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Abstract Background The liver‒brain axis is critical in neurodegenerative diseases (NDs), with lipid metabolism influencing neuroinflammation and microglial function. A systematic investigation of the genetic relationship between lipid metabolism abnormalities and ND, namely, Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), is lacking. To assess potential causal links between ND and six lipid parameters, two-sample Mendelian randomization (MR) was used. Methods Large-scale European ancestry GWAS data for lipid parameters and ND (AD, ALS, PD, and MS) were used. Genetic variants demonstrating significant correlations (P

Mendelian randomization (MR) is a statistical method that uses genetic variants as instrumental variables to estimate the causal effect of exposure on an outcome in the presence of unmeasured confounding. In this review, we argue that it is crucial to acknowledge the instrumental variable assumptions in MR analysis. We describe widely used MR methods, using an example from obesity-related metabolic disorders. We describe situations in which instrumental variable assumptions are violated and explain how to evaluate these violations and employ robust methods for accommodating such violations.

Miao Hu, Yi Deng, Yujie Bai, Jiayan Zhang, Xiahong Shen, Lei Shen, Ling Zhou Department of Nephrology, The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of ChinaCorrespondence: Ling Zhou, Email zl66060@163.comBackground: Renal failure related death caused by diabetic kidney disease (DKD) is an inevitable outcome for most patients. This study aimed to identify the critical genes involved in the onset and progression of DKD and to explore potential therapeutic targets of DKD.Methods: We conducted a batch of protein quantitative trait loci (pQTL) Mendelian randomization analysis to obtain a group of proteins with causal relationships with DKD and then identified key proteins through colocalization analysis to determine correlations between variant proteins and disease outcomes. Subsequently, the specific mechanisms of key regulatory genes involved in disease progression were analyzed through transcriptome and single-cell analysis. Finally, we validated the mRNA expression of five key genes in the DKD mice model using reverse transcription quantitative PCR (RT-qPCR).Results: Five characteristic genes, known as protein kinase B beta (AKT2), interleukin-2 receptor beta (IL2RB), neurexin 3(NRXN3), slit homolog 3(SLIT3), and TATA box binding protein like protein 1 (TBPL1), demonstrated causal relationships with DKD. These key genes are associated with the infiltration of immune cells, and they are related to the regulatory genes associated with immunity. In addition, we also conducted gene enrichment analysis to explore the complex network of potential signaling pathways that may regulate these key genes. Finally, we identified the effectiveness and reliability of these selected key genes through RT-qPCR in the DKD mice model.Conclusion: Our results indicated that the AKT2, IL2RB, NRXN3, SLIT3, and TBPL1 genes are closely related to DKD, which may be useful in the diagnosis and therapy of DKD.Keywords: Mendelian randomization analysis, diabetic kidney disease, clinical correlated genes, biomarker, immune cell infiltration

Abstract Previous observational studies have reported inconsistent associations between nut consumption and cardiovascular diseases (CVD). This study aims to identify the causal relationship between different types of nuts consumption and CVD, and to quantify the potential mediating effects of cardiometabolic factors. We utilized Genome-Wide Association Study (GWAS) data to assess the causal effects of nut consumption on CVD using two-sample Mendelian randomization (MR) and a two-step MR analysis. The inverse variance weighted (IVW) method indicated that processed (salted or roasted) peanuts were potentially and positively associated with ischaemic heart disease (IHD) (OR 1.4866; 95%CI 1.0491-2.1065). No causal relationships were found between nuts consumption and other CVD outcomes, including atrial fibrillation, angina, coronary atherosclerosis, coronary heart disease, IHD, myocardial infarction, subarachnoid hemorrhage, intracerebral haemorrhage and stroke. Both MR-Egger and median-based methods yielded similar results to IVW. Furthermore, in the two-step MR analysis, fasting insulin, low-density lipoprotein cholesterol and fasting blood glucose were identified as mediators in the potential causal relationship between processed peanuts and IHD, explaining 16.98%, 6.38% and 4.91% of the mediation, respectively. In total, these mediators accounted for 28.27% of the association between salted or roasted peanuts and IHD.

Qingqing Li,* Jing Yin,* Qibin Lin, Jilong He, Xiu Shi, Hanxiang Nie Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hanxiang Nie, Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, Wuchang District, Wuhan, 430060, People’s Republic of China, Email nhxiang@whu.edu.cnBackground: Lung transplantation is the only effective therapeutic option for patients with end-stage lung disease. However, ischemia/reperfusion injury (IRI) during transplantation is a leading cause of primary graft dysfunction (PGD). Ferroptosis, a form of iron-dependent cell death driven by lipid peroxidation, has been implicated in IRI across various organs. This study aims to explore the role of ferroptosis in lung transplantation-related ischemia/reperfusion injury and to identify its potential molecular mechanisms through bioinformatics analysis.Methods: Transcriptome data from lung transplant patients were obtained from the Gene Expression Omnibus (GEO) database. Ferroptosis-related differentially expressed genes (FRGs) were identified by analyzing gene expression profiles before and after reperfusion. Weighted gene co-expression network analysis (WGCNA) was used to identify module genes, and overlapping genes were further analyzed using two machine learning algorithms. The CIBERSORT algorithm was applied to assess immune cell infiltration, while Mendelian randomization (MR) analysis was used to investigate causal relationships between candidate genes and PGD. Finally, Consensus clustering based on FRGs was performed to identify subtypes.Results: We identified four candidate genes associated with ferroptosis during lung reperfusion: tumor necrosis factor alpha-induced protein 3 (TNFAIP3), C-X-C motif chemokine ligand 2 (CXCL2), neural precursor cell expressed developmentally down-regulated 4-like (NEDD4L), and sestrin 2 (SESN2). These genes were closely associated with immune cell infiltration. MR analysis suggested that SESN2 might play a protective role against PGD. Additionally, consensus clustering revealed distinct immune infiltration patterns across subtypes, providing insights for personalized therapeutic approaches to lung ischemia/reperfusion injury (LIRI).Conclusion: This study highlights TNFAIP3, CXCL2, NEDD4L, and SESN2 as candidate genes associated with ferroptosis during LIRI, with SESN2 potentially protecting against PGD. These findings offer promising therapeutic targets for preventing LIRI and improving outcomes in lung transplantation.Keywords: lung ischemia/reperfusion injury, ferroptosis, biomarkers, immune cell infiltration

Ping Huang,* Yong Zhao,* Haiyan Wei, Wenhui Wu, Ziwen Guo, Shiyi Ma, Meng Xu, Qin Wang, Cheng Jia, Ting Xiang, Huamao Li Department of Rehabilitation Medicine, General Hospital of Central Theater Command, Wuhan, 430065, People’s Republic of China*These authors contributed equally to this workCorrespondence: Huamao Li; Ting Xiang, Department of Rehabilitation Medicine, General Hospital of Central Theater Command, Wuhan, 430065, People’s Republic of China, Email 71831102@qq.com; 42254403@qq.comBackground: In preliminary research and literature review, we identified a potential link between chronic obstructive pulmonary disease (COPD) and lipid metabolism. Therefore, this study employed Mendelian randomization (MR) analysis to investigate the potential causal connection between blood lipids and COPD.Materials and Methods: A genome-wide association study (GWAS) on COPD was conducted, encompassing a total of 112,583 European participants from the MRC-IEU. Additionally, extensive UK Biobank data pertaining to blood lipid profiles within European cohorts included measurements for low-density lipoprotein cholesterol (LDL-C) with 440,546 individuals, high-density lipoprotein cholesterol (HDL-C) with 403,943 individuals, triglycerides (TG) with 441,016 individuals, total cholesterol (TC) with 187,365 individuals, apolipoprotein A-I (apoA-I) with 393,193 individuals, and apolipoprotein B (apoB) with 439,214 individuals. Then, MR analyses were performed for lipids and COPD, respectively. The primary analytical technique employed was the inverse-variance weighted (IVW) approach, which included a 95% confidence interval (CI) to calculate the odds ratio (OR). Additionally, a sensitivity analysis was conducted to assess the dependability of the MR analysis outcomes.Results: MR analysis was primarily based on IVW, unveiled a causal link between COPD and LDL-C (OR=0.994, 95% CI (0.989, 0.999), P=0.019), TG (OR=1.005, 95% CI (1.002, 1.009), P=0.006), and apoA-I (OR=0.995, 95% CI (0.992, 0.999), P=0.008), in addition, no causal link was found with HDL-C, TC, apoB. Sensitivity analysis demonstrated the robustness of these causal relationships. However, through multivariate MR(MVMR) and multiple testing correction, LDL-C and TG had no causal effect on the outcome. ApoA-I remained a protective factor for the risk of COPD (OR=0.994, 95% CI (0.990– 0.999), P=0.008).Conclusion: Through MR analysis, this study offers evidence of a causal link between apoA-I with COPD. This further substantiates the potential role of lipid metabolism in COPD, and has significant clinical implications for the prevention and management of COPD.Keywords: lipid metabolism, COPD, Mendelian randomization analysis, apolipoprotein A-I

Abstract Urolithiasis is a common and recurrent condition in the urological spectrum. Despite various proposed mechanisms, the causal relationship between sleep traits and the risk of urolithiasis remains unclear. We used publicly available genome-wide association study (GWAS) summary data from the UK Biobank and FinnGen to perform a two-sample Mendelian randomization (MR) analysis and genetic correlation analysis, evaluating the causal relationship and genetic correlation between sleep traits (chronotype, getting up in the morning, sleep duration, nap during the day, and insomnia) and urolithiasis (calculus of the kidney and ureter, and calculus of the lower urinary tract). Additionally, multivariable MR (MVMR) analysis adjusted for body mass index (BMI) and other sleep characteristics was conducted to assess the direct impact of sleep traits on the risk of urinary tract stones. The LD score regression (LDSC) analysis indicated a genetic correlation between insomnia and upper urinary tract stones (rg = 0.082, P = 0.017, Adjusted P = 0.085), but no significant genetic correlation was found for other sleep traits. Our results indicated no causal relationship between sleep traits and upper urinary tract stones. However, insomnia was significantly associated with a higher risk of lower urinary tract stones (IVW [inverse variance weighted] OR [odds ratio] = 5.91, 95% CI [confidence interval] 1.52–22.98, P = 0.010, Adjusted P = 0.030), while early rising exhibited a protective effect (IVW OR = 0.29, 95% CI 0.11–0.76, P = 0.012, Adjusted P = 0.030). In the MVMR analysis, insomnia consistently showed a similar trend, whereas daytime napping significantly reduced the risk of lower urinary tract stones (OR = 0.28, 95% CI 0.12–0.65, P = 0.003). This study provides MR-based evidence suggesting that insomnia may increase the risk of lower urinary tract stones, while daytime napping may reduce this risk. No causal relationship was found between sleep characteristics and upper urinary tract stones.

Abstract Background Pancreatic cancer is among the most lethal malignancies, characterized by a poor prognosis and limited modifiable factors. Emerging evidence indicates that serum mineral levels may influence the likelihood of developing pancreatic cancer. However, the causal relationship between serum minerals and pancreatic cancer remains unclear and warrants further investigation. Methods This Mendelian randomization (MR) study was conducted to explore the causal effects of serum mineral levels on pancreatic cancer risk. Genetic variants associated with serum mineral levels, including calcium, iron, magnesium, zinc, selenium, and copper, were selected as instrumental variables (IVs) from large-scale genome-wide association study (GWAS) data. Multiple methods, including inverse variance weighting (IVW), MR-Egger, weighted median, weight methods, were employed to perform MR analysis. The effect sizes from the MR analysis, using two independent GWAS summary datasets related to pancreatic cancer, were combined through meta-analysis. The Cochrane Q test, MR-Egger intercept test, MR-PRESSO global test, and leave-one-out test were conducted for sensitivity tests. Results Our MR analysis demonstrated a significant causal effect of genetically predicted serum calcium levels on increased pancreatic cancer risk [OR = 1.64, 95% CI 1.05–2.57, P = 0.029 (discovery cohort); OR = 1.52, 95% CI 1.07–2.15, P = 0.019 (validation cohort)], while no significant associations were found for other serum minerals (P > 0.05). Additional meta-analysis reinforces and substantiates this conclusion (pooled OR = 1.56, 95% CI 1.19–2.06, P = 0.001). No evidence of pleiotropy or heterogeneity was detected across multiple sensitivity tests (P > 0.05). Conclusion This study provides new evidence supporting the causal role of certain serum minerals, particularly calcium, in the development of pancreatic cancer. These findings may help inform future research into preventive strategies or therapies aimed at modulating mineral levels in patients at high risk of pancreatic cancer.

Hao Liu,1,2,* Zhengze Zhang,1,2,* Yuewen He,1,2 Longfei Ding,1,2 Tong Wu,1,2 Yong Wang,2,3 Wuhua Ma2 1Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 2Department of Anesthesiology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 3State Key Laboratory of Traditional Chinese Medicine Syndrome, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wuhua Ma; Yong Wang, Department of Anesthesiology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, 16 Jichang Road, Guangzhou, Guangdong, 510405, People’s Republic of China, Tel +86 13318860680 ; +86 15920382796, Email tuesdaymorninggz@126.com; wangyong@gzucm.edu.cnPurpose: Numerous studies have identified a correlation between sleep and delirium; however, the causal relationship remains ambiguous. This bidirectional two-sample Mendelian randomization (MR) study was conducted to examine the possible causal relationships between sleep traits and delirium.Patients and Methods: Utilizing genome-wide association studies (GWAS), we identified ten sleep traits: chronotype, sleep duration, short sleep duration, long sleep duration, daytime napping, daytime sleepiness, insomnia, number of sleep episodes (NSE), sleep efficiency, and rapid eye movement sleep behavior disorder (RBD). In this MR study, genetic variants independently associated with exposures were selected as instrumental variables (IVs). To establish causal inferences, three regression models were employed—inverse variance weighted (IVW), MR Egger, and weighted median (WM) —and conducted sensitivity analyses to assess the robustness of our findings.Results: Our results suggest no significant causal association between the ten sleep traits and the risk of delirium. The reverse MR analysis revealed that delirium is associated with an increased propensity for morning chronotype [ORIVW, 1.025; 95% CI, 1.012– 1.036; p = 1.50E-05; adjusted p values (padjusted)= 1.35E-04] and a decreased risk of long sleep duration [ORIVW, 0.996; 95% CI, 0.993– 0.999; p = 0.013; padjusted= 0.059]. However, no robust evidence currently exists to substantiate a causal relationship between delirium and other sleep traits.Conclusion: Our bidirectional, two-sample MR analysis study did not provide definitive evidence that sleep traits may augment the susceptibility to delirium. However, the reverse MR results indicate that delirium may predispose patients to an earlier sleep-wake cycle. Additional large-scale investigations are necessary to examine the bidirectional causality between delirium and sleep traits.Keywords: sleep traits, delirium, Mendelian randomization analysis, genome-wide association studies

Epilepsy is a neurological disorder characterized by recurrent, unprovoked seizures. Currently, the associations among skin microbiota, circulating metabolites, and epilepsy are still not well studied. In this study, we applied univariate and two-step Mendelian randomization analysis using single nucleotide polymorphisms as instrumental variables to analyze the possible associations. Five skin microbiota (asv022, asv008, bacillales, clostridiale, and micrococcaceae) and four circulating metabolites were found to be associated with epilepsy. Our results also showed that leucine level (p-value = 0.0487, OR = 1.067) and glutamine level (p-value = 0.0372, OR = 1.065) show a slight increased association with epilepsy, while phospholipids in medium LDL (p-value = 0.0302, OR = 0.9308) and ratio of saturated fatty acids (p-value = 0.0309, OR = 0.9017) appear to show a slight inverse correlation with epilepsy. In addition, the heterogeneity test and horizontal pleiotropy analysis indicated these results are robust in different situations. By mapping analysis, 54 genes were associated with at least two metabolites. By functional analysis, these genes were enriched in the immune-related pathways, which may have systemic effects on brain function. Our results provide a novel insight for understanding possible mechanisms of some epilepsy associations, which by further study might provide avenues for therapy research.

Wenjuan Qiu,1 Ruifang Wang,1 Lili Liang,1 Yuning Sun,1 Rong Zhou,2 Xiaoli Wang,2 Wen Sun,3 Xuefan Gu1 1Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Institute for Pediatric Research, Shanghai, 200092, People’s Republic of China; 2Medical Affairs, GeneScience Pharmaceuticals Co. Ltd. (Gensci), Shanghai, 200233, People’s Republic of China; 3Beijing Intelligent Decision Medical Technology Co. Ltd., Beijing, 100028, People’s Republic of ChinaCorrespondence: Xuefan Gu, Email gu_xfan@163.comIntroduction: Growth hormone (GH) is crucial for immune system development and regulation, potentially benefiting COVID-19 outcomes. However, there are limited studies on the role of GH treatment in COVID-19 in children with short stature.Methods: We conducted a survey study to evaluate the association between GH treatment and COVID-19 risk in short stature children aged 7 to 18 years. Two groups were defined: GH Treated and GH Untreated. The primary endpoint was the proportion of children with COVID-19 histories. Secondary endpoints included the presence, severity, and duration of COVID-19 symptoms. Exploratory endpoints included the frequency of common colds after GH treatment. We further performed two-sample Mendelian randomization (MR) analyses to explore the causal relationship between GH levels and COVID-19 susceptibility, hospitalization, and severity using genome-wide association study summary-level data.Results: Of the 201 children, 113 (56.2%) reported COVID-19 history, and 149 (74.1%) used GH. The mean age was 11.02 ± 2.10 years. GH treatment was associated with a somewhat lower proportion of COVID-19 history (− 9.77%, 95% confidence interval [CI] − 26.41% to 6.87%; P = 0.289), and the odds ratio (OR) is 0.58 (95% CI 0.29 to 1.14, P = 0.120) after adjusting for confounders. Among the 113 children with COVID-19 histories, the highest body temperature was significantly lower in the GH Treated group (P = 0.040). In the MR analyses, for one unit increase in GH level, the OR was 0.95 (95% CI 0.92 to 0.99, P = 0.022) for COVID-19 susceptibility, 0.86 (95% CI 0.77 to 0.96, P = 0.007) for COVID-19 hospitalization, and 0.95 (95% CI 0.84 to 1.07, P = 0.392) for COVID-19 severity.Conclusion: GH treatment was associated with somewhat decreased COVID-19 susceptibility but was not statistically significant. Higher GH levels were causally associated with a significantly lower rate of COVID-19 susceptibility and hospitalization.Keywords: Mendelian randomization analysis, growth hormone treatment, COVID-19, children with short stature

HanYu Wang,1,&ast; BoWen Yang,2,&ast; XiaoYu Zeng,1,&ast; ShiPeng Zhang,1 Yanjie Jiang,3 Lu Wang,1 Chao Liao1,4 1Clinical Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China; 2Dongguan Hospital, Guangzhou University of Chinese Medicine, Dongguan, Guangdong, People’s Republic of China; 3Department of Neurology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 4Department of Otorhinolaryngology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chao Liao, Department of Otorhinolaryngology, Hospital of Chengdu University of Traditional Chinese Medicine, No. 37 on the Street of Shi Er Bridge, City Chengdu, Province Sichuan, People’s Republic of China, Email lc_cdutcm@163.comBackground: Obesity is a significant risk factor for obstructive sleep apnea (OSA). The weight-adjusted-waist index (WWI) reflects weight-independent centripetal obesity. Our study aims to evaluate the relationship between WWI and OSA.Methods: The data used in the current cross-sectional investigation are from the National Health and Nutrition Examination Survey (NHANES), which was carried out between 2017 and 2020. We utilized weighted multivariable-adjusted logistic regression to evaluate the relationship between WWI and the risk of OSA. In addition, we applied various analytical methods, including subgroup analysis, smoothing curve fitting, threshold effect analysis and the receiver operating characteristic (ROC) curve. To further explore the relationship, we conducted a MR study using genome-wide association study (GWAS) summary statistics. We performed the main inverse variance weighting (IVW) method along with other supplementary MR methods. In addition, a meta-analysis was conducted to provide an overall evaluation.Results: WWI was positively related to OSA with the full adjustment [odds ratio (OR)=1.14, 95% confidence interval (95% CI): 1.06– 1.23, P< 0.001]. After converting WWI to a categorical variable by quartiles (Q1-Q4), compared to Q1 the highest WWI quartile was linked to an obviously increased likelihood of OSA (OR=1.26, 95% CI: 1.06– 1.50. P=0.01). Subgroup analysis revealed the stability of the independent positive relationship between WWI and OSA. Smoothing curve fitting identified a saturation effect of WWI and OSA, with an inflection point of 11.62. In addition, WWI had the strongest prediction for OSA (AUC=0.745). Sensitivity analysis was performed to verify the significantly positive connection between WWI and stricter OSA (OR=1.18, 95% CI: 1.05– 1.32, P=0.005). MR meta-analysis further supported our results (OR=2.11, 95% CI: 1.94– 2.30, P< 0.001). Sensitivity analysis confirmed the robustness and reliability of these findings.Conclusion: WWI was significantly associated with the risk of OSA, suggesting that WWI could potentially serve as a predictor for OSA.Keywords: weight-adjusted waist circumference index, WWI, obstructive sleep apnea, OSA, National Health and Nutrition Examination Survey, NHANES, Mendelian randomization analysis, cross-sectional study

Abstract Background The global burden of type 2 diabetes (T2D) and colorectal cancer (CRC) continues to rise. Observational studies have suggested a link between T2D and an elevated risk of CRC. However, these studies are often susceptible to confounding factors and reverse causation, leading to inconsistent findings. There is a specific gap in knowledge regarding the causal nature of the relationship between T2D and CRC, which this study aims to address using a more robust approach. To fill this gap, we employed Mendelian randomization (MR), a method that uses genetic variants as instrumental variables (IVs) to infer causality, providing clearer insight into the genetic links between T2D and CRC. Methods A bidirectional MR study was conducted to investigate the causal links between T2D and CRC. Genetic instruments for T2D were derived from two large genome-wide association studies (GWAS) with a total sample size of X individuals, and CRC genetic instruments were obtained from a GWAS with Y individuals. The MR analysis utilized the inverse-variance weighted (IVW) method as the primary analysis, alongside sensitivity analyses such as heterogeneity and pleiotropy analysis to account for potential pleiotropy and bias. Additionally, to enhance the robustness of the findings and minimize the influence of data from different GWAS sources, we performed a meta-analysis of the IVW results. Results The MR analysis and meta-analysis revealed that genetically predicted T2D is associated with an increased risk of CRC (Pooled ORIVW = 1.07, 95% CI 1.02–1.12, P = 0.003). However, the reverse analysis did not indicate a causal effect of genetically predicted CRC on T2D risk (Pooled ORIVW = 1.02, 95% CI 0.96–1.09, P = 0.469). Sensitivity analyses supported the robustness of these findings, indicating no evidence of heterogeneity or pleiotropic effects that could bias the results (all P > 0.05). Conclusion Our bidirectional MR study and meta-analysis provide evidence that T2D increases the risk of colorectal cancer. However, there is no evidence to support a reverse causal relationship. These findings highlight the importance of monitoring and managing T2D as part of CRC prevention strategies.

Abstract Background The gut microbiota of venous thromboembolism (VTE) patients exhibited significant alterations. However, the causal relationship between gut microbiota and VTE has not been fully understood. This study aimed to assess the causal relationship between gut microbiota and the risk of VTE using a two-sample Mendelian Randomization (MR) study. Methods The gut microbiota and VTE genetic data were collected from the MiBioGen consortium and the UK biobank, respectively. The potential causal relationship between gut microbiota and VTE was investigated using a two-sample MR analysis, including inverse variance weighted (IVW), weighted median, MR-Egger, simple mode, and weighted mode methods. Cochran’s Q-test, MR-PRESSO, and MR-Egger regression intercept analysis were utilized to perform sensitivity analysis. Results At the genus level, the results of MR analysis found that Coprococcus1 (OR: 1.0029, 95% CI: 1.0005–1.0054, p = 0.0202) was suggestively linked with an increased risk of VTE, while Slackia (odds ratio (OR): 0.9977, 95% confidence interval (CI): 0.9957–0.9998, p = 0.0298), Butyricicoccus (OR: 0.9971, 95% CI: 0.9945–0.9997, p = 0.0309), Eubacterium coprostanoligenes group (OR: 0.9972, 95% CI: 0.9946–0.9999, p = 0.0445), and Bacteroides (OR: 0.9964, 95% CI: 0.9932–0.9995, p = 0.0234) were suggestively associated with a reduced risk of VTE. No heterogeneity and horizontal pleiotropy was detected. Conclusion This study found that there were potential causal relationships between five gut microbiota and VTE. Our findings may provide new insights into the mechanisms of VTE.

Objective Numerous studies focused upon the association of uric acid with cardiovascular and metabolic diseases. However, whether or not there are causal relationships with these chronic diseases has remained unclear. We conducted the study to explore the causal relationship between uric acid and various chronic diseases. Methods Inverse variance weighting (IVW), MR-Egger regression, weighted median (WM), simple mode and weighted mode methods were utilized for Mendelian randomization (MR) analysis. The relevant data were obtained from the Genome-Wide Association Study (GWAS) pooled dataset with serum uric acid (SUA) levels as exposure and coronary artery disease (CAD), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), atrial fibrillation (AF), type 2 diabetes (T2D), chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), ischemic stroke (IS), osteoporosis (OP) and peripheral artery disease (PAD) as outcomes in the East Asian population. Sensitivity analyses were also performed for examining the data robustness of the results through heterogeneity test, horizontal multiple validity test and leave-one-out methods. Results SUA level had positive causal associations with CAD（OR=1.240，95%CI：1.152～1.335，P＜0.001）, DBP（OR=1.074，95% CI：1.030～1.120，P＜0.001）, MAP（OR =1.050，95% CI：1.016～1.086，P = 0.004）and CHF（OR = 1.146，95% CI：1.032～1.274，P = 0.011）and no causal associations with SBP, AF, T2D, COPD, IS, OP or PAD. However, the causal association of SUA with CAD was not robust due to the presence of horizontal pleiotropy. Conclusions A positive causal relationship exists between SUA level and DBP, MAP and CHF. And an elevation of SUA level boosts the levels of DBP and MAP and the risk of CHF.

Abstract Background Benign prostatic hyperplasia (BPH) is a common chronic condition in elderly men. Observational studies have identified several comorbidities associated with BPH. However, these studies are limited by various confounding factors and do not clearly explain the association between BPH and its comorbidities. We investigated the association between BPH and comorbidities using the Global Burden of Disease (GBD) database combined with Mendelian randomization (MR) methods. Methods Through an extensive PubMed search, we identified 22 diseases associated with BPH and selected 9 significant comorbidities from the GBD database for a detailed correlation analysis. We also considered socio-economic and environmental influences on BPH. Utilizing the GWAS database, we gathered data on BPH and 20 comorbidities, employing the Linkage Disequilibrium Score Regression (LDSC) method to unearth genetic connections. Causality was determined through both univariable and multivariable bidirectional MR analyses, supplemented by Steiger directionality tests to confirm causation. The study’s integrity was fortified by employing various MR models and conducting rigorous sensitivity analyses. The synthesis of GBD data with LDSC and MR findings offered a nuanced understanding of the BPH-comorbidity nexus. Additionally, we explored the genetic basis and the role of mediating factors between BPH and comorbidities through phenome-wide association studies (PheWAS), colocalization analysis, and mediation MR. Results Correlation analysis of GBD data found associations of prostate cancer, chronic kidney disease and depression with BPH. LDSC results indicated that prostatitis and bladder cancer are related to BPH. Two associations were replicated in bidirectional univariable MR, linking BPH with a higher risk of prostatitis and prostate cancer. conducted sensitivity analyses to confirm the robustness of the results and all Steiger directionality tests were correct. Multiple multivariable MR models validated these results. PheWAS analysis showed that outliers in MR do not significantly impact MR results. Through colocalization analysis, three shared loci between BPH and both prostatitis and prostate cancer were identified. Mediation analysis found that, after adjusting for BPH, fruit consumption was associated with a lower risk of prostatitis, and morning person and chronotype were associated with a lower risk of prostate cancer. Conclusions This study uncovered associations between BPH and various comorbidities, emphasizing the causal relationships between BPH, prostatitis, and prostate cancer. Our research provides a new perspective in understanding the comorbid associations of BPH.

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 Hearing loss(HL) represents a significant public health concern. This study aimed to determine the association between hearing loss and gout and to elucidate the underlying causative mechanisms. Data for this study were obtained from the National Health and Nutrition Examination Survey (NHANES) and Mendelian randomization (MR) basic databases. Initially, baseline characteristics of individuals with and without gout were compared. A nonlinear relationship between pure tone audiometry (PTA) values and gout prevalence was confirmed through restricted cubic spline (RCS) curve analysis. Subsequently, hearing loss was categorized into different levels based on PTA values, and multiple logistic regression analysis was employed to calculate the impact of varying degrees of hearing loss on the risk of gout. Finally, MR analysis was conducted to further elucidate the causal relationship between hearing loss and gout. A total of 3,258 individuals were included in this study, with a gout prevalence of 3.7%. Significant differences were observed between the gout group and the non-gout group in variables such as age, gender, blood uric acid level, BMI, hypertension, and diabetes. RCS curve analysis revealed a significant nonlinear relationship between PTA values and gout risk, particularly when PTA values exceed a specific threshold, where the curve flattens. Based on different levels of hearing loss derived from PTA values, multiple logistic regression analysis demonstrated that mild and moderate hearing loss significantly increased the risk of gout, remaining statistically significant after adjusting for covariates (odds ratio (OR) = 2.10–3.48, P

Abstract Background In recent years, the anti-tumor effects of vitamin D have garnered increasing attention. However, previous epidemiological studies on the relationship between vitamin D and nasopharyngeal carcinoma (NPC) have yielded inconsistent results. This study aims to further explore whether vitamin D helps reduce the risk of NPC through Mendelian randomization (MR) and meta-analysis. Methods Based on the core assumption of MR study, instrumental variables (IVs) for vitamin D, serving as genetic proxies, were obtained from summary data of large genome-wide association study (GWAS). Inverse-variance weighted (IVW) was utilized as the primary MR analytical method to explore the causal relationship between vitamin D and NPC. Sensitivity analyses included heterogeneity testing and horizontal pleiotropy testing. To further validate the robustness of the result, meta-analysis was employed to obtain pooled effects from databases of different sources. Results In the discovery cohort, the IVW result suggest that vitamin D is a potential protective factor against NPC (odds ratio (OR) = 0.35, 95% confidence interval (CI): 0.13–0.89, P = 0.028). The finding was further corroborated by two independent replication cohorts [OR = 0.32, 95% CI: 0.13–0.80, P = 0.018 (ukb-d-30890_irnt); OR = 0.34, 95% CI: 0.13–0.90, P = 0.029(ebi-a-GCST90025967)]. Subsequent meta-analysis indicated that vitamin D markedly reduces the risk of NPC (OR = 0.34, 95% CI: 0.19–0.58, P 0.05). Conclusion This study provides robust evidence that vitamin D significantly reduces the risk of NPC. Through MR and meta-analysis, we have demonstrated a protective role of vitamin D in NPC development. These findings suggest that maintaining adequate vitamin D levels may be a potential strategy for reducing NPC. Further research is warranted to confirm these results and explore the underlying mechanisms involved.

AIM: To assess whether there is a possible causal link between the intake of cheese and the risk of diabetic retinopathy (DR) utilizing a two-sample Mendelian randomization (MR) analysis. METHODS: The research data were obtained from summary statistics of genome-wide association studies (GWAS). Genetic loci closely related to cheese intake were extracted as instrumental variables (IVs), and DR was the outcome variable. The data were extracted from individuals of European ethnicity. The data of cheese intake consisted of 451 486 samples with 9 851 867 single nucleotide polymorphisms (SNPs), while the DR data consisted of 206 234 samples with 16 380 446 SNPs. Sixty-one genetic loci closely related to cheese intake were selected as IVs. MR analysis was performed by inverse-variance weighted (IVW) method and MR-Egger regression respectively. The causal relationship between cheese intake and DR was evaluated using odds ratios (ORs) and 95% confidence intervals (CIs). Egger-intercept test was used to test horizontal pleiotropy and sensitivity analysis was performed by leave-one-out test. RESULTS: The P value of the IVW method was less than 0.05, indicating a significant negative correlation between cheese intake and DR. MR-Egger regression showed that the intercept was 0.01 with a standard error of 0.022, and a P-value of 0.634, indicating no evidence of horizontal pleiotropy affecting the IVs related to the exposure factors. Besides, heterogeneity tests confirmed the absence of heterogeneity, and the “leave-one-out” sensitivity analysis demonstrated that the results were stable. CONCLUSION: Cheese intake is causally negatively correlated with the occurrence of DR, and cheese intake could reduce the risk of DR.

Purpose: Explore the causal relationship between the gut microbiota and erectile dysfunction (ED) at phylum, class, order, family, and genus levels, and identify specific pathogenic bacteria that may be associated with the onset and progression of ED. Materials and Methods: The genetic variation data of 196 human gut microbiota incorporated in our study came from the human gut microbiome Genome Wide Association Studies (GWAS) dataset released by the MiBioGen Consortium. The GWAS statistics for ED were extracted from one study by Bovijn et al., which included 223,805 participants of European ancestry, of whom 6,175 were diagnosed with ED. Subsequently, Mendelian randomization (MR) analysis was carried out to explore whether a causal relationship exists between the gut microbiota and ED. Additionally, bidirectional MR analysis was performed to examine the directionality of the causal relationship. Results: Through MR analysis, we found that family Lachnospiraceae (odds ratio [OR]: 1.27, 95% confidence interval [CI]: 1.05–1.52, p=0.01) and its subclass genus LachnospiraceaeNC2004 group (OR: 1.17, 95% CI: 1.01–1.37, p=0.04) are associated with a higher risk of ED. In addition, genus Oscillibacter (OR: 1.17, 95% CI: 1.02–1.35, p=0.03), genus Senegalimassilia (OR: 1.32, 95% CI: 1.06–1.64, p=0.01) and genus Tyzzerella3 (OR: 1.14, 95% CI: 1.02–1.27, p=0.02) also increase the risk of ED. In contrast, the inverse variance weighted estimate of genus RuminococcaceaeUCG013 (OR: 0.77, 95% CI: 0.61–0.96, p=0.02) suggests that it has a protective effect against the occurrence of ED. Conclusions: This study preliminarily identified 6 bacterial taxa that may have a causal relationship with ED, including family Lachnospiraceae, genus Lachnospiraceae NC2004 group, Oscillibacter, Senegalimassilia, Tyzzerella 3 and Ruminococcaceae UCG013. These identified important bacterial taxa may serve as candidates for microbiome intervention in future ED clinical trials.

Abstract Background Numerous observational studies have indicated that patients with Guillain-Barré syndrome (GBS) frequently had infections with various pathogens before the onset of the disease, particularly several viral infections. Some of these infections are linked to specific clinical and immunological subgroups of GBS, suggesting a potential correlation between viral infections and the development of GBS. However, observational studies have several limitations, including the presence of confounding factors. Method We explored the potential correlation between HIV, SARS-CoV-2, varicella-zoster virus, herpes simplex virus, Epstein-Barr virus, hepatitis B virus, and influenza virus with GBS using a two-sample Mendelian randomization approach. The data was derived from published summary statistics from genome-wide association studies (GWAS). After removing linkage disequilibrium, selecting strong instrumental variables and addressing confounding factors, we would conduct a two-sample Mendelian randomization analysis along with sensitivity testing and the MR-Steiger directional test. Result HIV may have a causal association with GBS (IVW: p = 0.010, OR [95% CI] 1.240 [1.052–1.463]), while no such relationship exists with COVID-19 (IVW: p = 0.275, OR [95% CI] 0.831[0.596–1.159]), varicella (IVW: p = 0.543, OR [95% CI] 0.919 [0.701–1.206]), herpes zoster (IVW: p = 0.563, OR [95% CI] 0.941 [0.766–1.156]), HSV (IVW: p = 0.280, OR [95% CI] 1.244 [0.837–1.851]), EBV (IVW: p = 0.218, OR [95% CI] 0.883 [0.724–1.076]), HBV (IVW: p = 0.179, OR [95% CI] 1.072 [0.969–1.187]), or influenza virus (IVW: p = 0.917, OR [95% CI] 0.971 [0.553–1.703]). We did not find any abnormal SNPs, pleiotropy, or heterogeneity, nor is there any reverse causation. Conclusion Our study results indicate a causal relationship between HIV and GBS, providing new research directions for the etiology of GBS.

Background This study employed a bidirectional Mendelian Randomization (MR) approach to explore the causal relationships between Oral Lichen Planus (OLP), diabetes mellitus (DM), and glycemic control. It also aims to identify potential pharmacological and herbal treatments that effectively address both OLP and the metabolic dysfunctions associated with DM. Methods This study employs a two-way MR approach to investigate the potential causal relationships between diabetes type and glycated hemoglobin (HbA1c) levels, and the risk of OLP. We analyzed differentially expressed genes from the OLP dataset in the Genomics Expression Omnibus (GEO) database, cross-referencing these with HbA1c-related genes for enrichment analysis. Additionally, the Drug-Gene Interaction Database (DGIdb) and Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) were utilized to assess the effectiveness of specific drugs, herbs, and ingredients in treating OLP while managing blood glucose levels. Results The MR analysis revealed a significant association between Type 1 Diabetes mellitus (T1DM) and an increased risk of OLP, unlike Type 2 Diabetes mellitus (T2DM). This finding indicates a unique immunological interaction in T1DM that may predispose individuals to OLP. The drug prediction analysis focused on core targets linked to OLP and HbA1c, evaluating the therapeutic potential of retinoic acid, prednisone, and thalidomide for treating OLP and regulating blood glucose levels. Additionally, herbal medicines such as Ecliptae herbaand Amygdalus communis vas, along with herbal ingredients like quercetin, luteolin, and 17-beta-estradiol, were identified for their anti-inflammatory properties and potential to mitigate metabolic dysfunction in diabetes. Conclusion The study highlighted a complex interplay between diabetes and OLP, underscoring the efficacy of integrated therapeutic strategies that target both conditions. The findings suggest that both pharmaceutical and herbal treatments can effectively manage the clinical manifestations of OLP and associated metabolic challenges. This holistic approach to treatment could significantly enhance patient outcomes by addressing the interconnected aspects of these chronic conditions.

Abstract Objective Previous observational studies have indicated associations between various inflammatory cytokines and diabetic nephropathy (DN) caused by type 2 diabetes mellitus (T2DM). However, the causality remains unclear. We aimed to further evaluate the causal association between 91 inflammatory cytokines and DN using bidirectional two-sample Mendelian randomization (MR) analysis. Method Summary statistics for DN were obtained from a publicly available genome-wide association study (GWAS) analysis. Data pertaining to inflammatory cytokines were derived from a GWAS protein quantitative trait locus (pQTL) study. The primary analytical approach employed the inverse variance weighted (IVW) method, complemented by MR-Egger regression, weighted mode (WM), and weighted median (WME) methods to evaluate the causal association between inflammatory cytokines and DN. Sensitivity analyses were conducted to validate the robustness of the findings. Result Among individuals of European ancestry, the IVW method results revealed a positive causal association between the gene expression of tumor necrosis factor ligand superfamily member 14 (TNFSF14), and TNF-related activation-induced cytokine (TRANCE) with DN. Conversely, a negative causal association was observed between the gene expression of interleukin-1-alpha (IL-1α), and transforming growth factor-alpha (TGF-α) with DN. Among individuals of East Asian ancestry, the IVW method results indicated a negative causal association between the gene expression of glial cell line-derived neurotrophic factor (GDNF) and DN. Notably, these findings persisted without evidence of horizontal pleiotropy or heterogeneity, ensuring their robustness and reliability. Conclusion The MR analysis underscores a causal association between inflammatory cytokines and DN, providing an important reference and evidence for the study of DN.

Abstract Background Endometriosis, a prevalent chronic condition, afflicts approximately 10% of women in their reproductive years. Emerging evidence implicates immune cells in the pathogenesis of endometriosis, particularly in angiogenesis, tissue proliferation, and lesion invasion. This investigation employs two-sample Mendelian Randomization (MR) to dissect the bidirectional causal relationships between immune cell profiles and endometriosis. Methods We leveraged publicly available genome-wide association study (GWAS) data to elucidate the causal interplay between immune cell traits and endometriosis. Utilizing GWAS summary statistics ranging from accession numbers GCST90001391 to GCST90002121 and endometriosis data from the FinnGen study GWAS (8,288 endometriosis cases and 68,969 controls), we adopted stringent criteria for instrumental variable selection. We applied MR-Egger, weighted median, inverse variance weighted (IVW), and weighted mode methods to derive causal estimates. To address potential heterogeneity and pleiotropy, Cochran’s Q test, MR-Egger intercept, and leave-one-out analyses were executed. Reverse-direction MR and bidirectional MR analyses evaluated potential reciprocal causation and the influence of endometriosis on immune cell composition. Results Our analysis identified five immune phenotypes inversely associated with endometriosis risk. These phenotypes comprise: a percentage of CD11c + HLA-DR + + monocytes, CD25 expression on CD39 + CD4 + T cells, elevated CD25 on CD45RA + CD4 + non-regulatory T cells, HLA-DR intensity on HLA-DR + CD8 bright (CD8br) T cells, and the proportion of naïve double-negative (CD4 − CD8− %DN) T cells. In contrast, eleven phenotypes were positively correlated with endometriosis risk, including: CD127 expression on T cells, the proportion of CD24 + CD27 + B cells within lymphocytes, CD25 expression on CD28 + CD4 + T cells, CD28 expression on CD39 + activated regulatory T cells (activated Tregs), the frequency of bright CD33 HLA-DR + CD14 − cells within the CD33br HLA-DR + compartment, CD45 expression on lymphocytes and natural killer (NK) cells, activation status of central memory CD8 bright (CM CD8br) T cells, CX3CR1 expression on monocytes, and the percentage of HLA-DR + NK cells within the NK cell subset. Sensitivity assessments that excluded significant heterogeneity and pleiotropy confirmed the stability of these associations, thereby reinforcing the validity of our findings. Conclusion This study provides novel evidence of the potential causal impact of specific immune cells on the risk of developing endometriosis. These findings enhance our understanding of endometriosis pathophysiology and may inform innovative approaches for its diagnosis and management. While our findings provide novel insights, limitations such as potential horizontal pleiotropy and reliance on European ancestry data should be considered. Future research should expand to diverse populations and incorporate individual-level data to refine these findings.

Shiya Zeng,1,&ast; Yanyue Tan,1,2,&ast; Zhiwei Cao,3 Yunhao Zheng,1 Tiqian Liu,1 Yifei Deng,1 Xin Xiong1 1State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Nursing, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3School of Stomatology, Tianjin Medical University, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xin Xiong, State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No. 15, West Section 3, Second Ring Road, Chengdu, Sichuan, 610041, People’s Republic of China, Tel +86 028 85501425, Email drxiongxin@scu.edu.cnObjective: Growing researches explore vitamin D’s role in temporomandibular disorders (TMDs), but the link between vitamin D and TMDs remains debated. To clarify the causal relationship, we conducted a Mendelian randomization (MR) analysis using data from genome-wide association studies (GWAS).Subjects and Methods: The GWAS dataset of vitamin D (GWAS ID: ukb-d-30890_irnt; sample size: 329247) was obtained from the IEU Open GWAS project. And that of TMDs (GWAS ID: finn-b-TEMPORO; sample size: 134280), initiated on August 25th, 2017 and publicly released on December 18th, 2023, was extracted from the FinnGen dataset, whose cases were diagnosed based on the revised International Classification of Diseases, 10th Edition (ICD-10) code K07.6. Both datasets were obtained from the European population. According to three assumptions of MR analysis, a bi-directional MR analysis was performed to measure the causal relationship, with Inverse variance weighted (IVW) as the primary method and MR Egger and Weighted median as supplement. Moreover, diverse sensitivity analyses, including Cochran’s Q test, MR Egger intercept, Mendelian randomized polymorphism RESidual Sum and Outlier (MR-PRESSO), and leave-one-out analysis, were used to verify the stability of the findings.Results: The MR analysis supported causal effects of vitamin D levels on TMDs risks within the European population using IVW method [odds ratio = 1.316; 95% confidence interval = 1.086 to 1.595; P = 0.005], supported by MR Egger and Weighted median. While there was no indication that TMDs have a direct impact on vitamin D levels [β: − 0.00738, standard error = 0.00665; P = 0.568].Conclusion: The study revealed that within the European population higher levels of vitamin D led to higher risks of developing temporomandibular disorders, but found no obvious evidence that TMDs are causally associated with vitamin D. The conclusion should be cautiously interpreted, given the selection bias of TMDs patients sample.Keywords: Mendelian randomization analysis, temporomandibular joint disorders, vitamin D, 25-hydroxyvitamin D

Abstract Metastasis is the major cause of treatment failure in patients with prostate adenocarcinoma (PRAD). Diverse programmed cell death (PCD) patterns play an important role in tumor metastasis and hold promise as predictive indicators for PRAD metastasis. Using the LASSO Cox regression method, we developed PCD score (PCDS) based on differentially expressed genes (DEGs) associated with PCD. Clinical correlation, external validation, functional enrichment analysis, mutation landscape analysis, tumor immune environment analysis, and immunotherapy analysis were conducted. The role of Prostaglandin D2 Synthase (PTGDS) in PRAD was examined through in vitro experiments, single-cell, and Mendelian randomization (MR) analysis. PCDS is elevated in patients with higher Gleason scores, higher T stage, biochemical recurrence (BCR), and higher prostate-specific antigen (PSA) levels. Individuals with higher PCDS are prone to metastasis, metastasis after BCR, BCR, and castration resistance. Moreover, PRAD patients with low PCDS responded positively to immunotherapy. Random forest analysis and Mendelian randomization analysis identified PTGDS as the top gene associated with PRAD metastasis and in vitro experiments revealed that PTGDS was considerably downregulated in PRAD cells against normal prostate cells. Furthermore, the overexpression of PTGDS was found to suppress the migration, invasion, proliferationof DU145 and LNCaP cells. To sum up, PCDS may be a useful biomarker for forecasting the possibility of metastasis, recurrence, castration resistance, and the efficacy of immunotherapy in PRAD patients. Additionally, PTGDS was identified as a viable therapeutic target for the management of PRAD.

Abstract While numerous studies have underscored the implication of immune cells and metabolites in temporomandibular disorders (TMD), conclusive evidence for causality remains elusive. Consequently, our aim is to explore the causal connections between immunophenotypes and plasma metabolites in relation to TMD employing a bidirectional Mendelian randomization (MR) approach. Summary statistics data on 731 immunophenotypes (n = 3757) and 1091 plasma metabolites (n = 8299) were obtained from comprehensive genome-wide association studies (GWAS), while TMD data (5668 cases and 205,355 controls) were acquired from the FinnGen Consortium. Bidirectional MR analyses and a two-step MR approach assessed causal relationships and potential intermediaries. Various corrections and sensitivity analyses were utilized to assess the robustness of the findings. Two immunophenotypes and seven metabolites were significantly associated with TMD risk. Specifically, Alpha-hydroxyisovalerate mediated the link between CD33 on CD33dim HLA DR + CD11b + and TMD (β = 0.034, P = 5.95 × 10–5), while CD8 on NKT cells mediated the causal relationship between 5-acetylamino-6-formylamino-3-methyluracil levels and TMD (β = 0.069, P = 5.11 × 10–5). Our findings revealed the causal relationships between immunophenotypes and plasma metabolites on TMD from a genetic perspective, potentially aiding in TMD prevention.

ABSTRACT Background Neurodegenerative diseases involve progressive neuronal dysfunction and cognitive decline, posing substantial global challenges. Although the precise causes remain unclear, several studies highlight the role of protein metabolism abnormalities in disease development. This study investigates the causal links between variations in mitochondrial protein genes and neurodegenerative diseases, aiming to elucidate their potential contributions to disease progression and identify novel therapeutic strategies. Methods Herein, we utilized data from genome‐wide association studies (GWAS) on mitochondrial proteins and neurodegenerative diseases. Bidirectional Mendelian randomization (MR), employing instrumental variables (IVs), was used to assess causal relationships. The primary method for estimating causal effects was the inverse variance‐weighted (IVW) method, supplemented by additional MR approaches. Results Bidirectional MR revealed significant associations between mitochondrial protein gene variants and neurodegenerative diseases. Specifically, associations were found with Alzheimer's disease (AD) (three proteins), Parkinson's disease (PD) (four proteins), amyotrophic lateral sclerosis (ALS) (six proteins), multiple sclerosis (two proteins), and dementia with Lewy bodies (four proteins). Conversely, analyses indicated significant associations of neurodegenerative diseases with mitochondrial protein gene variants, notably with AD, dementia with Lewy bodies, and multiple sclerosis, affecting multiple mitochondrial protein levels. Bidirectional causality was observed between dementia with Lewy bodies and C21orf33. Conclusions Using MR, we identified significant links between mitochondrial protein gene mutations and the risk of neurodegenerative diseases. These results highlight reciprocal relationships where certain neurodegenerative diseases influence mitochondrial protein expression levels. These findings underscore the pivotal role of mitochondrial proteins in neurodegenerative diseases, offering critical insights into disease mechanisms and potential therapeutic avenues.

Backgroundhyperthyroidism characterized by low thyrotropin, highlighting complications and risks, including cardiac issues, osteoporosis, adverse pregnancy outcomes, unintentional weight loss, and increased mortality associated with untreated hyperthyroidism. However, the casual association between telomere length (TL) and hyperthyroidism remains unclear.ObjectiveWe aim to explore the casual relationship between TL and hyperthyroidism.MethodsA two-sample bidirectional Mendelian randomization (MR) analysis employed the inverse variance weighted (IVW) method, supplemented by additional approaches such as Weighted Median (WM), and MR Egger.ResultsThe summary statistics for TL were derived from the UK Biobank, comprising 472,174 individuals, while the data for hyperthyroidism were sourced from the GWAS Catalog and the FinnGen database, encompassing cohorts of 460,499 and 173,938 individuals, respectively. Utilizing 139 genome-wide significant single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) for TL, forward MR analyses indicated a negative causal effect of TL on hyperthyroidism. The risk of hyperthyroidism decreased as genetically predicted TL increased by one standard deviation, as determined by the IVW form GWAS Catalog (OR:0.659,95%CI: 0.541-0.802, p 0.05). Sensitivity analyses confirmed the robustness of these results, suggesting minimal susceptibility to confounding factors and bias.ConclusionThe finding that longer telomeres reduce hyperthyroidism risk highlights the need to validate hyperthyroidism’s impact on telomere length, offering valuable insights for prevention and treatment.

BackgroundDyslipidemia is closely related to diabetic neuropathy. This study examined the potential causal relationship involving 179 lipid species and the disease.MethodsThe pooled data on 179 lipid species and diabetic neuropathy were obtained from previous genome-wide association studies (GWAS). A Mendelian Randomization (MR) method was employed to investigate the potential causal link, and the robustness of the findings was confirmed through comprehensive sensitivity analyses.ResultsGenetically, phosphatidylcholine might be associated with the risk of diabetic neuropathy. Upon adjusting for multiple comparisons, higher levels of phosphatidylcholine (16:0_20:2) (OR = 0.82, 95%CI: 0.73-0.91; P < 0.001, FDR = 0.033) and phosphatidylcholine (16:1_18:1) (OR = 0.77, 95%CI: 0.67-0.88; P < 0.001, FDR = 0.019) are associated with a decreased risk of diabetic neuropathy. Further multivariable MR (MVMR) analysis demonstrated the effect of genetically predicted phosphatidylcholine (16:1_18:1) remained after adjusting for body mass index (BMI) and glycated hemoglobin (HbA1c). Sensitivity assessments have confirmed the robustness of these findings, revealing no evidence of heterogeneity or pleiotropy.ConclusionOur research linked certain lipid species with diabetic neuropathy risk, suggesting that targeting lipids could be a therapeutic strategy in clinical trials addressing this condition.

Background: Cigarette smoking is a leading cause of preventable death worldwide, with its associated diseases and conditions. Emerging evidence suggests that cigarette smoking contributes to a range of pathological metabolic injuries, including diabetes and nonalcoholic fatty liver disease (NAFLD). The impact of gut microbiota on metabolic health and diseases has been observed, but the causality remains uncertain. Objective: To confirm the causal relationship between cigarette smoking and metabolic diseases, and to investigate the possible mediating effect of gut microbiota on these connections. Methods: The relationships among cigarette smoking, metabolic diseases, and the gut microbiome were analyzed by Univariate Mendelian randomization (UVMR). Furthermore, to mitigate the impact of confounding factors, adjusted models were conducted via the multivariate Mendelian randomization (MVMR) method, aiming to improve the accuracy of prediction. Ultimately, the study evaluated the effect of the intermediary factor, gut microbiome, on the relationship between cigarette smoke and metabolic diseases. Results: The phenomenon that a causal relationship between cigarette smoke (249752 individuals) and gut microbiota (7738 individuals), diabetes (406831 individuals), NAFLD (377998 individuals), hypercholesterolaemia (463010 individuals), and obesity (463010 individuals) was observed using UVMR. In the MVMR model, the genetic connection between cigarette smoking, gut microbiota, and type 2 diabetes remained significant. Of note, paraprevotella_clara served an important mediating role in the type 2 diabetes associated with cigarette smoke. Conclusion: This work offered genetic evidence linking cigarette smoke to metabolic diseases, suggesting that the gut microbiota, particularly paraprevotella_clara, might be a crucial mediator in the development of type 2 diabetes caused by cigarette smoke. Our future studies should consider conducting other ethnic groups MR analyses, particularly with larger sample sizes. Still, more in vivo and in vitro work should be carried out to validate the precise effect and molecular mechanisms of the gut microbiome.

ObjectivePrevious observational studies suggest a potential link between gut microbiota, metabolites, and diabetic nephropathy. However, the exact causal relationship among these factors remains unclear.MethodWe conducted a two-sample bidirectional Mendelian randomization study using summary statistics from the IEU OpenGWAS Project database to investigate gut microbiota, metabolites, and diabetic nephropathy. A range of methods, including inverse variance weighting, MR-Egger, weighted median, and simple median, were applied to examine causal associations. Sensitivity analyses were performed to assess the robustness of the results. Additionally, reverse Mendelian randomization analysis was conducted, treating significant gut microbiota as the outcome, to evaluate effects and perform sensitivity testing. This comprehensive approach provided an in-depth assessment of the interactions among gut microbiota, metabolites, and diabetic nephropathy.ResultThe Inverse Variance Weighted estimates revealed that the abundance of Lachnospiraceae, Parasutterella, and Eubacterium exhibited negative causal effects on diabetic nephropathy, while Coprococcus, Sutterella, Faecalibacterium prausnitzii, and Bacteroides vulgatus showed protective causal effects against the condition. However, reverse Mendelian randomization analysis did not identify any significant associations between diabetic nephropathy and the identified gut microbiota. Furthermore, the estimates indicated that Cholesterol, Pyridoxate, Hexanoylcarnitine, X-12007, Octanoylcarnitine, 10-nonadecenoate (19:1n9), X-12734, and the average number of double bonds in a fatty acid chain had negative causal effects on diabetic nephropathy. In contrast, Methionine, Glycodeoxycholate, X-06351, 1-stearoylglycerol (1-monostearin), 5-dodecenoate (12:1n7), X-13859, 2-hydroxyglutarate, Glycoproteins, Phospholipids in IDL, and the concentration of small HDL particles demonstrated protective causal effects. Notably, sensitivity analyses did not detect any heterogeneity or horizontal pleiotropy, ensuring the robustness of the findings.ConclusionModulating gut microbiota diversity and composition offers a promising strategy for improving the incidence and prognosis of diabetic nephropathy. This highlights the need for future clinical trials focusing on microbiome-based interventions, potentially utilizing microbiome-dependent metabolites. Such approaches could transform the treatment and management of diabetic nephropathy and its associated risk factors, paving the way for more effective therapeutic strategies to combat this debilitating condition.

ObjectiveThe main objective of this study was to explore and identify new genetic targets in small-cell lung cancer (SCLC) through transcriptomics analysis and Mendelian randomization (MR) analysis, which will help in the subsequent development of new therapeutic interventions.MethodsIn this study, we extracted the SCLC dataset from the Gene Expression Omnibus (GEO) database, processed the data, and screened out differentially expressed genes (DEGs) using R software. Based on expression quantitative trait loci data and the genome-wide association study data of SCLC, MR analysis was used to screen the genes closely related to SCLC disease, which intersect with DEGs to obtain co-expressed genes (CEGs), and the biological functions and pathways of CEGs were further explored by enrichment analysis. In addition, the CIBERSORT algorithm was applied to assess the level of immune cell infiltration in SCLC and to analyze the correlation between CEGs and immune cells. Meanwhile, we performed a survival analysis on these five CEGs using an independent cohort of SCLC patients. Finally, the results for the target genes were validated.ResultsIn this study, 857 DEGs were identified, including 443 up-regulated and 414 down-regulated genes, and 5 CEGs (PSAT1, PSRC1, COLEC12, PLLP, HP) that were significantly associated with SCLC were identified through further intersecting. The results of enrichment analyses indicated that CEGs play important roles in several key functions and pathways. Immune-cell-related analysis revealed the unique distribution of immune cell infiltration in SCLC and the mechanism of immune cell regulation by CEGs. Survival analysis results indicated that PSRC1 was significantly correlated with the overall survival of SCLC, and the survival rate of the high-expression group was markedly lower than that of the low-expression group. Finally, the consistency of the results between the validation group analyses and MR analysis confirmed that the results of this study is reliable.ConclusionThe CEGs and their associated functions and pathways screened in this study may be potential targets of therapeutic intervention in SCLC by targeting specific molecular pathways.

ObjectiveThe impact of lipid-lowering medications on chronic kidney disease (CKD) remains a subject of debate. This Mendelian randomization (MR) study aims to elucidate the potential effects of lipid-lowering drug targets on CKD development.MethodsWe extracted 11 genetic variants encoding targets of lipid-lowering drugs from published genome-wide association study (GWAS) summary statistics, encompassing LDLR, HMGCR, PCSK9, NPC1L1, APOB, ABCG5/ABCG8, LPL, APOC3, ANGPTL3, and PPARA. A Mendelian randomization analysis was conducted targeting these drug-related genes. CKD risk was designated as the primary outcome, while estimated glomerular filtration rate (eGFR) and blood urea nitrogen (BUN) were assessed as secondary outcomes. Additionally, mediation analysis was performed utilizing 731 immune cell phenotypes to identify potential mediators.ResultsThe meta-analysis revealed a significant association between ANGPTL3 inhibitors and a reduced risk of CKD (OR [95% CI] = 0.85 [0.75-0.96]). Conversely, LDLR agonists were significantly linked to an increased risk of CKD (OR [95% CI] = 1.11 [1.02-1.22]). Regarding secondary outcomes, lipid-lowering drugs did not significantly affect eGFR and BUN levels. Mediation analysis indicated that the reduction in CKD risk by ANGPTL3 inhibitors was mediated through modulation of the immune cell phenotype, specifically HLA-DR on CD14+ CD16+ monocytes (Mediated proportion: 4.69%; Mediated effect: -0.00899).ConclusionThrough drug-targeted MR analysis, we identified a causal relationship between lipid-lowering drug targets and CKD. ANGPTL3 and LDLR may represent promising candidate drug targets for CKD treatment.

OBJECTIVES Observational studies have reported that diabetes is a risk factor that increases the risk of atherosclerotic cardiovascular disease (ASCVD). However, the causal relationship remains a matter of debate. This study aimed to analyze the relationship between fasting serum glucose (FSG) and ASCVD. METHODS This study used data from the Korean Cancer Prevention Study-II (KCPS-II) Biobank, consisting of 159,844 people recruited with consent from 18 health examination centers from 2004 to 2013. Outcomes were confirmed based on diagnoses on hospital discharge summaries from National Health Insurance System. We used linear and non-linear Mendelian randomization (MR) methods. The outcome data were obtained from KCPS-II, and the exposure data were derived from the Korean Genome Epidemiology Study. RESULTS First, a prospective cohort study estimated that for each 10 mg/dL increase in FSG level, the risk of ASCVD increased by 4% (hazard ratio [HR], 1.04; 95% confidence interval [CI], 1.03 to 1.05). Second, the 2-sample MR study showed that every 10 mg/dL increase in FSG influenced the risk of ASCVD (odds ratio [OR], 1.11; 95% CI, 1.04 to 1.18). Third, the multivariable MR study showed that the OR per 10 mg/dL increase in FSG on ASCVD was 1.14 (p

ABSTRACT BACKGROUND There is an association between thyroid dysfunction and cerebral infarction (CI), but the causality cannot be determined. A two‐sample two‐way Mendelian randomization (MR) study was conducted to assess the causal relationship between thyroid function and CI. METHODS We selected single‐nucleotide polymorphisms (SNPs) associated with five phenotypes, including CI from the UK Biobank (n = 361,194), hyperthyroidism from the IEU Open GWAS database (n = 484,598), hypothyroidism from the IEU Open GWAS database (n = 473,703), normal thyroid‐stimulating hormone (TSH) (n = 271,040), and normal free thyroxine (FT4) (n = 119,120) from the Thyroidomics Consortium database. For the forward MR analysis, the exposures were hyperthyroidism, hypothyroidism, TSH, and FT4. The inverse variance weighted (IVW) method, weighted median (WM), and MR‐Egger revealed the causality with CI. For the reverse MR analysis, CI was regarded as the exposure, and four thyroid function phenotypes were the outcomes. The sensitivity and heterogeneity test was assessed using Cochran's Q test, MR‐Egger regression, and leave‐one‐out analysis. RESULTS The MR analysis indicated that genetic susceptibility to hyperthyroidism increased the risk of CI (IVW‐OR = 1.070; 95% CI: 1.015–1.128; p = 0.003). In reverse MR, genetic susceptibility to RA is not associated with hyperthyroidism (IVW‐OR = 1.001; 95% CI: 1.000–1.001; p = 0.144). Any positive or reverse causal relationship between hypothyroidism, FT4, and TSH with CI could not be established. Sensitivity and heterogeneity test consolidated our findings. CONCLUSION The causality between CI and hyperthyroidism demonstrated patients with hyperthyroidism have a risk of genetic variants for CI. In the future, further studies are needed to fully explore their mechanisms of action.

Background Previous observational studies have shown that immune cells play an important role in IgA nephropathy. However, the specific causal relationship between the two is inconsistent.Methods We used a two-sample mendelian randomization(MR) analysis to investigate the causal association between 731 immune cell signatures and IgA nephropathy in this study. Based on published GWAS data, immune cells were characterized by four immune types absolute cell (AC) counts, median fluorescence intensity (MFI), morphological parameters (MP), relative cell (RC) counts. Meanwhile, heterogeneity test, horizontal pleiotropy and sensitivity test were used to evaluate the robustness and reliability of the results.Results An important causal association was achieved for 14 RC traits/IgA nephropathy, 3 AC traits/IgA nephropathy, 10 MFI traits/IgA nephropathy, and 1 MP trait/IgA nephropathy. However, after false discovery rate (FDR) correction, only one immunophenotype was found to be protective against IgA nephropathy. The OR of herpesvirus entry mediator (HVEM) on terminally differentiated CD4+ T cell (maturation stages of T-cell panel) on IgA nephropathy risk was estimated to be 0.727 (95%CI: 0.624-0.847, p = 4.20e − 05, PFDR = 0.023) according to inverse variance weighting (IVW) method, and the weighted-median method yielded similar results (OR = 0.743, 95% CI: 0.596-0.927, p = 0.008). Although not statistically significant, the association was consistent with MR-Egger, simple mode and weighted mode.Conclusions Our study further confirmed that immune cells play a complex and important role in the pathogenesis of IgA nephropathy, providing evidence for clinical research.

Objective Previous observational studies have indicated associations between various immune cells and diabetic nephropathy (DN). However, the causality remains unclear. We aimed to further evaluate the causal association between immune cells and DN using bidirectional two-sample Mendelian randomization (MR) analysis.Method The DN data were retrieved from the IEU OpenGWAS Project database, while the data for 731 immune cells were sourced from GWAS summary statistics by Orru ̀ et al. The investigation into the causal relationship between immune cells and DN employed the inverse variance weighted (IVW), weighted median (WME), and MR-Egger methods. The stability and reliability of the findings underwent evaluation through Cochran’s Q test, MR-Egger intercept’s P-value, MR-PRESSO, and Leave-One-Out (LOO) method.Result The IVW estimates suggested a positive causal effect of CD25 on IgD-CD38dim B cell, CD25 on naive-mature B cell, CD127 on granulocyte, SSC-A on HLA DR + Natural Killer, HLA DR on plasmacytoid Dendritic Cell, and HLA DR on Dendritic Cell on DN. Conversely, the abundance of Myeloid Dendritic Cell, CD62L- Dendritic Cell %Dendritic Cell, CD86+ myeloid Dendritic Cell %Dendritic Cell, CD14- CD16-, CX3CR1 on CD14- CD16-, and SSC-A on CD4+ T cell had negative causal effects on DN. However, after correcting the P value for significant causality results using the FDR method, it was concluded that only Myeloid Dendritic Cells had a causal relationship with DN (FDR-p = 0.041), while the other immune cells showed no significant association with DN, so their relationship was suggestive. The results were stable with no observed horizontal pleiotropy and heterogeneity. Reverse MR analysis indicated no causal relationship between DN and the increased risk of positively identified immune cells.Conclusion This study provides an initial insight into the genetic perspective of the causal relationship between immune cells and DN. It establishes a crucial theoretical foundation for future endeavors in precision medicine and individualized treatment.

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 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 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.

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

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 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 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 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 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 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