cells is proposed but needs further investigation. [ABSTRACT FROM AUTHOR]

Background: While some studies have suggested a link between gut microbiota (GM) and abortion, the causal relationship remains unclear. Methods: To explore the causal relationship between GM and abortion, including spontaneous abortion (SA) and habitual abortion (HA), we performed a twosample Mendelian randomization (MR) analysis. We used summary statistics data from MiBioGen and FinnGen for genome-wide association studies (GWAS), with GM data as the exposure variable and abortion data as the outcome variable. Results: In the absence of heterogeneity and horizontal pleiotropy, the inversevariance weighted (IVW) method identified five genetically predicted GM genera linked to the risk of abortions. Lactococcus was negatively correlated with the risk of SA, whereas the Eubacterium fissicatena group was positively correlated with the risk of SA. Genetic predictions of Coprococcus3 and Odoribacter were linked to a reduced risk of HA, while the Eubacterium ruminantium group was associated with an increased risk of HA. Conclusion: Our study suggests a genetic causal relationship between specific GM and two types of abortions, improving our understanding of the pathological relationship between GM and abortion. [ABSTRACT FROM AUTHOR]

Background: Despite evidence showing a connection between inflammation and endometrial cancer (EC) risk, the surveys on genetic correlation and cohort studies investigating the impact on long-term outcomes have yet to be refined. We aimed to address the impact of inflammation factors on the pathogenesis, progression and consequences of EC. Methods: For the genetic correlation analyses, a two-sample of Mendelian randomization (MR) study was applied to investigate inflammation-related single-nucleotide polymorphisms involved with endometrial cancer from GWAS databases. The observational retrospective study included consecutive patients diagnosed with EC (stage I to IV) with surgeries between January 2010 and October 2020 at the Cancer Hospital of Shantou University Medical College. Results: The 2-sample MR surveys indicated no causal relationship between inflammatory cytokines and endometrial cancer. 780 cases (median age, 55.0 years) diagnosed with EC were included in the cohort and followed up for an average of 6.8 years. Increased inflammatory parameters at baseline were associated with a higher FIGO stage and invasive EC risk (odds ratios [OR] 1.01 to 4.20). Multivariate-cox regression suggested that multiple inflammatory indicators were significantly associated with overall survival (OS) and progression-free survival (PFS) (P < 0.05). Nomogram models based on inflammatory risk and clinical factors were developed for OS and PFS with C-index of 0.811 and 0.789, respectively. LASSO regression for the validation supported the predictive efficacy of inflammatory and clinical factors on the long-term outcomes of EC. Conclusions: Despite the fact that the genetic surveys did not show a detrimental impact of inflammatory cytokines on the endometrial cancer risk, our cohort study suggested that inflammatory level was associated with the progression and long-term outcomes of EC. This evidence may contribute to new strategies targeted at decreasing inflammation levels during EC therapy. [ABSTRACT FROM AUTHOR]

Background: Themost effective approach tomanaging Alzheimer's disease (AD) lies in identifying reliable biomarkers for AD to forecast the disease in advance, followed by timely early intervention for patients. Methods: Transcriptomic data on peripheral blood mononuclear cells (PBMCs) from patients with AD and the control group were collected, and preliminary data processing was completed using standardized analytical methods. PBMCs were initially segmented into distinct subpopulations, and the divisions were progressively refined until the most significantly altered cell populations were identified. A combination of high-dimensional weighted gene co-expression analysis (hdWGCNA), cellular communication, pseudotime analysis, and single-cell regulatory network inference and clustering (SCENIC) analysis was used to conduct single-cell transcriptomics analysis and identify key gene modules from them. Genes were screened using machine learning (ML) in the key gene modules, and internal and external dataset validations were performed using multiple ML methods to test predictive performance. Finally, bidirectional Mendelian randomization (MR) analysis, regional linkage analysis, and the Steiger test were employed to analyze the key gene. Result: A significant decrease in non-classical monocytes was detected in PMBC of AD patients. Subsequent analyses revealed the inherent connection of non-classical monocytes to AD, and the NAP1L1 gene identified within its gene module appeared to exhibit some association with AD as well. Conclusion: The NAP1L1 gene is a potential predictive biomarker for AD. [ABSTRACT FROM AUTHOR]

Background and Objective: The issue of falls poses a significant threat to the health of the elderly population. Although statins can cause myopathy, which implies that they may cause balance problems and increase the risk of falling, this has not been tested. Our objective was to assess whether the use of statins is linked to a higher risk of falls. Methods: A cross-sectional survey study and Mendelian randomization (MR) study were conducted to examine whether the use of statins was associated with an increased risk of falling and balance problems. The cross-sectional study included 2,656 participants from the US population (NHANES) who reported information on balance and falling problems in the past year and their use of statins. Univariate and multivariate logistic regression models were used to investigate the association between statin use and the likelihood of falling or experiencing balance problems. The MR study identified five Single Nucleotide Polymorphisms (SNPs) that predict statin use across five ancestry groups: Admixed African or African, East Asian, European, Hispanic, and South Asian. Additionally, SNPs predicting the risk of falls were acquired from the UK Biobank population. A two-sample MR analysis was performed to examine whether genetically predicted statin use increased the risk of falls. Results: The use of statins was found to be associated with an increased likelihood of balance and falling problems (balance problem, OR 1.25, 95%CI 1.02 to 1.55; falling problem, OR 1.27, 95%CI 1.03–1.27). Subgroup analysis revealed that patients under the age of 65 were more susceptible to these issues when taking statins (balance problem, OR 3.42, 95%CI 1.40 to 9.30; falling problem, OR 5.58, 95%CI 2.04–15.40). The MR analysis indicated that the use of statins, as genetically proxied, resulted in an increased risk of falling problems (OR 1.21, 95% CI 1.1–1.33). Conclusion: Our study found an association between the use of statins and an increased risk of balance problems and falls in adults over 40 years old, and the MR study result suggested statin use increased risk of falls. The risk was higher in participants under 65 years old compared to those over 65 years old. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to assess the causal relationship between Obstructive Sleep Apnea (OSA), dyslipidemia, and osteoporosis using Mendelian Randomization (MR) techniques. Methods: Utilizing a two-sample MR approach, the study examines the causal relationship between dyslipidemia and osteoporosis. Multivariable MR analyses were used to test the independence of the causal association of dyslipidemia with OSA. Single nucleotide polymorphisms (SNPs) were selected as instrumental variables based on genome-wide significance, independence, and linkage disequilibrium criteria. The data were sourced from publicly available Genome-Wide Association Studies (GWAS) of OSA (n = 375,657) from the FinnGen Consortium, the Global Lipids Genetics Consortium of dyslipidemia (n = 188,577) and the UK Biobank for osteoporosis (n = 456,348). Results: The MR analysis identified a significant positive association between genetically predicted OSA and triglyceride levels (OR: 1.15, 95% CI: 1.04--1.26, p = 0.006) and a negative correlation with high-density lipoprotein cholesterol (HDLC) (OR: 0.84, 95% CI: 0.77--0.93, p = 0.0003). Conversely, no causal relationship was found between dyslipidemia (total cholesterol, triglycerides, HDL-C, and low-density lipoprotein cholesterol) and OSA or the relationship between OSA and osteoporosis. Conclusion: The study provides evidence of a causal relationship between OSA and dyslipidemia, highlighting the need for targeted prevention and management strategies for OSA to address lipid abnormalities. The absence of a causal link with osteoporosis and in the reverse direction emphasizes the need for further research in this area. [ABSTRACT FROM AUTHOR]

Background: There are current clinical observations that atorvastatin may promote subdural hematoma resorption. We aimed to assess the causal effects of lipid-lowering agents 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) inhibitors, Proproteinconvertase subtilisin/kexin type 9 (PCSK9) inhibitors and Niemann-Pick C1-like protein 1 (NPC1L1) inhibitors on traumatic subdural hematomas. Methods: We used genetic instruments to proxy lipid-lowering drug exposure, with genetic instruments being genetic variants within or near low-density lipoprotein (LDL cholesterol)-associated drug target genes. These were analyzed by using a two-sample Mendelian randomization (MR) study. Results: A causal relationship was found between HMGCR inhibitors and traumatic subdural hematoma (Inverse variance weighted (β = -0.7593341 (Odds Ratio (OR) = 0.4679779), p = 0.008366947<0.05)). However, no causal relationship was found between PCSK9 inhibitors and NPC1L1 inhibitors and traumatic subdural hematoma (PCSK9 inhibitors: Inverse variance weighted (β = 0.23897796 (OR = 1.2699505), p = 0.1126327), NPC1L1 inhibitors: Inverse variance weighted (β = -0.02118558 (OR = 0.9790373), p = 0.9701686)). Sensitivity analysis of the data revealed good stability of the results. Conclusions: This two-sample MR study suggests a potential causal relationship between HMGCR inhibition (atorvastatin) and traumatic subdural hemorrhage. [ABSTRACT FROM AUTHOR]

Observational studies suggested that immune system disorder is associated with depression. However, the causal association has not been fully elucidated. Thus, we aim to assess the causality of the associations of immune cell profiles with risk of depression through Mendelian randomization analysis. We extracted genetic variances of immune cell traits from a large publicly available genome-wide association study (GWAS) involving 3757 participants and depression from a GWAS containing 246,363 cases and 561,190 controls of European ancestry. Inverse variance weighting (IVW) was performed as the MR primary analysis. Simultaneously apply MR-Egger and weighted median as supplementary enhancements to the final result. We further performed heterogeneity and horizontal pleiotropy test to validate the main MR results. Five immunophenotypes were identified to be significantly associated with depression risk: CD27 on IgD − CD38 dim B cell (OR = 1.019, 95 % CI = 1.010–1.028, P = 1.24 × 10−5), CD45RA − CD4 + T cell Absolute Count (OR = 0.974, 95 % CI = 0.962–0.986, P = 3.88 × 10−5), CD40 on CD14 − CD16 + monocyte (OR = 0.987, 95 % CI = 0.981–0.993, P = 2.1 × 10−4), CD27 on switched memory B cell (OR = 1.015, 95 % CI = 1.006–1.023, P = 2.6 × 10−4), CD27 on IgD − CD38 − B cell (OR = 1.017, 95 % CI = 1.008–1.027, P = 3.1 × 10−4). Our findings shed light on the intricate interaction pattern between the immune system and depression, offering a novel direction for researchers to investigate the underlying biological mechanisms of depression. • This study aims to explore the causality of the associations of immune cell profiles with risk of depression through Mendelian randomization analysis. • Five immunophenotypes were identified to be significantly associated with depression risk: CD27 on IgD- CD38dim B cell, CD45RA- CD4+ T cell Absolute Count, CD40 on CD14- CD16+ monocyte, CD27 on switched memory B cell, CD27 on IgD- CD38- B cell. • Our findings shed light on the intricate interaction pattern between the immune cells and depression, offering a novel direction for researchers to investigate the underlying biological mechanisms of depression. [ABSTRACT FROM AUTHOR]

Background and Aims: At present, there is still a lack of radical drug targets for intervention in alcoholic liver disease (ALD), and drug discovery through randomized controlled trials is a lengthy, risky, and expensive undertaking, so we aimed to identify effective drug targets based on human genetics. Methods: We used Mendelian randomization (MR) and Bayesian colocalization analysis to investigate 2639 genes encoding druggable proteins and examined the causal effects on ALD (PMID 34737426: 456348 European with 451 cases and 455897 controls). In addition, we conducted the mediation analysis to explore the potential mechanism using the genome-wide association study (GWAS) data of blood biomark-ers as mediators. Results: We finally identified the drug target: ENPP2/Autotaxin and genetically prox-ied ENPP2/Autotaxin was causally associated with the risk of ALD (OR = 2.28, 95% CI: 1.64 to 3.16, p = 7.49E-7). In addition, we found that the effect of ENPP2/Autotaxin on ALD may be partly mediated by effector memory CD8+ T cell (the proportion of mediation effect: 8.49%). Conclusions: Our integrative analysis suggested that genetically determined levels of circulating ENPP2/Autotaxin have a causal effect on ALD risk and are a promising drug target. [ABSTRACT FROM AUTHOR]

Objectives: The study was to explore the causal effects of sleep characteristics on temporomandibular disorder (TMD)-related pain using Mendelian randomization (MR) analysis. Materials and methods: Five sleep characteristics (short sleep, insomnia, chronotype, snoring, sleep apnea) were designated as exposure factors. Data were obtained from previous publicized genome-wide association studies and single nucleotide polymorphisms (SNPs) strongly associated with them were utilized as instrumental variables (IVs). TMD-related pain was designed as outcome variable and sourced from the FinnGens database. MR analysis was employed to explore the causal effects of the five sleep characteristics on TMD-related pain. The causal effect was analyzed using the inverse variance-weighted (IVW), weighted median, and MR-Egger methods. Subsequently, sensitivity analyses were conducted using Cochran’s Q tests, funnel plots, leave-one-out analyses, and MR-Egger intercept tests. Results: A causal effect of short sleep on TMD-related pain was revealed by IVW (OR: 1.60, 95% CI: 1.06–2.41, P = 0.026). No causal relationship was identified between other sleep characteristics (insomnia, chronotype, snoring, sleep apnea) and TMD-related pain. Conclusions: Our study suggests that short sleep may increase the risk of TMD-related pain, while there was no causal relationship between other sleep characteristics and TMD-related pain. Further studies are warranted to deepen and definitively clarify their relationship. Clinical relevance: These findings reveal that the short sleep may be a risk factor of TMD-related pain and highlight the potential therapeutical effect of extending sleep time on alleviating TMD-related pain. [ABSTRACT FROM AUTHOR]

Introduction Although observational data suggest a relationship between headache and smoking, there remain questions about causality. Smoking may increase headache risk, individuals may smoke to alleviate headaches, or smoking and headache may share common risk factors. Mendelian randomization (MR) is a method that uses genetic variants as instruments for making causal inferences about an exposure and an outcome. Aims and Methods First, we conducted logistic regression of observational data in UK Biobank assessing the association between smoking behaviors (smoking status, cigarettes per day amongst daily smokers, and lifetime smoking score) on the risk of self-reported headache (in the last month and for more than 3 months). Second, we used genetic instruments for smoking behaviors and headache (identified in independent genome-wide association studies [GWAS]) to perform bidirectional MR analysis. Results Observationally, there is a weak association between smoking behavior and experiencing headache, with increased cigarettes per day associated with increased headache risk. In the MR analysis, genetic liability to smoking initiation and lifetime smoking increased odds of headache in the last month but not odds of headaches lasting more than 3 months. In the opposite direction, there was weak evidence for higher genetic liability to headaches decreasing the chance of quitting. Conclusions There was weak evidence for a partially bidirectional causal relationship between smoking behaviors and headache in the last month. Given this relationship is distinct from smoking heaviness, it suggests headache and smoking may share common risk factors such as personality traits. Implications Using MR, this study addresses the uncertainty regarding the observed relationship between headache and smoking. There was evidence for weak causal effects of smoking initiation and lifetime smoking (but not smoking heaviness) on likelihood of experiencing headache in the last month, but not over a prolonged period of more than 3 months. Those with higher genetic liability to headaches were also less likely to successfully stop smoking. This partially bidirectional causal relationship distinct from smoking heaviness suggests that observed associations are unlikely due to biological effects of tobacco smoke exposure and may be explained by shared personality traits. [ABSTRACT FROM AUTHOR]

Background: Observational studies have shown an association between skin microbiota and alopecia areata (AA), but the causal connection remains ambiguous. Methods: We obtained data on skin microbiota and AA from summary statistics of Genome‐Wide Association Studies and applied statistical methods from Mendelian randomization (MR) to assess causal relationships. Additionally, we investigated whether the skin microbiota acts as a mediator in the pathway from gut microbiota to AA. Results: In the MR analysis of KORA FF4 and AA, the inverse‐variance weighting method indicated that Corynebacterium (odds ratio [OR] = 0.82, 95% confidence interval [CI]: 0.70–0.96, p = 0.02) and asv037 (OR = 0.87, 95% CI: 0.76–0.99, p = 0.05) exerted protective effects, while Betaproteobacteria (OR = 1.21, 95% CI: 1.01–1.44, p = 0.03), asv015 (OR = 1.27, 95% CI: 1.05–1.54, p = 0.02), and Burkholderiales (OR = 1.20, 95% CI: 1.04–1.38, p = 0.01) were identified as risk factors in AA. In the MR analysis of PopGen and AA, asv001 (OR = 1.12, 95% CI: 1.01–1.24, p = 0.04), asv054 (OR = 1.13, 95% CI: 1.01–1.25, p = 0.03), and asv059 (OR = 1.14, 95% CI: 1.02–1.27, p = 0.02) were found to potentially increase the risk in AA. Furthermore, in the influence of gut microbiota on AA, the skin microbiota did not act as a mediator. Conclusion: Our analysis suggests potential causal relationships between certain skin microbiota and AA, revealing insights into its pathogenesis and potential intervention strategies. [ABSTRACT FROM AUTHOR]

Objective: This study is designed to explore the potential causal relationship between psoriasis and psoriatic arthritis (PsA) while investigating the genetic basis shared by these inflammatory diseases. Methods: Significant single nucleotide polymorphisms (SNPs) associated with UC, psoriasis, and PsA were selected as genetic instrumental variables using Genome‐Wide Association Study (GWAS) datasets. Additionally, Mendelian randomization (MR) methods, including inverse‐variance weighting (IVW), MR‐Egger regression, and Weighted Median (WME), were utilized to evaluate the causal relationships between these diseases. Moreover, sensitivity analysis and heterogeneity testing were conducted to validate the stability of the results. Results: A total of 123 significant SNPs associated with psoriasis, PsA, and UC were identified as genetic instrumental variables based on GWAS datasets. The analysis revealed a 36% increased risk of UC with psoriasis (odds ratio [OR] = 1.350, 95% confidence interval [CI] = 1.065‐1.729, P = 0.012) and a 32.9% increased risk of UC with PsA (OR = 1.329, 95% CI = 1.176‐1.592, P < 0.001). Further analysis showed a 43.5% increased risk of psoriasis with UC (OR = 1.435, 95% CI = 1.274‐1.831, P < 0.001) and a 45.8% increased risk of PsA with UC (OR = 1.458, 95% CI = 1.166‐1.822, P = 0.0013). In addition, sensitivity analysis and heterogeneity testing demonstrated the high stability of these results. Particularly, neither MR‐Egger regression analysis nor leave‐one‐out analysis revealed significant heterogeneity or pleiotropy bias, indicating the reliability of these causal estimates. Moreover, the use of the MR‐PRESSO further confirmed the positive correlation between psoriasis and UC, and the corrected estimates remained consistent with IVW analysis results after excluding potential outlier SNPs, enhancing the credibility of the analysis. Conclusions: This study strengthens the understanding of the genetic and causal relationships among UC, psoriasis, and PsA through GWAS and MR methods, revealing the genetic basis they may share. These findings not only provide a novel perspective on the comorbidity mechanisms of these diseases but also offer a valuable reference for the development of future treatment strategies and intervention measures. [ABSTRACT FROM AUTHOR]

Abstract Purpose This study aimed to elucidate the causal relationship between Obstructive Sleep Apnea (OSA) and Chronic Respiratory Diseases (CRDs), employing Mendelian Randomization (MR) to overcome limitations inherent in observational studies. Methods Utilizing a two-sample MR approach, this study analyzed genetic variants as instrumental variables to investigate the causal link between OSA and various CRDs, including chronic obstructive pulmonary disease (COPD), asthma, bronchiectasis, and idiopathic pulmonary fibrosis (IPF). Data were sourced from the FinnGen Consortium (OSA, n = 375,657) and UK Biobank, focusing on genome-wide associations between single-nucleotide polymorphisms (SNPs) and the diseases. Instrumental variables were selected based on strict criteria, and analyses included a random-effects inverse-variance weighted method supplemented by several sensitivity analyses. Results The study suggests a protective effect of OSA against COPD (OR = 0.819, 95% CI 0.722–0.929, P-value = 0.002), which becomes non-significant after adjusting for BMI, indicating a potential mediating role of BMI in the OSA-COPD nexus. No significant causal links were found between OSA and other CRDs (asthma, IPF, bronchiectasis) or between COPD, asthma, and OSA. Conclusions Our findings reveal a BMI-mediated protective effect of OSA on COPD, with no causal connections identified between OSA and other CRDs. These results emphasize the complex relationship between OSA, BMI, and COPD, guiding future clinical strategies and research directions, particularly in light of the study’s genetic analysis limitations.

Longyi Zheng,1,&ast; Chengjing Zhang,2,&ast; Shichang Bu,1,&ast; Wencheng Guo,3,&ast; Tongtong Li,4 Ying Xu,5 Yunan Liu,4 Caimei Yuan,4 Chengwu Feng,4 Geng Zong,4 Jingwen Zhu,4 Maoying Xing,5 Xin Geng5 1Department of Endocrinology, Changhai Hospital, Naval Medical University, Shanghai, People’s Republic of China; 2Department of Nutrition, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, People’s Republic of China; 3Department of General Surgery and Vascular Surgery, Huashan Hospital, Fudan University, Shanghai, People’s Republic of China; 4CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, People’s Republic of China; 5National Center for Liver Cancer, Naval Medical University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Maoying Xing; Xin Geng, Email xmyxing@sina.com; gxouc@hotmail.comBackground: Neuregulin 4 (NRG4) was known to be associated with serum lipid levels and atherosclerosis. However, it is unknown whether the role of NRG4 in lipid homeostasis is causal to atherosclerosis and whether the effect is beneficial across different atherosclerosis subtypes.Methods: We investigated the causal role of the levels of serum low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides regulated by NRG4 in subtypes of atherosclerosis through two sample Mendelian randomization. Aggregated genome-wide association study (GWAS) summary data for serum lipid level of 1.32 million individuals with European ancestry were obtained from the Global Lipids Genetics Consortium. GWAS summary data for four atherosclerosis subtypes (peripheral, coronary, cerebral and the other atherosclerosis) were obtained from FinnGen Consortium. Generalized inverse-variance–weighted Mendelian randomization and several sensitivity analyses were used to obtain the causal estimates.Results: A 1-SD genetically elevated LDL-C level mediated by NRG4 was validated to be nominally associated with the risk of peripheral atherosclerosis (log (odds ratio)= 4.14, 95% confidence interval 0.11 to 8.17, P = 0.04), and the other associations were not significant or could not be validated by sensitivity analyses.Conclusion: LDL-C lowering mediated by NRG4 is likely to prevent peripheral atherosclerosis.Keywords: Mendelian randomization analysis, NRG4, atherosclerosis, lipid

Abstract Background The aim of this study was to explore the genetic effects of hormones modulated through the pituitary-thyroid/adrenal/gonadal axis on the risk of developing venous thromboembolism (VTE) and to investigate the potentially causal relationships between them. Methods A two-sample Mendelian randomization (MR) design was used. The single-nucleotide polymorphisms (SNPs) used as instrumental variables for various hormones and hormone-mediated diseases were derived from published genome-wide association studies (GWASs). Summary statistics for the risk of developing VTE (including deep venous thrombosis [DVT] and pulmonary embolism [PE]) were obtained from the UK Biobank and the FinnGen consortium. Inverse-variance weighting (IVW) was applied as the primary method to analyse causal associations. Other MR methods were used for supplementary estimates and sensitivity analysis. Results A genetic predisposition to greater free thyroxine (FT4) concentrations was associated with a greater risk of developing DVT (OR = 1.0007, 95%CI [1.0001–1.0013], p = 0.0174) and VTE (OR = 1.0008, 95%CI [1.0002–1.0013], p = 0.0123). Genetically predicted hyperthyroidism was significantly associated with an increased risk of developing DVT (OR = 1.0685, 95%CI [1.0139–1.1261], p = 0.0134) and VTE (OR = 1.0740, 95%CI [1.0165–1.1348], p = 0.0110). According to the initial MR analysis, testosterone concentrations were positively associated with the risk of developing VTE (OR = 1.0038, 95%CI [1.004–1.0072], p = 0.0285). After sex stratification, estradiol concentrations were positively associated with the risk of developing DVT (OR = 1.0143, 95%CI [1.0020–1.0267], p = 0.0226) and VTE (OR = 1.0156, 95%CI [1.0029–1.0285], p = 0.0158) in females, while the significant relationship between testosterone and VTE did not persist. SHBG rs858518 was identified as the only SNP that was associated with an increased risk of developing VTE, mediated by estradiol, in females. Conclusions Genetically predicted hyperthyroidism and increased FT4 concentrations were positively associated with the risk of developing VTE. The effects of genetically predicted sex hormones on the risk of developing VTE differed between males and females. Greater genetically predicted estradiol concentrations were associated with an increased risk of developing VTE in females, while the SHBG rs858518 variant may become a potential prevention and treatment target for female VTE.

Yu-Pei Wang,1,&ast; Hui-Xia Wei,2,&ast; Yuan-Yuan Hu,3 Yu-Ming Niu3,4 1Department of Stomatology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, People’s Republic of China; 2Department of Anesthesiology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, People’s Republic of China; 3Department of Stomatology, Gongli Hospital of Shanghai Pudong New Area, Shanghai, People’s Republic of China; 4Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yu-Ming Niu, Department of Stomatology, Gongli Hospital of Shanghai Pudong New Area, Shanghai, People’s Republic of China, Tel: +86 13581370999, Email niuyuming@yeah.netObjective: This study was conducted to investigate the bidirectional causal relationship between obstructive sleep apnea (OSA) and temporomandibular disorders (TMD).Methods: Using an online pooled dataset of genome-wide association studies (GWAS), a two-sample bi-directional Mendelian randomization (MR) method was implemented. Inverse variance weighting was used as the primary analyses approach, and other methods of MR Egger, weighted median method, MR-Egger, Simple mode, and Weighted mode analysis were conducted as supplements to evaluate the causal relationship between OSA and TMD with odds ratios (OR) and 95% confidence interval (CI). Furthermore, the Cochran Q, MR-Egger, and MR-PRESSO approaches were used to perform the heterogeneity test and multiple validity.Results: The general results of the forward MR analysis indicated that OSA had a significant causal influence on TMD (OR=1.241, 95% CI: 1.009– 1.526, P=0.041), but no significant correlation was observed in the reverse MR analysis (IVW: OR=0.975, 95% CI=0.918– 1.036, P=0.411).Conclusion: In summary, our research demonstrated a hereditary causative relationship between OSA and TMD, indicating that appropriate intervention is required for both prevention and treatment of TMD.Keywords: Mendelian randomization analysis, obstructive sleep apnea, temporomandibular disorders

Abstract Background Despite evidence showing a connection between inflammation and endometrial cancer (EC) risk, the surveys on genetic correlation and cohort studies investigating the impact on long-term outcomes have yet to be refined. We aimed to address the impact of inflammation factors on the pathogenesis, progression and consequences of EC. Methods For the genetic correlation analyses, a two-sample of Mendelian randomization (MR) study was applied to investigate inflammation-related single-nucleotide polymorphisms involved with endometrial cancer from GWAS databases. The observational retrospective study included consecutive patients diagnosed with EC (stage I to IV) with surgeries between January 2010 and October 2020 at the Cancer Hospital of Shantou University Medical College. Results The 2-sample MR surveys indicated no causal relationship between inflammatory cytokines and endometrial cancer. 780 cases (median age, 55.0 years ) diagnosed with EC were included in the cohort and followed up for an average of 6.8 years. Increased inflammatory parameters at baseline were associated with a higher FIGO stage and invasive EC risk (odds ratios [OR] 1.01 to 4.20). Multivariate-cox regression suggested that multiple inflammatory indicators were significantly associated with overall survival (OS) and progression-free survival (PFS) (P

Abstract Background The epigenetic-age acceleration (EAA) represents the difference between chronological age and epigenetic age, reflecting accelerated biological aging. Observational studies suggested that oral disorders may impact DNA methylation patterns and aging, but their causal relationship remains largely unexplored. This study aimed to investigate potential causal associations between dental traits and EAA, as well as to identify possible mediators. Methods Using summary statistics of genome-wide association studies of predominantly European ancestry, we conducted univariable and multivariable Mendelian randomization (MR) to estimate the overall and independent effects of ten dental traits (dentures, bleeding gums, painful gums, loose teeth, toothache, ulcers, periodontitis, number of teeth, and two measures of caries) on four EAA subtypes (GrimAge acceleration [GrimAA], PhenoAge acceleration [PhenoAA], HannumAge acceleration [HannumAA] and intrinsic EAA [IEAA]), and used two-step Mendelian randomization to evaluate twelve potential mediators of the associations. Comprehensive sensitivity analyses were used to verity the robustness, heterogeneity, and pleiotropy. Results Univariable inverse variance weighted MR analyses revealed a causal effect of dentures on greater GrimAA (β: 2.47, 95% CI: 0.93–4.01, p = 0.002), PhenoAA (β: 3.00, 95% CI: 1.15–4.85, p = 0.001), and HannumAA (β: 1.96, 95% CI: 0.58–3.33, p = 0.005). In multivariable MR, the associations remained significant after adjusting for periodontitis, caries, number of teeth and bleeding gums. Three out of 12 aging risk factors were identified as mediators of the association between dentures and EAA, including body mass index, body fat percentage, and waist circumference. No evidence for reverse causality and pleiotropy were detected (p > 0.05). Conclusions Our findings supported the causal effects of genetic liability for denture wearing on epigenetic aging, with partial mediation by obesity. More attention should be paid to the obesity-monitoring and management for slowing EAA among denture wearers.

BACKGROUND: There are conflicting data on whether nonalcoholic fatty liver disease (NAFLD) is associated with susceptibility to pancreatic cancer. Using Mendelian randomization (MR), we investigated the relationship between genetic predisposition to NAFLD and risk for pancreatic cancer. METHODS: Data from genome-wide association studies (GWAS) within the Pancreatic Cancer Cohort Consortium (PanScan; cases n = 5,090, controls n = 8,733) and the Pancreatic Cancer Case Control Consortium (PanC4; cases n = 4,163, controls n = 3,792) were analyzed. We used data on 68 genetic variants with four different MR methods [inverse variance weighting (IVW), MR-Egger, simple median, and penalized weighted median] separately to predict genetic heritability of NAFLD. We then assessed the relationship between each of the four MR methods and pancreatic cancer risk, using logistic regression to calculate ORs and 95% confidence intervals (CI), adjusting for PC risk factors, including obesity and diabetes. RESULTS: No association was found between genetically predicted NAFLD and pancreatic cancer risk in the PanScan or PanC4 samples [e.g., PanScan, IVW OR, 1.04; 95% confidence interval (CI), 0.88-1.22; MR-Egger OR, 0.89; 95% CI, 0.65-1.21; PanC4, IVW OR, 1.07; 95% CI, 0.90-1.27; MR-Egger OR, 0.93; 95% CI, 0.67-1.28]. None of the four MR methods indicated an association between genetically predicted NAFLD and pancreatic cancer risk in either sample. CONCLUSIONS: Genetic predisposition to NAFLD is not associated with pancreatic cancer risk. IMPACT: Given the close relationship between NAFLD and metabolic conditions, it is plausible that any association between NAFLD and pancreatic cancer might reflect host metabolic perturbations (e.g., obesity, diabetes, or metabolic syndrome) and does not necessarily reflect a causal relationship between NAFLD and pancreatic cancer.

Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.

ImportanceVitamin D deficiency is commonly associated with sarcopenia; however, the latest International Clinical Practice Guidelines for Sarcopenia do not recommend vitamin D supplementation for sarcopenia owing to a lack of an apparent therapeutic effect on the indices of sarcopenia among participants with replete vitamin D concentration (ie, 25-hydroxyvitamin D [25(OH)D] level >20 ng/mL) from randomized clinical trials. While there is consensus in all vitamin D guidelines that serum levels of 25(OH)D less than 10 ng/mL should be corrected, approximately 30% of the world population's 25(OH)D levels range from 10 to 20 ng/mL, and it remains unclear whether such suboptimal levels can maintain optimal health, including sarcopenia risk.ObjectiveTo investigate the association of serum 25(OH)D level, especially suboptimal levels, with sarcopenia risk.Design, setting, and participantsThis genome-wide genetic association study was performed from August 2022 to February 2023 among the 295 489 unrelated European participants from the UK Biobank (2006-2010). Nonlinear and standard mendelian randomization analyses were used to examine the association of serum 25(OH)D concentration with sarcopenia risk.ExposuresA weighted genetic risk score using 35 unrelated single-nucleotide variants from the UK Biobank and weights from the SUNLIGHT Consortium was selected as an instrumental variable for serum 25(OH)D concentration.Main outcomes and measuresThe primary outcome was sarcopenia, and the secondary outcomes consisted of grip strength, appendicular lean mass index, and gait speed.ResultsThe final genetic analyses included 295 489 participants (mean [SD] age, 56.3 [8.1] years; 139 216 female [52.9%]). There was an L-shaped association between genetically predicted serum 25(OH)D concentration and sarcopenia risk. The risk of sarcopenia decreased rapidly as 25(OH)D concentration increased until 20 ng/mL and then leveled off. The odds ratio of sarcopenia for serum 25(OH)D level of 10 vs 20 ng/mL was 1.74 (95% CI, 1.17-2.59). Similar patterns were also observed when the association between serum 25(OH)D concentration and risks of each of the sarcopenia indices were evaluated.Conclusions and relevanceIn this mendelian randomization genetic association study of adults in the UK Biobank, the findings supported a nonlinear association between suboptimal 25(OH)D levels and sarcopenia risk. Randomized clinical trials among participants with suboptimal 25(OH)D levels are required to verify the potential causality.

Mendelian randomization (MR) has emerged as a powerful approach to leverage genetic instruments to infer causality between pairs of traits in observational studies. However, the results of such studies are susceptible to biases owing to weak instruments, as well as the confounding effects of population stratification and horizontal pleiotropy. Here, we show that family data can be leveraged to design MR tests that are provably robust to confounding from population stratification, assortative mating, and dynastic effects. We show in simulations that our approach, MR-Twin, is robust to confounding from population stratification and is not affected by weak instrument bias, whereas standard MR methods yield inflated false positive rates. We then conduct an exploratory analysis of MR-Twin and other MR methods applied to 121 trait pairs in the UK Biobank data set. Our results suggest that confounding from population stratification can lead to false positives for existing MR methods, whereas MR-Twin is immune to this type of confounding, and that MR-Twin can help assess whether traditional approaches may be inflated owing to confounding from population stratification.

Background Lung cancer remains a significant global health challenge, with both its incidence and mortality rates on the rise worldwide. Despite numerous investigations into its etiology, progression, and prognostic indicators, a pressing need persists for straightforward and efficient methods to assess the early prognosis of lung cancer. Objective This study aims to investigate the prognostic significance of absolute eosinophil count level in patients with lung cancer. Methods We conducted a retrospective analysis of clinical data from 152 lung cancer patients admitted to the First Affiliated Hospital of Anhui Medical University between June 2019 and December 2022, with follow-up conducted until May 2023. Patients experiencing tumor recurrence, metastasis, or mortality were categorized into the poor prognosis group, while the remaining patients comprised the good prognosis group. Progression-free survival time (PFS) was meticulously recorded. Group comparisons were made to identify factors influencing lung cancer prognosis, followed by multivariate Cox regression analysis. Additionally, Kaplan-Meier survival analysis was employed to assess the impact of absolute eosinophil count on survival. Receiver operating characteristic (ROC) curve analysis was utilized to evaluate the prognostic efficacy of lung cancer, with the area under the ROC curve (AUC) calculated to gauge its predictive value. To further explore the relationship between eosinophil counts and lung cancer, datasets were procured from genome-wide association analysis pooled data and the International Consortium for Lung Cancer Research for Mendelian randomization analysis, elucidating potential causal links. Results Patients were stratified into good and poor prognosis groups based on their lung cancer prognosis. A statistically significant contrast in absolute eosinophil count was observed between these groups (P=0.004). Multivariate Cox regression analysis highlighted absolute eosinophil count as an independent risk factor for lung cancer survival outcomes (HR=1.58, 95%CI=1.03-2.44, P=0.037). Kaplan-Meier analysis revealed that the PFS time for patients with elevated absolute eosinophilic counts (n=76) (618.44±72.57 ) days was shorter compared to those with normal counts (n=76) (842.32±76.04) days (P=0.048). Furthermore, the AUC was 0.634. Mendelian randomization findings indicated that eosinophil count might serve as an adverse overall risk factor for lung cancer in the East Asian population (OR=1.07, 95%CI=1.01-1.13, P=0.030) . Conclusion The elevation of absolute eosinophil count levels may adversely impact the prognosis of lung cancer patients.

Abstract Background Despite emerging evidence linking blood cell indices (BCIs) to sepsis mortality, the inconsistency of observational studies obscures the clarity of these associations. This study aims to clarify the causal influence of BCIs on 28-day mortality rates in sepsis patients. Methods Utilizing univariable and multivariable Mendelian randomization (MR) analyses, we examined the impact of BCIs on sepsis mortality by analyzing data from extensive genome-wide association studies. The inverse-variance weighted (IVW) method was our primary analytic tool, complemented by several robustness checks to mitigate pleiotropy, including weighted median, mode-based estimates, MR-Egger regression, and MR-PRESSO. Subsequently, we conducted a retrospective study to further explore the correlation between platelet indices and 28-day mortality of sepsis using real-world data. Results Our findings highlight a significant causal relationship between platelet distribution width (PDW) and 28-day mortality in sepsis, with the univariable Mendelian randomization approach yielding an odds ratio of 1.12 (95% CI, 1.06–1.26; P

Abstract Background The role of hemoglobin (HGB) in common malignant tumors remains unclear. Methods A retrospective analysis was conducted to identify the correlation between HGB levels and risk of 15 malignant tumors using 50,085 samples from the National Health and Nutrition Examination Survey. Mendelian Randomization analyses (MRAs) were performed based on genome-wide association study data to assess the causal relationship between HGB levels and these malignant tumors using more than 700,000 samples. The robustness of the MRA results was confirmed through various analytical methods. Fifty-six in-house samples were used to investigate the correlation between HGB levels and the prognosis in prostate cancer (PRCA) using the Kaplan-Meier curve. Results High HGB levels were associated with a higher risk for patients with cervix cancer, melanoma, and non-melanoma skin cancer (OR > 1.000, p 0.05), suggesting the robustness of the results. The results derived from the in-house data revealed a relationship between higher HGB values and a more favorable prognosis in PRCA (p

Abstract Background Inflammatory bowel disease (IBD), a chronic inflammatory condition, is caused by several factors involving aberrant immune responses. Genetic factors are crucial in IBD occurrence. Mendelian randomization (MR) can offer a new perspective in understanding IBD’s genetic background. Methods Single nucleotide polymorphisms (SNPs) were considered instrumental variables (IVs). We analyzed the relationship between 731 immunophenotypes, 1,400 metabolite phenotypes, and IBD. The total effect was decomposed into indirect and direct effects, and the ratio of the indirect effect to the total effect was calculated. Results We identified the causal effects of HLA-DR-expressing CD14 + monocytes on IBD through MR analysis. The phenotype “HLA-DR expression on CD14 + monocytes” showed the strongest association among the selected 48 immune phenotypes. Chiro-inositol metabolites mediated the effect of CD14 + monocytes expressing HLA-DR on IBD. An increase in Chiro-inositol metabolites was associated with a reduced risk of IBD occurrence, accounting for 4.97%. Conclusion Our findings revealed a new pathway by which HLA-DR-expressing CD14 + monocytes indirectly reduced the risk of IBD occurrence by increasing the levels of Chiro-inositol metabolites. The results provided a new perspective on the immunoregulatory mechanisms underlying IBD, laying a theoretical foundation for developing new therapeutic targets in the future.

Abstract Background Some previous observational studies have linked deep venous thrombosis (DVT) to thyroid diseases; however, the findings were contradictory. This study aimed to investigate whether some common thyroid diseases can cause DVT using a two-sample Mendelian randomization (MR) approach. Methods This two-sample MR study used single nucleotide polymorphisms (SNPs) identified by the FinnGen genome-wide association studies (GWAS) to be highly associated with some common thyroid diseases, including autoimmune hyperthyroidism (962 cases and 172,976 controls), subacute thyroiditis (418 cases and 187,684 controls), hypothyroidism (26,342 cases and 59,827 controls), and malignant neoplasm of the thyroid gland (989 cases and 217,803 controls. These SNPs were used as instruments. Outcome datasets for the GWAS on DVT (6,767 cases and 330,392 controls) were selected from the UK Biobank data, which was obtained from the Integrative Epidemiology Unit (IEU) open GWAS project. The inverse variance weighted (IVW), MR-Egger and weighted median methods were used to estimate the causal association between DVT and thyroid diseases. The Cochran’s Q test was used to quantify the heterogeneity of the instrumental variables (IVs). MR Pleiotropy RESidual Sum and Outlier test (MR-PRESSO) was used to detect horizontal pleiotropy. When the causal relationship was significant, bidirectional MR analysis was performed to determine any reverse causal relationships between exposures and outcomes. Results This MR study illustrated that autoimmune hyperthyroidism slightly increased the risk of DVT according to the IVW [odds ratio (OR) = 1.0009; p = 0.024] and weighted median methods [OR = 1.001; p = 0.028]. According to Cochran’s Q test, there was no evidence of heterogeneity in IVs. Additionally, MR-PRESSO did not detect horizontal pleiotropy (p = 0.972). However, no association was observed between other thyroid diseases and DVT using the IVW, weighted median, and MR-Egger regression methods. Conclusions This study revealed that autoimmune hyperthyroidism may cause DVT; however, more evidence and larger sample sizes are required to draw more precise conclusions.

Abstract Meat intake, particularly from oily fish, has been associated with various chronic diseases. However, its relationship with acne has always been controversial. Therefore, we have adopted Mendelian randomization (MR) analysis to investigate the causal relationship between different types of meat intake and acne. The exposure and outcome datasets for this study were obtained from the Integrative Epidemiology Unit (IEU) Open GWAS project. Seven datasets on meat intake were included, which consisted of non‐oily fish, oily fish, lamb/mutton, poultry, pork, beef, and processed meat. The main methods used for MR analysis were inverse variance weighted, weighted median, and MR‐egger. To ensure the accuracy of the results, heterogeneity, pleiotropy, and Mendelian randomization pleiotropy residual sum and outlier (MR‐PRESSO) analyses were conducted. Additionally, an analysis of four risk factors (fasting insulin, insulin resistance, total testosterone level, and estradiol level) was performed to investigate the underlying mechanisms linking statistically significant meat intake to acne. Oily fish intake was found to be a protective factor for acne (OR: 0.22, 95% CI: 0.10–0.49, p

Abstract Introduction Lung cancer is a common malignant tumor, and different types of immune cells may have different effects on the occurrence and development of lung cancer subtypes, including lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD). However, the causal relationship between immune phenotype and lung cancer is still unclear. Methods This study utilized a comprehensive dataset containing 731 immune phenotypes from the European Bioinformatics Institute (EBI) to evaluate the potential causal relationship between immune phenotypes and LUSC and LUAD using the inverse variance weighted (IVW) method in Mendelian randomization (MR). Sensitivity analyses, including MR-Egger intercept, Cochran Q test, and others, were conducted for the robustness of the results. The study results were further validated through meta-analysis using data from the Transdisciplinary Research Into Cancer of the Lung (TRICL) data. Additionally, confounding factors were excluded to ensure the robustness of the findings. Results Among the final selection of 729 immune cell phenotypes, three immune phenotypes exhibited statistically significant effects with LUSC. CD28 expression on resting CD4 regulatory T cells (OR 1.0980, 95% CI: 1.0627–1.1344, p

Abstract Background Observational studies have explored the relationships of periodontitis with brain atrophy and cognitive impairment, but these findings are limited by reverse causation, confounders and have reported conflicting results. Our study aimed to investigate the causal associations of periodontitis with brain atrophy and cognitive impairment through a comprehensive bidirectional Mendelian randomization (MR) research. Methods We incorporated two distinct genome-wide association study (GWAS) summary datasets as an exploration cohort and a replication cohort for periodontitis. Four and eight metrics were selected for the insightful evaluation of brain atrophy and cognitive impairment, respectively. The former involved cortical thickness and surface area, left and right hippocampal volumes, with the latter covering assessments of cognitive performance, fluid intelligence scores, prospective memory, and reaction time for mild cognitive impairment to Alzheimer's disease (AD), Lewy body dementia, vascular dementia and frontotemporal dementia for severe situations. Furthermore, supplementary analyses were conducted to examine the associations between the longitudinal rates of change in brain atrophy and cognitive function metrics with periodontitis. The main analysis utilized the inverse variance weighting (IVW) method and evaluated the robustness of the results through a series of sensitivity analyses. For multiple tests, associations with p-values < 0.0021 were considered statistically significant, while p-values ≥ 0.0021 and < 0.05 were regarded as suggestive of significance. Results In the exploration cohort, forward and reverse MR results revealed no causal associations between periodontitis and brain atrophy or cognitive impairment, and only a potential causal association was found between AD and periodontitis (IVW: OR = 0.917, 95% CI from 0.845 to 0.995, P = 0.038). Results from the replication cohort similarly corroborated the absence of a causal relationship. In the supplementary analyses, the longitudinal rates of change in brain atrophy and cognitive function were also not found to have causal relationships with periodontitis. Conclusions The MR analyses indicated a lack of substantial evidence for a causal connection between periodontitis and both brain atrophy and cognitive impairment.

Inflammatory bowel disease (IBD) is a complex condition resulting from environmental, microbial, immunologic, and genetic factors. With the advancement of Mendelian randomization research in IBD, we have gained new insights into the relationship between these factors and IBD. Many animal models of IBD have been developed using different methods, but few studies have attempted to model IBD by combining environmental factors and microbial factors. In this review, we examine how environmental factors and microbial factors affect the development and progression of IBD, and how they interact with each other and with the intestinal microbiota. We also summarize the current methods for creating animal models of IBD and compare their advantages and disadvantages. Based on the latest findings from Mendelian randomization studies on the role of environmental factors in IBD, we discuss which environmental and microbial factors could be used to construct a more realistic and reliable IBD experimental model. We propose that animal models of IBD should consider both environmental and microbial factors to better mimic human IBD pathogenesis and to reveal the underlying mechanisms of IBD at the immune and genetic levels. We highlight the importance of environmental and microbial factors in IBD pathogenesis and offer new perspectives and suggestions for improving experimental animal modeling. Our goal is to create a model that closely resembles the clinical picture of IBD.

Abstract Background Recent research suggests that periodontitis can increase the risk of chronic obstructive pulmonary disease (COPD). In this study, we performed two-sample Mendelian randomization (MR) and investigated the causal effect of periodontitis (PD) on the genetic prediction of COPD. The study aimed to estimate how exposures affected outcomes. Methods Published data from the Gene-Lifestyle Interaction in the Dental Endpoints (GLIDE) Consortium’s genome-wide association studies (GWAS) for periodontitis (17,353 cases and 28,210 controls) and COPD (16,488 cases and 169,688 controls) from European ancestry were utilized. This study employed a two-sample MR analysis approach and applied several complementary methods, including weighted median, inverse variance weighted (IVW), and MR-Egger regression. Multivariable Mendelian randomization (MVMR) analysis was further conducted to mitigate the influence of smoking on COPD. Results We chose five single-nucleotide polymorphisms (SNPs) as instrumental variables for periodontitis. A strong genetically predicted causal link between periodontitis and COPD, that is, periodontitis as an independent risk factor for COPD was detected. PD (OR = 1.102951, 95% CI: 1.005–1.211, p = 0.039) MR-Egger regression and weighted median analysis results were coincident with those of the IVW method. According to the sensitivity analysis, horizontal pleiotropy’s effect on causal estimations seemed unlikely. However, reverse MR analysis revealed no significant genetic causal association between COPD and periodontitis. IVW (OR = 1.048 > 1, 95%CI: 0.973–1.128, p = 0.2082) MR Egger (OR = 0.826, 95%CI:0.658–1.037, p = 0.1104) and weighted median (OR = 1.043, 95%CI: 0.941–1.156, p = 0.4239). The results of multivariable Mendelian randomization (MVMR) analysis, after adjusting for the confounding effect of smoking, suggest a potential causal relationship between periodontitis and COPD (P = 0.035). Conclusion In this study, periodontitis was found to be independent of COPD and a significant risk factor, providing new insights into periodontitis-mediated mechanisms underlying COPD development.

Abstract Aging is a recognized risk factor for periodontitis, while biological aging could provide more accurate insights into an individual's functional status. This study aimed to investigate the potential association between biological aging and periodontitis. Epidemiological data from 9803 participants in the 2009–2014 National Health and Nutrition Examination Survey were analyzed at a cross-sectional level to assess this link. Three biological ages [Klemera–Doubal method (KDM), PhenoAge, and homeostatic dysregulation (HD)] and two measures of accelerated biological aging (BioAgeAccel and PhenoAgeAccel) were set as primary exposure and were calculated. Logistic regression and restricted cubic spline regression were employed to examine the relationship between biological aging and periodontitis. Additionally, Mendelian randomization analysis was conducted to explore the causal connection between accelerated biological aging and periodontitis. After adjusting for age, gender, race, educational level, marital status, ratio of family income, and disease conditions, this study, found a significant association between subjects with older higher biological ages, accelerated biological aging, and periodontitis. Specifically, for a per year increase in the three biological ages (HD, KDM, and PhenoAge), the risk of periodontitis increases by 15%, 3%, and 4% respectively. Individuals who had positive BioAgeAccel or PhenoAgeAccel were 20% or 37% more likely to develop periodontitis compared with those who had negative BioAgeAccel or PhenoAgeAccel. Furthermore, a significant non-linear positive relationship was observed between the three biological ages, accelerated biological aging, and periodontitis. However, the Mendelian randomization analysis indicated no causal effect of accelerated biological aging on periodontitis. Our findings suggest that biological aging may contribute to the risk of periodontitis, highlighting the potential utility of preventive strategies targeting aging-related pathways in reducing periodontitis risk among older adults.

Background: Despite emerging evidence linking blood cell indices (BCIs) to sepsis mortality, the inconsistency of observational studies obscures the clarity of these associations. This study aims to clarify the causal influence of BCIs on 28-day mortality rates in sepsis patients. Methods: Utilizing univariable and multivariable Mendelian randomization (MR) analyses, we examined the impact of BCIs on sepsis mortality by analyzing data from extensive genome-wide association studies. The inverse-variance weighted (IVW) method was our primary analytic tool, complemented by several robustness checks to mitigate pleiotropy, including weighted median, mode-based estimates, MR-Egger regression, and MR-PRESSO. Subsequently, we conducted a retrospective study to further explore the correlation between platelet indices and 28-day mortality of sepsis using real-world data. Results: Our findings highlight a significant causal relationship between platelet distribution width (PDW) and 28-day mortality in sepsis, with the univariable Mendelian randomization approach yielding an odds ratio of 1.12 (95% CI, 1.06–1.26; P < 0.05). Multivariable analysis further substantiated PDW's robust association with mortality risk (OR 1.23; 95% CI, 1.03–1.48; P < 0.05). Conversely, our analysis did not uncover significant correlations between the genetic predispositions to other BCIs—including red blood cell count, erythrocyte distribution width, platelet count, mean platelet volume, white blood cell count, neutrophil count, neutrophil percentage, lymphocyte count, and lymphocyte percentage—and 28-day mortality in sepsis. Additionally, an inverse MR analysis did not establish a causal impact of 28-day mortality in sepsis on PDW (OR 1.00; 95% CI, 1.00—1.07; P = 0.29). Moreover, a similar result was observed in the retrospective study. Conclusions: The study underscores the independent causal role of PDW in predicting 28-day mortality in sepsis, suggesting its potential utility in early patient assessment, risk stratification, and tailoring of therapeutic interventions. [ABSTRACT FROM AUTHOR]

Background: For children who are unable to cooperate due to severe dental anxiety (DA), dental treatment of childhood caries under Dental General Anesthesia (DGA) is a safe and high-quality treatment method. This study aims to evaluate the impact on neurocognitive functions and the growth and development of children 2 years after dental procedure based on previous research, and further establish a causal relationship between general anesthesia (GA) and changes in children's neurocognitive functions by incorporating Mendelian Randomization (MR) analysis. Methods: Data were collected and analyzed from 340 cases of S-ECC procedures of preschool children conducted in 2019. This involved comparing the neurocognitive outcomes 2 years post-operation of preschool children receiving dental procedures under general anesthesia or local anesthesia. Physical development indicators such as height, weight, and body mass index (BMI) of children were also compared at baseline, half a year post-operation, and 2 years post-operation. We performed a Mendelian randomization analysis on the causal relationship between children's cognitive development and general anesthesia, drawing on a large-scale meta-analysis of GWAS for anesthesia, including multiple general anesthesia datasets. Results: Outcome data were obtained for 111 children in the general anesthesia group and 121 children in the local anesthesia group. The mean FSIQ score for the general anesthesia group was 106.77 (SD 6.96), while the mean score for the local anesthesia group was 106.36 (SD 5.88). FSIQ scores were equivalent between the two groups. The incidence of malnutrition in children in the general anesthesia group was 27.93% (p < 0.001) before surgery and decreased to 15.32% (p > 0.05) after 2 years, which was not different from the general population. The IVW method suggested that the causal estimate (p = 0.99 > 0.05, OR = 1.04, 95% CI = 5.98 10-4--1.82 - 103) was not statistically significant for disease prevalence. This indicates no genetic cause-and-effect relationship between anesthesia and childhood intelligence. Conclusion: There were no adverse outcomes in neurocognitive development in 2 years after severe early childhood caries (S-ECC) procedure under total sevoflurane-inhalation in preschool children. The malnutrition condition in children can be improved after S-ECC procedure under general anesthesia. Limited MR evidence does not support a correlation between genetic susceptibility to anesthesia and an increased risk for intelligence in children. [ABSTRACT FROM AUTHOR]