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Chen Z, Yang Y, Peng C, Zhou Z, Wang F, Miao C, Li X, Wang M, Feng S, Chen T, Chen R, Liang Z. Mendelian randomisation studies for causal inference in chronic obstructive pulmonary disease: A narrative review. Pulmonology 2025; 31:2470556. [PMID: 39996617 DOI: 10.1080/25310429.2025.2470556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 02/14/2025] [Indexed: 02/26/2025] Open
Abstract
BACKGROUND AND OBJECTIVE Most non-randomised controlled trials are unable to establish clear causal relationships in chronic obstructive pulmonary disease (COPD) due to the presence of confounding factors. This review summarises the evidence that the Mendelian randomisation method can be a powerful tool for performing causal inferences in COPD. METHODS A non-systematic search of English-language scientific literature was performed on PubMed using the following keywords: 'Mendelian randomisation', 'COPD', 'lung function', and 'GWAS'. No date restrictions were applied. The types of articles selected included randomised controlled trials, cohort studies, observational studies, and reviews. RESULTS Mendelian randomisation is becoming an increasingly popular method for identifying the risk factors of COPD. Recent Mendelian randomisation studies have revealed some risk factors for COPD, such as club cell secretory protein-16, impaired kidney function, air pollutants, asthma, and depression. In addition, Mendelian randomisation results suggest that genetically predicted factors such as PM2.5, inflammatory cytokines, growth differentiation factor 15, docosahexaenoic acid, and testosterone may have causal relationships with lung function. CONCLUSION Mendelian randomisation is a robust method for performing causal inferences in COPD research as it reduces the impact of confounding factors.
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Affiliation(s)
- Zizheng Chen
- Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Department of Clinical Medicine, Guangzhou Medical University, Guangzhou, China
| | - Yuqiong Yang
- Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Chusheng Peng
- Department of Clinical Medicine, Guangzhou Medical University, Guangzhou, China
| | - Zifei Zhou
- Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Department of Clinical Medicine, Guangzhou Medical University, Guangzhou, China
| | - Fengyan Wang
- Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Department of Clinical Medicine, Guangzhou Medical University, Guangzhou, China
| | - Chengyu Miao
- Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Department of Clinical Medicine, Guangzhou Medical University, Guangzhou, China
| | - Xueping Li
- Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Department of Clinical Medicine, Guangzhou Medical University, Guangzhou, China
| | - Mingdie Wang
- Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Department of Clinical Medicine, Guangzhou Medical University, Guangzhou, China
| | - Shengchuan Feng
- Department of Clinical Medicine, Guangzhou Medical University, Guangzhou, China
| | - Tingnan Chen
- Department of Clinical Medicine, Guangzhou Medical University, Guangzhou, China
| | - Rongchang Chen
- Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Department of Respiratory and Critical Care Medicine, Hetao Institute of Guangzhou National Laboratory, Shenzhen, Guangdong, China
| | - Zhenyu Liang
- Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Department of Clinical Medicine, Guangzhou Medical University, Guangzhou, China
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Zhang Z, Niu J, Sun W, Sun Y, Tan Y, Yu J. Dietary habits and risk of diabetic kidney disease: a two-sample and multivariate Mendelian randomization study. Ren Fail 2025; 47:2438848. [PMID: 40074716 PMCID: PMC11912233 DOI: 10.1080/0886022x.2024.2438848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Revised: 11/13/2024] [Accepted: 12/02/2024] [Indexed: 03/14/2025] Open
Abstract
OBJECTIVE We explored the causal relationship between certain dietary habits and the risk of developing diabetic kidney disease (DKD) using two-sample Mendelian randomization and multivariate Mendelian randomization. RESEARCH DESIGN AND METHODS This study is based on pooled data from a genome-wide association study (GWAS) of 83 dietary habits in a European population. We performed a two-sample Mendelian randomization analysis using GAWS data on diabetic nephropathy in a European population. Validation was then performed against positive results (p < 0.05) in different GAWS data on diabetic nephropathy of European origin. Finally, multivariate Mendelian randomization analyses were performed on dietary habits with positive results (p < 0.05) in both datasets and GWAS data on postprandial glucose in the European population. RESULTS This study showed causal relationships between 18 dietary habits and the risk of developing DKD. After validation, causal relationships were found between the risk of DKD and two dietary habits: abstaining from sugar consumption (OR 2.86; 95%CI 1.35, 6.08; p = 0.006) and consuming whole grain/multigrain bread (OR 0.53; 95%CI 0.32, 0.89; p = 0.016). Correcting for the effect of postprandial glucose, the multivariate MR results showed that never eating sugar increased the risk of developing DKD (OR 0.08; 95%CI 0.018, 0.36; p = 0.001), whereas eating whole grain/multigrain bread did not reduce the risk of developing DKD (OR 1.37; 95%CI 0.55, 3.41; p = 0.50). CONCLUSIONS Our MR results suggest a causal relationship between never eating sugar and an increased risk of developing DKD. Therefore, people with diabetes need a reasonable range of sugar intake.
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Affiliation(s)
- Ziqi Zhang
- Department of Endocrinology, Nanjing Hospital of Chinese Medicine, Nanjing Hospital of Chinese Medicine affiliated to Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China
| | - Jieyu Niu
- Department of Traditional Chinese Medicine, Chang’an Town Health Center, Haining City, Zhejiang Province, China
| | - Wenhao Sun
- First School of Clinical Medicine, Nanjing University of Traditional Chinese Medicine, Nanjing, Jiangsu Province, China
| | - Yuqing Sun
- First School of Clinical Medicine, Nanjing University of Traditional Chinese Medicine, Nanjing, Jiangsu Province, China
| | - Ying Tan
- Department of Endocrinology, Jiangsu Provincial Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China
| | - Jiangyi Yu
- Department of Endocrinology, Jiangsu Provincial Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu Province, China
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Lv SJ, Yuan Q, Zong SS, Ye L. Dissecting the causal effects of interleukin receptor-related factors and the risk of developing endometriosis: a two-sample Mendelian randomization study. Gynecol Endocrinol 2025; 41:2512837. [PMID: 40448966 DOI: 10.1080/09513590.2025.2512837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 04/23/2025] [Accepted: 05/23/2025] [Indexed: 06/02/2025] Open
Abstract
This study investigates the causal associations between interleukin receptor-related factors and the development of endometriosis, as their etiology and pathophysiology remain largely unknown. A two-sample Mendelian randomization (MR) approach was employed to analyze genetic variants associated with interleukin receptor related factors as instrumental variables (IVs). The F-values have to be > 10 to exclude weak instrumental bias. The primary analysis was conducted using the inverse variance weighted (IVW) method, with confirmation using the MR-Egger, weighted median (WM), simple mode, and weighted mode methods. Sensitivity analyses were performed to ensure robustness, including tests for heterogeneity, pleiotropy, and leave-one-out. Multivariable MR (MVMR) analysis was used to assess the direct and mediated effects of immune cells. The results indicated significant causal associations between interleukin receptor factors prot-a-1542 (IL-6Rβ), prot-a-1530 (IL-3Rα), and prot-b-38 (IL-1RL1) and endometriosis. Reverse MR analysis showed that endometriosis did not significantly affect prot-a-1530 or prot-b-38. After adjusting for confounders like body mass index and smoking, these factors retained their significance. Additionally, immune cells(ebi-a-GCST90001951) were found to mediate the relationship between prot-b-38 and endometriosis, with an indirect effect accounting for approximately 6.38% of the total effect. This study provides new insights into endometriosis mechanisms involving specific interleukin receptor factors.
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Affiliation(s)
- Si-Ji Lv
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Qing Yuan
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Shan-Shan Zong
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Lei Ye
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
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Lei X, Wang F, Zhang X, Huang J, Huang Y. The potential mechanisms by which Xiaoyao Powder may exert therapeutic effects on thyroid cancer were examined at various levels. Comput Biol Chem 2025; 117:108412. [PMID: 40056710 DOI: 10.1016/j.compbiolchem.2025.108412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 02/13/2025] [Accepted: 02/24/2025] [Indexed: 03/10/2025]
Abstract
BACKGROUND Thyroid cancer (TC) is the most prevalent endocrine malignancy, with a rising incidence necessitating safer treatment strategies to reduce overtreatment and its side effects. Xiaoyao Powder (XYP), a widely used herbal formula, shows promise in treating TC. This study aims to investigate the mechanisms by which XYP may affect TC. METHODS The components of XYP were identified through database retrieval, and targets related to TC were collected to construct a target network for key screening. GEO dataset samples analyzed immune cells and identified significantly differentially expressed core genes (SDECGs). Based on SDECG expression and clustering, samples were classified for comparison. WGCNA was employed to identify gene modules linked to clinical characteristics. ML models screened characteristic genes and constructed a nomogram validated using another GEO dataset. MR methods explored causal relationships between genes and TC. RESULTS The top ten active components of XYP were identified, along with 27 SDECGs that exhibited significant differences in immune cell infiltration between TC patients and normal controls. The nomogram effectively predicted TC risk, validated through ROC curves. Key characteristic genes included SMIM1, PPP1R16A, KIAA1462, DNAJC22, and EFNA5. CONCLUSION XYP may treat TC by regulating SMIM1, PPP1R16A, KIAA1462, DNAJC22, EFNA5, and associated immune pathways; this provides theoretical support for its potential mechanisms.
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Affiliation(s)
- Xiaoli Lei
- The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Feifei Wang
- Department of Quality Control, Liaocheng Traditional Chinese Medicine Hospital, Liaocheng, China
| | - Xinying Zhang
- Department of Endocrinology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jiaxi Huang
- Department of Pharmacy, Huoqiu County First People's Hospital, Liuan, China
| | - Yanqin Huang
- Department of Endocrinology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.
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Jian C, Xia J, Wang N, Li Y, Shi L, Ding Q, Yan Y, He J, Tian H, Gao W. Mendelian randomization analysis with the GEO database: Exploring the molecular mechanism underlying insulin therapy for Perioperative Neurocognitive Disorders. Eur J Pharmacol 2025; 1002:177843. [PMID: 40513938 DOI: 10.1016/j.ejphar.2025.177843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Revised: 05/31/2025] [Accepted: 06/11/2025] [Indexed: 06/16/2025]
Abstract
Central insulin resistance is a significant factor in perioperative neurocognitive disorders (PND), yet the therapeutic effects and underlying molecular mechanisms of insulin remain unclear. We conducted a bidirectional Mendelian randomization (MR) study to investigate the causal relationships between insulin use and PND. The forward MR analysis revealed that insulin use considerably reduced the risk of delirium (odds ratio [OR] = 0.01, 95% confidence interval [CI]: 0.0007-0.22, P = 0.003) and enhanced cognitive performance (OR = 8.03, 95% CI: 2.83-22.78, P = 0.001). Importantly, the reverse MR analysis indicated that cognitive impairment or delirium did not causally affect insulin use (OR ≈ 1.0, P > 0.5). Utilizing GEO datasets, we identified 63 differentially expressed genes (DEGs) common to both postoperative delirium and insulin treatment. Subsequent analyses, including the construction of a protein-protein interaction network and Gene Ontology (GO) and KEGG pathway analyses, identified EPN2, DNAJC6, ARFGAP1, and HIP1R as key hub genes that could serve as potential therapeutic targets for PND. Further research showed that these hub genes are part of a multi-pathway interactive network, which may significantly contribute to the onset and progression of PND, with insulin also affecting their regulation. Our results establish a unidirectional genetic causality for the therapeutic effects of insulin in PND and reveal new molecular targets, thereby improving our understanding of the mechanisms behind insulin treatment for PND.
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Affiliation(s)
- Chenxin Jian
- Department of Anesthesiology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Ji Xia
- Department of Anesthesiology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Nisha Wang
- Department of Anesthesiology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Yajuan Li
- Department of Anesthesiology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Lei Shi
- Department of Anesthesiology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Qiyang Ding
- Department of Anesthesiology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Yixiao Yan
- Department of Anesthesiology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Jiansheng He
- Department of Anesthesiology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Hao Tian
- Center for Brain Science, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
| | - Wei Gao
- Department of Anesthesiology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
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Wang W, Zhang Z, Shi Q, Wang F, Cao Y, Fan B, Yang Y. Causal effect of body mass index on herpes zoster and postherpetic neuralgia: A Mendelian randomization study. Medicine (Baltimore) 2025; 104:e42775. [PMID: 40489821 DOI: 10.1097/md.0000000000042775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/11/2025] Open
Abstract
Although observational studies have reported the relationship between body mass index (BMI), herpes zoster (HZ), and postherpetic neuralgia (PHN), the impacts of BMI on the incidence of HZ and PHN are still controversial. Our study aimed to explore the causal effect of BMI on HZ and PHN by a 2-sample Mendelian randomization (MR) approach. Genome-wide association studies data on BMI, HZ, and PHN were derived from publicly available genetic summary datasets. A total of 28 phenotypic single-nucleotide polymorphisms were selected as instrumental variables for BMI. Inverse-variance weighted (IVW) method was conducted as the primary MR analysis method to explore the causal effect of BMI on HZ and PHN. Several sensitivity analyses were performed to test the robustness of the MR results. Our study found no strong evidence for an effect of BMI on HZ incidence (IVW: OR = 1.018, 95% CI = 0.964-1.075, P = .524). However, it demonstrated that increased BMI was related to a higher risk of PHN (IVW: OR = 1.234, 95% CI = 1.002-1.520, P = .048). Besides, no significant heterogeneity or horizontal pleiotropy was observed in our study, and sensitivity analysis was consistent with the results. There is no causal effect of BMI on HZ risk, but it may be causally associated with a risk of PHN.
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Affiliation(s)
- Wen Wang
- Department of Pain Management, China-Japan Friendship Hospital, Beijing, China
| | - Ze Zhang
- Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China
| | - Qing Shi
- Department of Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Fuquan Wang
- Department of Pain Management, China-Japan Friendship Hospital, Beijing, China
| | - Yanting Cao
- Department of Anesthesiology, China-Japan Friendship Hospital, Beijing, China
| | - Bifa Fan
- Department of Pain Management, China-Japan Friendship Hospital, Beijing, China
| | - Yang Yang
- Department of Pain Management, China-Japan Friendship Hospital, Beijing, China
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Huang Z, Zhou J, Liu S, Zhang Y, Meng J, Zhu X, Du Y. The interplay between systemic inflammation and myopia: A bidirectional Mendelian randomization and experimental validation study. Int Immunopharmacol 2025; 157:114803. [PMID: 40327989 DOI: 10.1016/j.intimp.2025.114803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 04/29/2025] [Accepted: 05/02/2025] [Indexed: 05/08/2025]
Abstract
PURPOSE Though the pathogenesis of myopia remains unclear, emerging evidence suggests a potential link between the onset of myopia and systemic inflammation. This study aims to elucidate the causal relationships between the two via Mendelian randomization (MR). METHODS We utilized genome-wide association study data on circulating inflammatory proteins (n = 14,824), immune cell traits (n = 3757), and myopia (n cases = 4106, n controls = 394,028) for a standard two-sample bidirectional MR analysis, followed by sensitivity analyses employing diverse approaches. The validation of seven inflammatory molecules was conducted through ELISA analysis of 116 plasma samples from a hospital-based cohort, as well as proteomics data from 3310 participants in the UK Biobank cohort. RESULTS Our analysis identified three inflammatory proteins (CXCL9, CXCL11, and T cell surface glycoprotein CD5) and six immune phenotypes, primarily related to T cells, as risk factors for myopia, and IL-5 and eight traits as protective factors. Meanwhile, we observed that myopia may elevate the levels of two inflammatory agents (TNFRSF9 and IL-24) and 12 peripheral immunophenotypes, predominantly associated with T cells and monocytes. Validation analysis in two independent cohorts further corroborated the proinflammatory state in highly myopic patients manifested by significantly elevated plasma levels of CXCL9, CXCL11, and TNFRSF9. CONCLUSIONS Our study identified a potential bidirectional causal relationship between systemic immune dynamics and myopia, underscoring the importance of considering myopia in the context of systemic condition. Research is warranted to further identify underlying mechanisms.
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Affiliation(s)
- Zhiqian Huang
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai 200031, China; NHC Key laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai 200031, China; Key Laboratory of Myopia, Chinese Academy of Medical Science, Shanghai 200031, China; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai 200031, China
| | - Jitong Zhou
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai 200031, China; NHC Key laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai 200031, China; Key Laboratory of Myopia, Chinese Academy of Medical Science, Shanghai 200031, China; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai 200031, China
| | - Shuyu Liu
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai 200031, China; NHC Key laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai 200031, China; Key Laboratory of Myopia, Chinese Academy of Medical Science, Shanghai 200031, China; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai 200031, China
| | - Ye Zhang
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai 200031, China; NHC Key laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai 200031, China; Key Laboratory of Myopia, Chinese Academy of Medical Science, Shanghai 200031, China; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai 200031, China
| | - Jiaqi Meng
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai 200031, China; NHC Key laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai 200031, China; Key Laboratory of Myopia, Chinese Academy of Medical Science, Shanghai 200031, China; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai 200031, China
| | - Xiangjia Zhu
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai 200031, China; NHC Key laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai 200031, China; Key Laboratory of Myopia, Chinese Academy of Medical Science, Shanghai 200031, China; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai 200031, China
| | - Yu Du
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai 200031, China; NHC Key laboratory of Myopia and Related Eye Diseases; Key Laboratory of Myopia and Related Eye Diseases, Chinese Academy of Medical Sciences, Shanghai 200031, China; Key Laboratory of Myopia, Chinese Academy of Medical Science, Shanghai 200031, China; Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai 200031, China.
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Zhang X, Lian C, Shi S, Li J, Wang L, Guo Z, Liu N, Wang H, Hu Y, Du B. The 2-Step Mendelian Randomisation Study Assesses Genetic Causality and Potential Mediators of Periodontal Disease and Atrial Fibrillation. Int Dent J 2025; 75:2093-2103. [PMID: 39988492 DOI: 10.1016/j.identj.2024.12.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 12/12/2024] [Accepted: 12/13/2024] [Indexed: 02/25/2025] Open
Abstract
INTRODUCTION AND AIMS This study aims to examine the possible causal link between periodontal diseases and atrial fibrillation (AF), with a focus on the modifiable risk factors that facilitate this connection. METHOD Firstly, bidirectional and multivariable Mendelian Randomisation (MR) analyses were conducted using genome-wide association studies (GWAS) data on periodontal disease (87,497 cases/259,234 controls) from FinnGen and AF (55,114 cases/482,295 controls) from AFGen. Then, a 2-step MR approach was employed to evaluate the mediating role and proportions of 25 candidate factors among the direct causality between periodontal disease and AF. RESULTS Periodontal disease was found to be associated with an increased risk of AF (odds ratio 1.16, 95% CI 1.027-1.314, p = .017), independent of other covariates such as dental caries, pulp, and periapical diseases. Conversely, no causal relationship was detected indicating that AF leads to periodontal disease condition. Furthermore, in the 2-step MR analysis, 5 out of 25 candidate mediators were screened as statistically significant. Ranked by partial mediation proportion, these modifiable mediators included weight (30.3%), IL-17 (17.2%), TNF (14.08%), coronary atherosclerosis (13.4%), and hypertension (11.6%). CONCLUSION Our findings demonstrated the genetic causality between periodontal disease and AF. Maintaining oral hygiene, adopting standardised periodontal therapy, and restricting body weight are critical goals for patients with periodontal disease to mitigate disease progression to AF.
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Affiliation(s)
- Xiaohan Zhang
- Department of Cardiovascular Medicine, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Chengzhong Lian
- Department of Oral Medicine, Shanxi Provincial People's Hospital, Taiyuan, Shanxi, China
| | - Shuqing Shi
- Department of Cardiovascular Medicine, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jiaran Li
- Department of Cardiovascular Medicine, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Lianxin Wang
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zezhen Guo
- Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, New South Wales, Australia
| | - Naixu Liu
- Department of Pediatrics, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Huan Wang
- Department of Cardiovascular Medicine, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yuanhui Hu
- Department of Cardiovascular Medicine, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Bai Du
- Department of Cardiovascular Medicine, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.
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Burke C, Taylor G, Freeman TP, Sallis H, Wootton RE, Munafò MR, Dardani C, Khouja J. Disentangling the effects of nicotine versus non-nicotine constituents of tobacco smoke on major depressive disorder: A multivariable Mendelian randomisation study. Addiction 2025; 120:1240-1252. [PMID: 39931798 PMCID: PMC12046462 DOI: 10.1111/add.70001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 01/15/2025] [Indexed: 05/03/2025]
Abstract
BACKGROUND AND AIMS There is growing evidence that tobacco smoking causes depression, but it is unclear which constituents of tobacco smoke (e.g. nicotine, carbon monoxide) may be responsible. We used Mendelian randomisation (MR) to measure the independent effect of nicotine on depression, by adjusting the effect of circulating nicotine exposure [via nicotine metabolite ratio (NMR)] for the overall effect of smoking heaviness [via cigarettes per day (CPD)] to account for the non-nicotine constituents of tobacco smoke. DESIGN Univariable MR and multivariable MR (MVMR) were used to measure the total and independent effects of genetic liability to NMR and CPD on major depressive disorder (MDD). Our primary method was inverse variance weighted (IVW) regression, with other methods as sensitivity analyses. SETTING AND PARTICIPANTS For the exposures, we used genome-wide association study (GWAS) summary statistics among European ancestry individuals for CPD (n = 143 210) and NMR (n = 5185). For the outcome, a GWAS of MDD stratified by smoking status was conducted using individual-level data from UK Biobank (n = 35 871-194 881). MEASUREMENTS Genetic variants associated with NMR (n = 6) and CPD (n = 53). FINDINGS Univariable MR-IVW indicated a causal effect of CPD on MDD [odds ratio (OR) = 1.13, 95% confidence interval (CI) = 1.04-1.23, P = 0.003] but no clear evidence for an effect of NMR on MDD (OR = 0.98, 95% CI = 0.97-1.00, P = 0.134). MVMR indicated a causal effect of CPD on MDD when accounting for NMR (IVW: OR = 1.19, 95% CI = 1.03-1.37, P = 0.017; Egger: OR = 1.13, 95% CI = 0.89-1.43, P = 0.300) and weak evidence of a small effect of NMR on MDD when accounting for CPD (IVW: OR = 0.98, 95% CI = 0.96-1.00, P = 0.057; Egger: OR = 0.98, 95% CI = 0.96-1.00, P = 0.038). CONCLUSIONS The role of nicotine exposure in risk of depression cannot be entirely dismissed. However, the causal effect of tobacco smoking increasing depression risk appears to be largely independent of circulating nicotine exposure, which implies the role of alternative causal pathways.
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Affiliation(s)
- Chloe Burke
- School of Psychological ScienceUniversity of BristolBristolUK
- Medical Research Council Integrative Epidemiology UnitUniversity of BristolBristolUK
- Department of PsychologyUniversity of BathBathUK
| | - Gemma Taylor
- Department of PsychologyUniversity of BathBathUK
| | | | - Hannah Sallis
- Population Health Sciences, Bristol Medical SchoolUniversity of BristolBristolUK
| | - Robyn E. Wootton
- School of Psychological ScienceUniversity of BristolBristolUK
- Medical Research Council Integrative Epidemiology UnitUniversity of BristolBristolUK
- Lovisenberg Diakonale SykehusNic Waals InstituteOsloNorway
- PsychGen Centre for Genetic Epidemiology and Mental HealthNorwegian Institute of Public HealthOsloNorway
| | - Marcus R. Munafò
- School of Psychological ScienceUniversity of BristolBristolUK
- Medical Research Council Integrative Epidemiology UnitUniversity of BristolBristolUK
- NIHR Bristol Biomedical Research CentreBristolUK
| | - Christina Dardani
- Medical Research Council Integrative Epidemiology UnitUniversity of BristolBristolUK
| | - Jasmine Khouja
- School of Psychological ScienceUniversity of BristolBristolUK
- Medical Research Council Integrative Epidemiology UnitUniversity of BristolBristolUK
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10
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Zheng Y, Yang D, Wang L, Zhu X, Li X, Miao J, Xu Y. Causal Relationship Between Gut Microbiota, Blood Metabolites, and Intervertebral Disc Degeneration: A Two-Step, Two-Sample Bidirectional Mendelian Randomization Study. JOR Spine 2025; 8:e70078. [PMID: 40444211 PMCID: PMC12120259 DOI: 10.1002/jsp2.70078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 03/12/2025] [Accepted: 05/02/2025] [Indexed: 06/02/2025] Open
Abstract
Background Some studies have shown that gut microbiota may be associated with intervertebral disc degeneration. However, the causal effects between gut microbiota and IVDD and whether blood metabolites act as a mediator remain unclear. The objective of this study was to investigate the causal relationship between gut microbiota and intervertebral disc herniation, with a focus on the potential mediating role of blood metabolites. Methods Gut microbiota, blood metabolites, and IVDD data were identified from large-scale genome-wide association studies (GWAS) summary data. Then we used Mendelian randomization analysis to investigate the causal relationships between gut microbiota, blood metabolites, and intervertebral disc degeneration, using the inverse variance-weighted method as the primary outcome measure. Subsequently, we conducted sensitivity analyses to ascertain the robustness of the results by testing for heterogeneity and horizontal pleiotropy. In addition, we explored blood metabolites as a mediating factor in the pathway from gut microbiota to IVDD. Results We identified 6 taxa that were strongly associated with the incidence of intervertebral disc herniation. There were 8 positive and 13 negative causal effects between genetic liability in the blood metabolites and IVDD. The mediation analysis revealed that the connections among genus Comamonas B, family Halomonadaceae, family UBA6960, and IVDD were mediated by ADP to glycine ratio, 1,3-dimethylurate levels, 3-hydroxy-2-methylpyridine sulfate levels, and Histidine levels. Each of these accounted for 7.77%, 9.04%, 12.56%, and 11.76%, respectively. Conclusions Our study provides evidence supporting a potential causal relationship between certain microbial taxa and intervertebral disc degeneration. This study focuses on the mediation of specific blood metabolites, which suggests that they may represent potential targets for intervention.
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Affiliation(s)
- Yi‐Ping Zheng
- Department of OrthopaedicThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Dong‐Lin Yang
- Department of OrthopaedicThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Lu‐Yang Wang
- Department of OrthopaedicThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Xi‐Zhong Zhu
- Department of OrthopaedicThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Xing‐Chen Li
- Department of OrthopaedicThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Jin‐Hong Miao
- Department of Quality ControlThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Yu‐Sheng Xu
- Department of OrthopaedicThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
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11
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You G, Li M, Zhang M, Liu H, Chen X, Fan H. Genetic Insights Into Dietary Factors, Metabolic Traits and Myasthenia Gravis Risk: A Large-Scale Two-Sample Mendelian Randomization Study in European Populations. Food Sci Nutr 2025; 13:e70236. [PMID: 40444113 PMCID: PMC12121443 DOI: 10.1002/fsn3.70236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 04/17/2025] [Accepted: 04/19/2025] [Indexed: 06/02/2025] Open
Abstract
The impact of dietary factors and metabolic traits on the risk of myasthenia gravis (MG) is not well understood. This study utilized two-sample Mendelian randomization (MR) to investigate the causal relationships between 16 dietary factors and 10 metabolic traits with MG risk. Using the inverse variance weighted (IVW) method, we identified significant causal associations and tested for heterogeneity using Cochran's Q test. The MR-Egger intercept was used to assess horizontal pleiotropy, and the Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) framework was applied to detect and correct for potential outliers. Our analysis revealed that increased fresh fruit intake was associated with a reduced risk of MG (odds ratio [OR] = 0.023, 95% confidence interval [CI] = 0.001-0.683, p = 0.029). In contrast, higher body mass index (BMI) (OR = 2.696; 95% CI = 1.524-4.770; p < 0.001), waist circumference (OR = 2.995, 95% CI = 1.457-6.156, p = 0.003), hypothyroidism (OR = 1.337, 95% CI = 1.033-1.730, p = 0.027), and hyperthyroidism (OR = 2.240, 95% CI = 1.001-4.683, p < 0.001) were positively associated with MG risk. After adjusting for the false discovery rate (FDR), BMI and hyperthyroidism remained significantly linked to MG. No significant associations were found between MG and the other 15 dietary factors or 6 metabolic traits. These findings highlight the potential nutritional and metabolic pathways that may contribute to MG risk, suggesting that dietary interventions, particularly increasing fruit intake, and managing metabolic factors like BMI and thyroid health could play a role in the prevention and management of MG.
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Affiliation(s)
- Guoliang You
- Department of NeurologyTaiyuan City Central Hospital, The Ninth Clinical Medical College of Shanxi Medical UniversityTaiyuanShanxi ProvinceChina
| | - Meng Li
- Department of NeurologyTaiyuan City Central Hospital, The Ninth Clinical Medical College of Shanxi Medical UniversityTaiyuanShanxi ProvinceChina
| | - Minheng Zhang
- Department of GerontologyThe First People's Hospital of JinzhongJinzhongShanxi ProvinceChina
| | - Hongwei Liu
- Department of NeurologyTaiyuan City Central Hospital, The Ninth Clinical Medical College of Shanxi Medical UniversityTaiyuanShanxi ProvinceChina
| | - Xuan Chen
- Department of NeurologyTaiyuan City Central Hospital, The Ninth Clinical Medical College of Shanxi Medical UniversityTaiyuanShanxi ProvinceChina
| | - Haixia Fan
- Department of Sleep CenterFirst Hospital of Shanxi Medical UniversityTaiyuanShanxi ProvinceChina
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12
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Tu Y, Miao J, Wu Q, Lu K, Ren R, Lin C, Wang X, Jin H. Obstructive sleep apnea and osteoporosis: A bidirectional two-sample mendelian randomization analysis. Respir Med 2025; 242:108090. [PMID: 40215796 DOI: 10.1016/j.rmed.2025.108090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 11/28/2024] [Accepted: 04/04/2025] [Indexed: 05/12/2025]
Abstract
BACKGROUND Previous epidemiological studies have explored the association between obstructive sleep apnea (OSA) and osteoporosis (OP), with inconclusive results due to various biases. Herein, we sought to determine the causal association between OSA and OP through bidirectional two-sample Mendelian randomization analysis. METHODS Summary-level data for OSA were acquired from the FinnGen consortium, while data for fractures and BMDs (FA-BMD, FN-BMD, LS-BMD and eBMD) were derived from the UKBB and GEFOS. The inverse variance weighted (IVW) method was conducted as the main method, and several supplementary methods were further utilized for sensitivity analysis to strengthen the reliability of our findings. RESULTS The study findings strongly suggest a causal association between OSA and FA-BMD based on the IVW method (BETA = 0.404; 95 % CI = 0.208, 0.599; p = 5.28 × 10-5). However, OSA showed no significant causal relationship with eBMD (BETA = 0.052; 95 % CI = -0.018, 0.123; p = 0.145), FN-BMD (BETA = 0.095; 95 % CI = -0.009, 0.2; p = 0.073), LS-BMD (BETA = 0.021; 95 % CI = -0.082, 0.124; p = 0.695), and fractures (OR = 0.998; 95 % CI = 0.907, 1.098; p = 0.971). The conclusions from other analytical strategies were generally aligned with those of the IVW. No definitive causal effect of OP on OSA was observed in reverse analysis. CONCLUSION This research provided clear evidence of a causal association between OSA and FA-BMD, shedding light on the potential impact of OSA on bone metabolism.
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Affiliation(s)
- Yiting Tu
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China; Key Laboratory of Orthopedics of Zhejiang Province, Wenzhou, China.
| | - Jiansen Miao
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China; Key Laboratory of Orthopedics of Zhejiang Province, Wenzhou, China.
| | - Qihang Wu
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China; Key Laboratory of Orthopedics of Zhejiang Province, Wenzhou, China.
| | - Keyu Lu
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China; Key Laboratory of Orthopedics of Zhejiang Province, Wenzhou, China.
| | - Rufeng Ren
- School of the Second Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China.
| | - Chihao Lin
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China; Key Laboratory of Orthopedics of Zhejiang Province, Wenzhou, China.
| | - Xiangyang Wang
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China; Key Laboratory of Orthopedics of Zhejiang Province, Wenzhou, China.
| | - Haiming Jin
- Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China; Key Laboratory of Orthopedics of Zhejiang Province, Wenzhou, China.
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13
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Wang SQ, Zhang H, Hui XS, Zhang Q, Chen R, Xie F. Assessing the Causal Relationships Between Lipid Species and Stroke by Using Mendelian Randomization. Mol Neurobiol 2025; 62:7174-7182. [PMID: 39856455 PMCID: PMC12078454 DOI: 10.1007/s12035-025-04697-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 01/09/2025] [Indexed: 01/27/2025]
Abstract
Circulating lipids and changes in lipid profiles have long been associated with the development of stroke but causal relationships remain unclear.In this study, we aimed to assess the causal relationships between lipid species and multiple stroke phenotypes to inform stroke prevention and treatment strategies. We conducted a two-sample Mendelian randomization analysis using data from genome-wide association studies. The primary method for causal assessment was inverse variance weighting (IVW), complemented by the MR-Egger, weighted median, and weighted mode methods. Sensitivity analyses, based on MR-Egger, MR-PRESSO, and Cochran's Q statistics, were also applied to reinforce the results. In total, potential causality was observed for 133 pairs of lipids with stroke types(P < 0.05). After multiple testing correction (PFDR < 0.05), potential causal associations remained for 10 pairs of lipids, including specific sterol esters and phosphatidylcholines, with various stroke subtypes. The findings demonstrate the significant role that genetically determined lipid profiles may play in the pathogenesis of stroke. Further research is needed to establish whether these biomarkers can be used for stroke prevention or treatment.
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Affiliation(s)
- Shi-Qi Wang
- First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, 450099, China
| | - Hao Zhang
- Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Xiao-Shan Hui
- Guang'anmen Hospital, China Academy of Chinese Medical Science, Beijing, 100053, China
| | - Qi Zhang
- First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, 450099, China
| | - Rubing Chen
- First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, 450099, China
| | - Fei Xie
- College of Pulmonary and Critical Care Medicine, Chinese PLA General Hospital, Beijing, 100039, China.
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14
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Zhu Y, Hong GJ, Hu Y, Wu R. Relationship of α-Klotho with Frailty Index and Sarcopenia: A Bidirectional Mendelian Randomization Study. Rejuvenation Res 2025; 28:146-155. [PMID: 39899348 DOI: 10.1089/rej.2024.0057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2025] Open
Abstract
Previous studies have established associations between α-Klotho and frailty or sarcopenia; however, the causal nature of these relationships remains unclear. This study investigates the causal effects of α-Klotho on frailty and sarcopenia-related traits using Mendelian randomization (MR). Genetic instruments for circulating α-Klotho concentrations, frailty index (FI), low grip strength (LGS), appendicular lean mass (ALM), and walking pace were developed based on data from large genome-wide association studies. Two-sample MR analyses were performed, supplemented by sensitivity analyses to ensure the robustness of the findings. Reverse MR analyses were also conducted to explore potential reverse causation. The findings demonstrated an inverse causal relationship of circulating α-Klotho levels with FI (β = -0.020, 95% confidence interval [95% CI] = -0.036 to -0.004; p = 0.017) and LGS (β = -0.033, 95% CI = -0.061 to -0.004; p = 0.023). However, no causal relationship was observed between circulating α-Klotho levels and ALM or walking pace. Additionally, no evidence of reverse causation was identified between FI or sarcopenia-related traits and circulating α-Klotho levels. In conclusion, this MR analysis establishes an inverse causal relationship of circulating α-Klotho levels with both FI and LGS.
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Affiliation(s)
- Yue Zhu
- Division of Life Sciences and Medicine, Hefei Ion Medical Center, the First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China
| | - Guo-Jun Hong
- Department of Pharmacy, Nanjing Gaochun People's Hospital, Nanjing, China
| | - Yong Hu
- Department of General Surgery, The People's Hospital of Huangshan, Huangshan, China
| | - Rui Wu
- Division of Life Sciences and Medicine, Hefei Ion Medical Center, the First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China
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15
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Mi Y, Chen L, Liao N, Wan M. Mendelian randomization analysis revealed a gut microbiota-eye axis in acute anterior uveitis. Eye (Lond) 2025; 39:1562-1570. [PMID: 39979613 DOI: 10.1038/s41433-025-03715-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Revised: 02/07/2025] [Accepted: 02/10/2025] [Indexed: 02/22/2025] Open
Abstract
BACKGROUND Observational studies suggest that gut microbiome (GM) may contribute to acute anterior uveitis (AAU) development, but causality remains unclear. This study was conducted to test whether specific GM taxa were causally associated with AAU. METHODS The GM data were obtained from the DMP, which included 7738 individuals' faecal samples and an analysis of host genotype-taxa abundance associations. The AAU data were derived from the FinnGen Consortium (8624 cases and 473,095 controls). We primarily employed the inverse-variance weighted method, complemented by supplementary sensitivity analyses. RESULTS Higher abundance of Lachnospiraceae noname (OR = 0.86, 95% CI 0.81-0.91, P = 5.7 × 10-8), Alistipes finegoldii (OR = 0.87, 95% CI 0.78-0.96, P = 0.008), Erysipelotrichaceae (OR = 0.90, 95% CI 0.81-0.99, P = 0.037), Erysipelotrichia (OR = 0.90, 95% CI 0.81-0.99, P = 0.037), Erysipelotrichales (OR = 0.90, 95% CI 0.81-0.99, P = 0.037), and Bacteroides ovatus (OR = 0.93, 95% CI 0.87-1.00, P = 0.039) predicted a lower AAU risk. Conversely, higher abundance of Bifidobacterium catenulatum (OR = 1.06, 95% CI: 1.02-1.10, P = 0.005), Bacteroides coprocola (OR = 1.11, 95% CI: 1.02-1.21, P = 0.014), Parabacteroides unclassified (OR = 1.12, 95% CI 1.03-1.22, P = 0.010), and Prevotella (OR = 1.15, 95% CI: 1.01-1.29, P = 0.029) predicted a higher AAU risk. The results also showed a reverse causation from AAU to Bifidobacterium catenulatum (OR = 1.39, 95% CI: 1.03-1.86, P = 0.005). CONCLUSION This study suggests that specific GM is causally associated with AAU risk, warranting more mechanistic validation and clinical trials.
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Affiliation(s)
- Yuze Mi
- National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou, China
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Lu Chen
- National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou, China
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Na Liao
- National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou, China.
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, China.
| | - Minghui Wan
- National Clinical Research Center for Ocular Diseases, Eye Hospital, Wenzhou Medical University, Wenzhou, China.
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, China.
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16
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Xie P, Peng W. Thyroid Dysfunction and Oral Lichen Planus: Evidence From Two-Sample Mendelian Randomization Analysis. Int Dent J 2025; 75:1621-1631. [PMID: 40138996 PMCID: PMC11985110 DOI: 10.1016/j.identj.2025.02.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 02/04/2025] [Accepted: 02/24/2025] [Indexed: 03/29/2025] Open
Abstract
INTRODUCTION AND AIMS Epidemiological studies have shown that the association between thyroid dysfunction (TD) and oral lichen planus (OLP) is controversial, and the causal relationship remains ill-defined. This study aims to investigate their probable mutual causality using bidirectional Mendelian randomization (MR) analyses. METHODS We extracted genetic instruments for OLP and 10 phenotypes of TD from the genome-wide association studies database. The inverse variance weighted method was primarily used to evaluate the bidirectional causal relationship between TD and OLP. The results' robustness was verified by sensitivity analysis (Cochran's Q test, MR-Egger intercept, and leave-one-out test). Bonferroni correction threshold (0.05/10) was applied to determine significant differences. RESULTS Forward MR analysis indicated that Hashimoto's thyroiditis (HT) was suggestively linked to a higher likelihood of developing OLP (P = .0077), while hypothyroidism significantly increased the risk of OLP occurrence (P = .0002). The reverse MR study found that OLP was suggestively related to the occurrence of hyperthyroidism (P = .0126) and thyroid cancer (P = .0244). Furthermore, OLP was found to significantly increase the risk of HT (P = 3.47 × 10-⁸), Graves' disease (P = 1.03 × 10-⁵), hypothyroidism (P = 1.08 × 10-⁸), and elevated thyroid-stimulating hormone levels (P = 1.99 × 10-⁶). No major pleiotropy or heterogeneity was detected (P > .05). CONCLUSION These findings suggest that hypothyroidism significantly increases the risk of OLP, while OLP may contribute to the development of autoimmune thyroid disorders, particularly HT, Graves' disease, hypothyroidism, and thyroid-stimulating hormone. These findings highlight the complex interaction between endocrine and immune systems, emphasizing the need for further research into shared molecular pathways and potential clinical implications. CLINICAL RELEVANCE This study provides a genetic foundation for understanding the relationship between TD and OLP, which aids early screening and diagnosis and informs therapy development.
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Affiliation(s)
- Pengxian Xie
- College of Stomatology, North China University of Science and Technology, Tangshan, Hebei, China
| | - Wei Peng
- College of Stomatology, North China University of Science and Technology, Tangshan, Hebei, China.
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17
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Zhang J, Yu H, Jiao L, Wang D, Gu Y, Meng G, Wu H, Wu X, Zhu D, Chen Y, Wang D, Wang Y, Geng H, Huang T, Niu K. Causal Association of Sleep Traits with All-Cause and Cause-Specific Mortality: A Prospective Cohort and Mendelian Randomization Study. Rejuvenation Res 2025; 28:136-145. [PMID: 39883542 DOI: 10.1089/rej.2024.0058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2025] Open
Abstract
The study aimed to explore the association between different sleep traits and all-cause mortality as well as to validate causality in the association through mendelian randomization (MR). We analyzed 451,420 European ancestry participants from the UK Biobank. Multivariable-adjusted Cox proportional hazards model was conducted to evaluate the association between sleep traits and all-cause mortality. In MR analysis, the inverse variance weighting (IVW) method was applied as the primary analysis to investigate the causal association between sleep traits and mortality. During a median follow-up period of 12.68 years, 34,397 individuals died. Observational analyses showed the multivariate-adjusted hazard ratio (HR) and 95% confidence intervals (CIs) for short sleep, long sleep, early chronotype, daytime sleepiness, daytime napping, and insomnia with mortality, 1.246 (1.195, 1.298), 1.735 (1.643, 1.831), 0.931 (0.909, 0.953), 1.276 (1.212, 1.344), 1.299 (1.254, 1.346), and 1.117 (1.091, 1.142) (All p < 0.0001). Based on UK Biobank, MR analysis indicated the association between daytime napping and an increased risk of all-cause mortality (odd ratio [OR]: 1.219, 95% CI: 1.071-1.387, p = 0.003), which may be largely attributable to cancer disease mortality (OR: 1.188, 95% CI: 1.009-1.399, p = 0.039). We found no causal association between sleep duration, short sleep, long sleep, chronotype, daytime sleepiness, insomnia, and mortality risk. The causal associations between sleep traits and all-cause mortality risk were directionally replicated in FinnGen. Our findings suggest a potential causal association between daytime napping and increased risk of all-cause mortality in middle-aged and older persons. The finding could have important implications for evaluating daytime napping habits to decrease the risk of mortality.
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Affiliation(s)
- Jinjin Zhang
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, Tianjin, China
- School of Public Health, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Hao Yu
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, Tianjin, China
- School of Public Health, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Lirui Jiao
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, Tianjin, China
- School of Public Health, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Di Wang
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, Tianjin, China
- School of Public Health, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yeqing Gu
- Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Ge Meng
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, Tianjin, China
| | - Hongmei Wu
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, Tianjin, China
- School of Public Health, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xuehui Wu
- School of Public Health, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Dandan Zhu
- School of Public Health, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yinxiao Chen
- School of Public Health, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Dongli Wang
- School of Public Health, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yaxiao Wang
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, Tianjin, China
- School of Public Health, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Hao Geng
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, Tianjin, China
- School of Public Health, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Tao Huang
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China
| | - Kaijun Niu
- Nutritional Epidemiology Institute and School of Public Health, Tianjin Medical University, Tianjin, China
- School of Public Health, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
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18
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Wei J, Yang Z, Wu X, Zheng N, Wu D. Unveiling the role of lipid metabolism in haemorrhagic disorders: genetic insights and therapeutic perspectives. Thromb J 2025; 23:55. [PMID: 40450254 DOI: 10.1186/s12959-025-00731-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Accepted: 04/29/2025] [Indexed: 06/03/2025] Open
Abstract
BACKGROUND Coagulation defects, including purpura and other haemorrhagic conditions, are a critical area of medical research because of their significant health effects worldwide. Understanding the metabolic basis of these conditions may improve therapeutic strategies. METHODS A two-sample Mendelian randomization (MR) approach was employed to evaluate the causal relationships between the levels of 1,400 metabolites and coagulation defects. Colocalization analysis confirmed significant shared genetic influences. Pathway and protein‒protein interaction (PPI) analyses identified rate-limiting enzymes and drug targets. The impacts of lifestyle factors on metabolite levels were also explored through MR. RESULTS MR analysis revealed four metabolites whose abundance was significantly associated with coagulation defects: docosapentaenoate n3 DPA 22:5n3 (DPA) (OR: 1.594, 95% CI: 1.263-2.011, P < 0.001), 1-palmitoyl-2-stearoyl-gpc (PSPC) (16:0/18:0) (OR: 1.294, 95% CI: 1.134-1.477, P < 0.001), 1-stearoyl-2-docosahexaenoyl-gpc (SDPC) (18:0/22:6) (OR: 1.232, 95% CI: 1.101-1.380, P < 0.001) and hydroxypalmitoyl sphingomyelin (HPSM) (d18:1/16:0 (OH)) (OR: 0.803, 95% CI: 0.719-0.896, P < 0.001). Colocalization analysis provided robust evidence for shared genetic loci. Pathway analysis highlighted the importance of lipid metabolism, identifying key enzymes such as FADS1, FADS2 and TCP1. PPI analysis revealed an interaction between TCP1 and plasminogen, indicating potential therapeutic synergy. Further analysis revealed that lifestyle factors, including dried fruit and oily fish intake, were linked to the abundance of metabolites associated with coagulation risk. CONCLUSIONS This study identifies specific metabolites and metabolic pathways involved in coagulation defects, proposes novel therapeutic targets and highlights the roles of dietary and lifestyle interventions in the management of these conditions. These findings pave the way for personalized strategies to manage coagulation-related conditions.
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Affiliation(s)
- Jiaqi Wei
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, 215006, China
| | - Zhen Yang
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, 215006, China
| | - Xiaojin Wu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, 215006, China
| | - Nana Zheng
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, 215006, China.
| | - Depei Wu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, 215006, China.
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Zhao X, He L, Wu X, Zhang L, Xiao J, Xiao C, Qu Y, Zhu J, Qin C, Huang D, Shen P, Han T, Fan M, Li J, Burgess S, Jiang X. Disentangling the divergent causal pathways underlying the association between body mass index and bone mineral density: a comprehensive Mendelian randomization study. BMC Med 2025; 23:305. [PMID: 40437494 PMCID: PMC12121138 DOI: 10.1186/s12916-025-04139-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Accepted: 05/15/2025] [Indexed: 06/01/2025] Open
Abstract
BACKGROUND While the protective role of body mass index (BMI) in bone mass has been well-documented, the divergent associations between BMI and estimated bone mineral density (eBMD), attributed to its highly heterogeneous nature, remain insufficiently understood. METHODS Leveraging the hitherto largest genome-wide summary statistics, we conducted a two-sample Mendelian randomization (MR) to re-evaluate the effect of genetically predicted BMI on eBMD. Then, MR-Clust was applied to examine the potential presence of distinct causal pathways underlying the BMI-eBMD link. Utilizing tissue-partitioned MR, we estimated the distinct effects of separated tissue-specific subcomponents of BMI on eBMD, further supplemented by multivariable MR of body composition phenotypes on eBMD. RESULTS We reconfirmed the significant positive association between genetically predicted BMI and eBMD (βIVW = 0.13, P value = 1.28 × 10-34). Potential distinct causal pathways contributing to the observed total effect were identified by MR-Clust, with some exerting a protective effect while others leading to its deterioration. Tissue-partitioned MR suggested a marginally independent protective association between skeletal muscle-tissue instrumented BMI and eBMD (βIVW = 0.14, P value = 4.98 × 10-2) after accounting for adipose-tissue instrumented BMI, which was supported by the independent association between genetically predicted lean mass and eBMD after accounting for other body composition phenotypes. CONCLUSIONS Our results shed preliminary insights into the intricate relationship between obesity and bone mass, highlighting divergent causal pathways underlying the association between BMI and eBMD. Our findings emphasize the potential importance of precision obesity management over merely a general indicator as BMI in future public health strategies for osteoporosis prevention.
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Affiliation(s)
- Xunying Zhao
- Department of Epidemiology and Health Statistics and West China Institute of Preventive and Medical Integration for Major Diseases, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Lin He
- Department of Epidemiology and Health Statistics and West China Institute of Preventive and Medical Integration for Major Diseases, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
- Longquanyi District of Chengdu Maternity and Child Care Health Hospital, Chengdu, Sichuan, China
| | - Xueyao Wu
- Department of Epidemiology and Health Statistics and West China Institute of Preventive and Medical Integration for Major Diseases, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
| | - Li Zhang
- Department of Epidemiology and Health Statistics and West China Institute of Preventive and Medical Integration for Major Diseases, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jinyu Xiao
- Department of Epidemiology and Health Statistics and West China Institute of Preventive and Medical Integration for Major Diseases, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Changfeng Xiao
- Department of Epidemiology and Health Statistics and West China Institute of Preventive and Medical Integration for Major Diseases, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yang Qu
- Department of Epidemiology and Health Statistics and West China Institute of Preventive and Medical Integration for Major Diseases, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jingwei Zhu
- Department of Epidemiology and Health Statistics and West China Institute of Preventive and Medical Integration for Major Diseases, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Chenjiarui Qin
- Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, West China, China
| | - Deqin Huang
- Department of Epidemiology and Health Statistics and West China Institute of Preventive and Medical Integration for Major Diseases, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Pengyue Shen
- Department of Epidemiology and Health Statistics and West China Institute of Preventive and Medical Integration for Major Diseases, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Tao Han
- Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, West China, China
| | - Mengyu Fan
- Department of Epidemiology and Health Statistics and West China Institute of Preventive and Medical Integration for Major Diseases, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jiayuan Li
- Department of Epidemiology and Health Statistics and West China Institute of Preventive and Medical Integration for Major Diseases, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China.
| | - Stephen Burgess
- MRC Biostatistics Unit, Cambridge Institute of Public Health, University of Cambridge, Cambridge, UK.
| | - Xia Jiang
- Department of Epidemiology and Health Statistics and West China Institute of Preventive and Medical Integration for Major Diseases, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China.
- Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, West China, China.
- Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Solna, Stockholm, Sweden.
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Zhao J, Wang Y, Lv C, Peng J, Lu S, Shen L. The Mediating Role of Plasma Inflammatory Proteins in Gut Microbiota-Driven Valvular Heart Disease: A Mendelian Randomization Study. Cell Biochem Biophys 2025:10.1007/s12013-025-01780-9. [PMID: 40425948 DOI: 10.1007/s12013-025-01780-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/08/2025] [Indexed: 05/29/2025]
Abstract
This study investigates the causal relationships between gut microbiota (GM), plasma inflammatory proteins (PIPs), and valvular heart disease (VHD) using two-sample Mendelian Randomization (MR) analysis. We also assess whether PIPs mediate the link between GM and VHD. We conducted bidirectional MR analyses to explore causal associations between GM, PIPs, and VHD, and used multivariable MR to test the independence of associations. Genome-wide association study (GWAS) data on 196 GM taxa, 91 PIPs, and VHD were analyzed. MR methods including inverse-variance weighted (IVW), MR-Egger regression, and weighted median approaches were applied. Sensitivity analyses ensured robustness. Actinobacteria and Defluviitaleaceae were associated with lower VHD risk, while Oxalobacteraceae increased risk. At the genus level, Intestinibacter, Lachnospiraceae NC2004 group, Oscillospira, and Ruminococcaceae UCG004 were protective, whereas Oscillibacter increased risk. Among PIPs, Interleukin-10, Interleukin-17C, Leukemia inhibitory factor receptor (LIFR), and monocyte chemoattractant protein 2 were protective, while TNF-beta elevated risk. Multivariable MR confirmed the independent roles of TNF-beta, LIFR, and MCP-2. Actinobacteria's protective effect appeared partially mediated through increased LIFR expression, accounting for 14% of the effect. Our findings suggest that modulating gut microbiota, particularly enhancing Actinobacteria, may serve as a novel strategy for VHD prevention and treatment.
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Affiliation(s)
- Jiajing Zhao
- Internal Medicine of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing City, Jiangsu Province, China
| | - Yuhan Wang
- Internal Medicine of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing City, Jiangsu Province, China
| | - Chuxin Lv
- Internal Medicine of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing City, Jiangsu Province, China
| | - Jiang Peng
- Department of Cardiology, Wuxi Traditional Chinese Medicine Hospital, Wuxi City, Jiangsu Province, China
| | - Shu Lu
- Department of Cardiology, Wuxi Traditional Chinese Medicine Hospital, Wuxi City, Jiangsu Province, China.
| | - Lijuan Shen
- ICU, Wuxi Traditional Chinese Medicine Hospital, Wuxi City, Jiangsu Province, China.
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21
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Stensrud VH, Rogne T, Flatby HM, Mohus RM, Gustad LT, Nilsen TIL. Examining socioeconomic differences in sepsis risk and mediation by modifiable factors: a Mendelian randomization study. BMC Infect Dis 2025; 25:739. [PMID: 40410669 PMCID: PMC12103053 DOI: 10.1186/s12879-025-11130-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Accepted: 05/15/2025] [Indexed: 05/25/2025] Open
Abstract
BACKGROUND Educational attainment is inversely related to sepsis risk, but the causal nature is still unclear. We therefore conducted the first Mendelian randomization (MR) study of genetically predicted educational attainment on sepsis that also uses a within-family genetic instrument for education. To further explore possible mechanistic pathways that can inform strategies to reduce sepsis risk, we examined the mediating effects of factors that are modifiable or can be prevented. METHODS The association between genetically predicted educational attainment and sepsis was estimated using summary-level data from recent genome-wide association studies. Possible bias due to population stratification, dynastic effects, and assortative mating in the genetic instrument for education was evaluated using summary-level data from a within-sibship genome-wide association study. We used inverse variance weighted MR analysis to estimate the effect of one standard deviation increase in years of education on sepsis risk. The robustness of the findings was assessed in sensitivity analyses, applying weighted median, weighted mode, and MR Egger regression. Finally, we applied multivariable MR analyses to estimate the mediating effects of smoking initiation, alcohol consumption, body mass index, high-density lipoprotein (HDL)-cholesterol, systolic blood pressure and type 2 diabetes. RESULTS For each standard deviation increase in genetically predicted educational attainment (3.4 years), the odds ratio (OR) for sepsis was 0.72 (95% confidence interval (CI) 0.66 to 0.78). The results of the analysis using the within-sibship genetic instrument and other sensitivity analyses were in line with this finding: within-sibship OR 0.88 (95% CI 0.64 to 1.18), weighted median OR 0.70 (95% CI 0.62 to 0.80), weighted mode OR 0.70 (95% CI 0.43 to 1.13), and MR Egger OR 0.65 (95% CI 0.50 to 0.85). The mediation analysis showed that 56% of the effect of educational attainment on sepsis risk can be explained by modifiable or preventable factors. CONCLUSIONS Higher educational attainment is strongly associated with a reduced risk of sepsis, pointing to important socioeconomic differences in this disease. The results also suggest that interventions targeting modifiable or preventable factors could contribute to reducing the socioeconomic differences in sepsis risk.
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Affiliation(s)
- Vilde Hatlevoll Stensrud
- Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway.
- Mid-Norway Centre for Sepsis Research, Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway.
| | - Tormod Rogne
- Department of Community Medicine and Global Health, University of Oslo, Oslo, Norway
- Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA
| | - Helene Marie Flatby
- Mid-Norway Centre for Sepsis Research, Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Randi Marie Mohus
- Mid-Norway Centre for Sepsis Research, Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
- Clinic of Anaesthesia and Intensive Care, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
| | - Lise Tuset Gustad
- Faculty of Nursing and Health Sciences, Nord University, Levanger, Norway
- Department of Internal Medicine, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway
| | - Tom Ivar Lund Nilsen
- Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway
- Clinic of Emergency Medicine and Prehospital Care, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway
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22
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Wang X, Xiao G, Xu W, Ni C. Causal validation of the relationship between air pollution and lung cancer: A bidirectional Mendelian randomization study and meta-analysis. Medicine (Baltimore) 2025; 104:e42450. [PMID: 40419866 DOI: 10.1097/md.0000000000042450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/28/2025] Open
Abstract
Recent studies suggest a link between air pollution and lung cancer, but causality remains uncertain due to confounding and reverse causation. Mendelian randomization (MR) reduces such bias and offers a new way to explore this relationship. MR is a method that uses genetic variants as instrumental variables to assess the causal relationship between an exposure and an outcome, effectively controlling for confounding and reverse causation. The inverse-variance weighted method is a commonly used approach in MR analysis, which estimates the overall causal effect by weighting the effect ratios of multiple single nucleotide polymorphisms, assuming all instruments are valid. Based on 2-sample MR, this study incorporated 5 air pollution indices and conducted MR analyses with lung cancer outcome data from 2 different sources. Subsequently, a meta-analysis was performed on the primary inverse-variance weighted results, followed by multiple corrections of the thresholds after the meta-analysis to ensure accuracy. Finally, reverse causality was tested through MR analysis for air pollution indices significantly associated with lung cancer. And the selection criteria for instrumental variables were: P < 5 × 10⁻⁶, F > 10, minor allele frequency > 0.01, clump_kb = 10,000, and clump_r2 = 0.001. Five air pollution indices were analyzed using MR analysis and meta-analysis with lung cancer data from the FinnGen R12 and OpenGWAS databases. Multiple corrections were applied to the significance threshold results after the meta-analysis. The final results showed that only nitrogen dioxide (NO₂) exhibited a significant association, with an OR of 3.426 (95% CI: 1.897-6.186, P = 2.21 × 10⁻⁴). Additionally, the positive air pollution index NO₂ showed no evidence of reverse causality with lung cancer from either data source. This study demonstrates a significant causal association between NO₂ and lung cancer, indicating that NO₂ may be a potential risk factor for lung cancer.
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Affiliation(s)
- Xiaomin Wang
- The First People's Hospital of Kunming City and Calmette Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Guihua Xiao
- Zhoupu Hospital, Pudong New District, Shanghai, China
| | - Wanxian Xu
- The First People's Hospital of Kunming City and Calmette Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Changguo Ni
- The First People's Hospital of Kunming City and Calmette Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
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23
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Xiao X, Xiao Z, Shi D, Wang X, Zhang J. Exploring the causal relationship between Hashimoto thyroiditis and metabolic-associated fatty liver disease: A Mendelian randomization study. Medicine (Baltimore) 2025; 104:e42533. [PMID: 40419925 DOI: 10.1097/md.0000000000042533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/28/2025] Open
Abstract
This study aims to investigate the possible causal link between Hashimoto thyroiditis (HT), an autoimmune disorder, and metabolic-associated fatty liver disease (MAFLD), previously referred to as nonalcoholic fatty liver disease (NAFLD), a common metabolic condition. Using genome-wide association study data from large European populations, we performed a bidirectional Mendelian randomization (MR) analysis. We identified single nucleotide polymorphisms strongly associated with HT and MAFLD/NAFLD, which we used as instrumental variables to probe the causal relationship between these 2 conditions. The forward MR analysis, using the inverse variance weighted method, showed that HT may increase the risk of MAFLD/NAFLD (odds ratio = 1.065, 95% confidence intervals: 1.014-1.119, P = .011). However, the reverse MR analysis did not establish a significant causal effect of MAFLD/NAFLD on HT (P > .05). Sensitivity analyses were carried out to assess potential heterogeneity or pleiotropy, and the results supported the robustness of our findings, indicating no significant concerns. These results suggest that HT may be a risk factor for the development of MAFLD/NAFLD. The bidirectional MR study revealed an elevated risk of MAFLD/NAFLD in individuals with HT, but no causal relationship was found from MAFLD/NAFLD to HT in the opposite direction. This understanding could assist healthcare professionals in improving their comprehension and management of both HT and MAFLD/NAFLD, leading to more comprehensive clinical guidance for patients and promoting the development of interdisciplinary treatment strategies.
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Affiliation(s)
- Xi Xiao
- Department of Geriatrics, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Zhengping Xiao
- Department of Colorectal Hernia Surgery, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Doufei Shi
- Department of Geriatrics, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Xiaoning Wang
- Department of Geriatrics, Binzhou Medical University Hospital, Binzhou, Shandong, China
| | - Jie Zhang
- Department of Geriatrics, Binzhou Medical University Hospital, Binzhou, Shandong, China
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24
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Wu J, Chen S, Xu R, Chen Y, Guo J, Li J, Zeng X, Wang B, Zhu X. Multidimensional investigation of thyroid hormones and prostate cancer: insights from NHANES, Mendelian randomization, genetic markers, and bioinformatics analyses. Discov Oncol 2025; 16:843. [PMID: 40397285 PMCID: PMC12095733 DOI: 10.1007/s12672-025-02672-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Accepted: 05/12/2025] [Indexed: 05/22/2025] Open
Abstract
BACKGROUND Prostate cancer remains a major global health burden for men, with its incidence and mortality steadily rising. Thyroid hormones, critical regulators of metabolism and cell growth, have been implicated in tumorigenesis, yet their specific role in prostate cancer risk remains unclear. This study systematically investigates the relationship between thyroid hormones and prostate cancer using multidimensional approaches. METHODS A three-phase study design was employed: (1) A cross-sectional analysis of The National Health and Nutrition Examination Survey (NHANES) data to examine thyroid hormone levels (FT3 and T3) and prostate cancer risk; (2) Mendelian randomization (MR) analysis using genome-wide association studies (GWAS) data to explore causal relationships; (3) Bioinformatics analyses to annotate key Single Nucleotide Polymorphism(SNPs), identify related genes, and assess their biological roles in prostate cancer. RESULTS Observational analysis revealed significantly lower FT3 and T3 levels in high-risk prostate cancer patients, with adjusted models confirming an inverse association (p < 0.001). MR analysis supported a causal relationship between thyroid hormone replacement therapy and reduced prostate cancer risk (b < 0, p < 0.05). Four key genes-ADM5, INPP5B, NEURL4, and TYK2-were identified as downregulated in prostate cancer tissues, with prognostic and immune regulatory implications. CONCLUSIONS Thyroid hormones exhibit a protective role against prostate cancer. ADM5, INPP5B, NEURL4, and TYK2 emerge as potential biomarkers and therapeutic targets, warranting further mechanistic and clinical validation.
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Affiliation(s)
- Jinhai Wu
- Department of Urology, Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, China
| | - Sian Chen
- Department of Urology, Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, China
| | - Ran Xu
- Department of Urology, Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yanfei Chen
- Department of Urology, Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, China
| | - Jiadin Guo
- Department of Urology, Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, China
| | - Jing Li
- Department of Urology, Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, China
| | - Xiheng Zeng
- Department of Urology, Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, China
| | - Bin Wang
- Department of Urology, Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, China.
| | - Xuejin Zhu
- Department of Urology, Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, China.
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Zhang J, Lin L, Li W, Guo J. Role of the "inflammation-immunity-metabolism" network in non-small cell lung cancer: a multi-omics analysis. Discov Oncol 2025; 16:847. [PMID: 40397292 PMCID: PMC12095725 DOI: 10.1007/s12672-025-02692-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2025] [Accepted: 05/12/2025] [Indexed: 05/22/2025] Open
Abstract
Lung cancer remains one of the leading causes of cancer-related mortality, with non-small cell lung cancer (NSCLC) accounting for 85% of cases worldwide. NSCLC pathogenesis and progression are intricately linked to inflammatory stimuli, immune evasion, and metabolic reprogramming. In this study, the impact of inflammation, immunity, and metabolism on NSCLC was investigated by a Mendelian randomization analysis taking 91 inflammatory factors, 731 immune cells, and 1400 metabolites as exposures, and the FinnGen database NSCLC cohort (ncases = 5315, ncontrol = 314,193) was the outcome. A number of metabolites, inflammatory proteins, and immune cells were identified as potentially associated with NSCLC based on mendelian randomization analysis. Validation in the UK Biobank database lung cancer cohort (ncases = 2671, ncontrols = 372,016) further confirmed the inhibitory role of the metabolite N-acetyl-aspartyl-glutamate (NAAG) on lung cancer. Subsequently, single-cell and protein-protein interaction analyses identified inflammatory protein expression patterns in NSCLC, distribution ratios of immune cells in NSCLC. Subsequent multi-omics network analysis showed key interaction nodes between NAAG and inflammatory proteins. These findings enhance the understanding of the roles of inflammation, immunity, and metabolism in NSCLC occurrence and progression, offering potential targets and strategies for further research on its treatment and management.
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Affiliation(s)
- Jingqi Zhang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Liping Lin
- Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Wenyuan Li
- Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jing Guo
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
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Hu R, Liang Y, He T, Zhou Y, Lv Y. Causal association of hypertension in family members with preeclampsia-eclampsia in pregnant women: A two-sample Mendelian randomization study. Pregnancy Hypertens 2025; 40:101223. [PMID: 40403523 DOI: 10.1016/j.preghy.2025.101223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 02/01/2025] [Accepted: 05/11/2025] [Indexed: 05/24/2025]
Abstract
OBJECTIVES The genetic risk factors for hypertension are also high-risk factors for preeclampsia-eclampsia. This study examined the association of hypertension in family members with preeclampsia-eclampsia in pregnant women through two-sample Mendelian randomization (MR). STUDY DESIGN Mendelian randomization. MAIN OUTCOME MEASURES The data for hypertension in siblings, mother, and father were from the UK Biobank, including 364,661, 426,391, and 402,899 individuals, respectively. The data for preeclampsia-eclampsia were FinnGEN R9 (7217 cases and 194,266 controls). Inverse-variance weighted was used as the main analysis method. Weighted median, MR-Egger, simple mode, and weighted mode were complementary MR methods. Heterogeneity was detected using Cochran's Q-test, horizontal pleiotropy using MR-Egger regression, and driving single-nucleotide polymorphisms (SNPs) using the leave-one-out method. RESULTS Mendelian randomization analysis showed that hypertension in family members was positively correlated with preeclampsia-eclampsia risk. The risk of preeclampsia-eclampsia in pregnant women who have siblings with hypertension was the highest (OR = 179.41, 95 % CI: 23.10-1393.65, P = 6.98E-07), followed by hypertension in the mothers (OR = 26.83, 95 % CI: 5.42-132.87, P = 5.56E-05) and the fathers (OR = 18.97, 95 % CI: 1.28-281.29, P = 0.032). The MR-Egger regression test indicated no horizontal pleiotropy (P > 0.05). Cochran's Q-test showed that the effects of the included SNPs exhibited heterogeneity (P < 0.05). The leave-one-out analysis did not reveal SNPs driving the results by themselves. CONCLUSION The risk of preeclampsia-eclampsia in pregnant women who have siblings with hypertension was the highest, followed by pregnant women with a mother or father with hypertension. Having siblings with hypertension should be considered as a high-risk factor for the early prediction of preeclampsia-eclampsia.
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Affiliation(s)
- Rui Hu
- Department of Obstetrics and Gynecology Intensive Care Unit, Northwest Women's and Children's Hospital, Xi'an, Shaanxi Province 710061, China
| | - Yan Liang
- Department of Obstetrics and Gynecology Intensive Care Unit, Northwest Women's and Children's Hospital, Xi'an, Shaanxi Province 710061, China
| | - Tongqiang He
- Department of Obstetrics and Gynecology Intensive Care Unit, Northwest Women's and Children's Hospital, Xi'an, Shaanxi Province 710061, China
| | - Ying Zhou
- Department of Obstetrics and Gynecology Intensive Care Unit, Northwest Women's and Children's Hospital, Xi'an, Shaanxi Province 710061, China
| | - Yanxiang Lv
- Department of Obstetrics and Gynecology Intensive Care Unit, Northwest Women's and Children's Hospital, Xi'an, Shaanxi Province 710061, China.
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Yang Y, Ma Y, Li M, Han Y, Liu L. Unraveling the causal pathway between phosphatidylinositol, metabolites, and metabolic syndrome: a Mendelian randomization study. Diabetol Metab Syndr 2025; 17:162. [PMID: 40394636 PMCID: PMC12090523 DOI: 10.1186/s13098-025-01731-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 05/06/2025] [Indexed: 05/22/2025] Open
Abstract
INTRODUCTION Observational studies have increasingly acknowledged the influence of Phosphatidylinositol (PI) on metabolic syndrome (MetS). Nevertheless, the causal association between PI and MetS remains unclear due to the presence of confounding factors and the potential for reverse causation in observational settings. This study seeks to clarify the causal link between PI and MetS while investigating the role of mediating metabolites. METHODS A two-sample Mendelian randomization (MR) analysis was performed to examine the association between PI and MetS, utilizing aggregated data from genome-wide association studies (GWAS). Additionally, a two-step MR approach was applied to quantify the mediation effect of metabolites on the PI-MetS relationship. The inverse variance weighted (IVW) method served as the primary analytical approach, complemented by various sensitivity analyses employing alternative techniques. RESULTS A significant positive association was found between genetically predicted PI and a 17% increased risk of MetS. Genetically predicted metabolites, including 4-cholesten-3-one (IVW: OR 1.264, 95% CI 1.076-1.483, p = 0.004), N-acetylalliin (IVW: OR 1.189, 95% CI 1.008-1.402, p = 0.040), and the Adenosine 5'-diphosphate to 5-oxoproline ratio (IVW: OR 1.191, 95% CI 1.045-1.357, p = 0.009), were each significantly associated with an increased risks of MetS, accounting for 14.50, 11.41%, 11.87% and % of the total effect, respectively. Notably, the Retinol to oleoyl-linoleoyl-glycerol ratio (IVW: OR 0.643, 95% CI 0.466-0.887, p = 0.007) mediated 62.6% of the effect, highlighting its pivotal role in the causal pathway linking PI to MetS. Moreover, 1-palmitoyl-2-dihomo-linolenoyl-GPC (IVW: OR 0.865, 95% CI 0.752-0.995, p = 0.042) and the Creatine to carnitine ratio (IVW: OR 0.853, 95% CI 0.740-0.983, p = 0.028) were associated with a reduced risk of MetS, demonstrating inhibitory effects within their respective pathways that accounted to 35.03% and 8.45% reductions in risk, respectively. CONCLUSIONS Our MR analysis demonstrated a positive association between PI and an increased risk of MetS. Furthermore, the metabolite-mediated PI significantly influenced MetS risk. These findings may offer valuable insights into the pathogenesis of MetS and inform future clinical research.
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Affiliation(s)
- YueGuang Yang
- Heilongjiang University of Chinese Medicine;, Heilongjiang, P.R. China
| | - YanLing Ma
- Heilongjiang University of Chinese Medicine;, Heilongjiang, P.R. China
| | - Ming Li
- Heilongjiang University of Chinese Medicine;, Heilongjiang, P.R. China
| | - YuBo Han
- The First Department of Cardiovascular, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, 26 Heping Road, Xiangfang, Harbin, Heilongjiang, 150040, P.R. China.
| | - Li Liu
- The First Department of Cardiovascular, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, 26 Heping Road, Xiangfang, Harbin, Heilongjiang, 150040, P.R. China.
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Tribble JR, Wong VHY, Stuart KV, Chidlow G, Nicol A, Rombaut A, Rabiolo A, Hoang A, Lee PY, Rutigliani C, Enz TJ, Canovai A, Lardner E, Stålhammar G, Nguyen CTO, Garway-Heath DF, Casson RJ, Khawaja AP, Bui BV, Williams PA. Dysfunctional one-carbon metabolism identifies vitamins B 6, B 9, B 12, and choline as neuroprotective in glaucoma. Cell Rep Med 2025; 6:102127. [PMID: 40345183 DOI: 10.1016/j.xcrm.2025.102127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 02/03/2025] [Accepted: 04/15/2025] [Indexed: 05/11/2025]
Abstract
Glaucoma, characterized by the loss of retinal ganglion cells (RGCs), is a leading cause of blindness for which there are no neuroprotective therapies. To explore observations of elevated homocysteine in glaucoma, we elevate vitreous homocysteine, which increases RGC death by 6% following ocular hypertension. Genetic association with higher homocysteine does not affect glaucoma-associated outcomes from the UK Biobank and serum homocysteine levels have no effect on glaucomatous visual field progression. This supports a hypothesis in which elevated homocysteine is a pathogenic, rather than causative, feature of glaucoma. Further exploration of homocysteine metabolism in glaucoma animal models demonstrates early and sustained dysregulation of genes involved in one-carbon metabolism and the interaction of essential cofactors and precursors (B6, B9, B12, and choline) in whole retina and optic nerve head and RGCs. Supplementing these provides neuroprotection in an acute model and prevents neurodegeneration and protects visual function in a chronic model of glaucoma.
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Affiliation(s)
- James R Tribble
- Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden.
| | - Vickie H Y Wong
- Department of Optometry and Vision Sciences, University of Melbourne, Parkville, VIC, Australia
| | - Kelsey V Stuart
- NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK
| | - Glyn Chidlow
- Discipline of Ophthalmology & Visual Sciences, Level 7 Adelaide Health and Medical Sciences Building, University of Adelaide, North Terrace, Adelaide, SA 5000, Australia
| | - Alan Nicol
- Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Anne Rombaut
- Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Alessandro Rabiolo
- Department of Ophthalmology, University Hospital Maggiore della Carita', Novara, Italy; Department of Health Sciences, Università del Piemonte Orientale "A.Avogadro", Novara, Italy
| | - Anh Hoang
- Department of Optometry and Vision Sciences, University of Melbourne, Parkville, VIC, Australia
| | - Pei Ying Lee
- Department of Optometry and Vision Sciences, University of Melbourne, Parkville, VIC, Australia
| | - Carola Rutigliani
- Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Tim J Enz
- Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden; Department of Ophthalmology, University of Basel, Basel, Switzerland
| | - Alessio Canovai
- Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Emma Lardner
- Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Gustav Stålhammar
- Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Christine T O Nguyen
- Department of Optometry and Vision Sciences, University of Melbourne, Parkville, VIC, Australia
| | - David F Garway-Heath
- NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK
| | - Robert J Casson
- Discipline of Ophthalmology & Visual Sciences, Level 7 Adelaide Health and Medical Sciences Building, University of Adelaide, North Terrace, Adelaide, SA 5000, Australia
| | - Anthony P Khawaja
- NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK
| | - Bang V Bui
- Department of Optometry and Vision Sciences, University of Melbourne, Parkville, VIC, Australia
| | - Pete A Williams
- Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden.
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Kim BR, Kim G, Jin SP, Choi CW, Kim J, Park H. Causal association between polyunsaturated fatty acids and acne: a two-sample Mendelian randomization study. Br J Dermatol 2025; 192:1106-1114. [PMID: 39936505 DOI: 10.1093/bjd/ljaf052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2024] [Revised: 02/03/2025] [Accepted: 02/03/2025] [Indexed: 02/13/2025]
Abstract
BACKGROUND Observational studies have demonstrated a close association between polyunsaturated fatty acids (PUFAs) and acne. However, the findings of clinical trials have been inconsistent, leaving the causal relationship between PUFAs and acne unclear. OBJECTIVES To investigate the causal association between genetically proxied PUFAs and acne risk. METHODS Mendelian randomization (MR) was performed using single nucleotide polymorphisms associated with PUFAs as instrumental variables. The causal associations between PUFAs and acne were estimated among 115 006 UK Biobank participants and 363 927 participants of Finnish descent. RESULTS Genetically predicted docosahexaenoic acid (DHA) levels [β = -0.303, 95% confidence interval (CI) -0.480 to -0.126; P = 7.74 × 10-4] and its percentage to total fatty acids (β = -0.402, 95% CI -0.651 to -0.258; P = 5.91 × 10-6) showed a significant causal association with a decreased risk of acne. Conversely, genetically predicted percentages of linoleic acid (LA) in total fatty acids (β = 0.768, 95% CI 0.411-0.126; P = 2.87 × 10-4) and omega-6 : omega-3 ratio (β = 0.373, 95% CI 0.142-0.604; P = 4.48 × 10-3) were robustly associated with an increased risk of acne. These effects were attenuated after excluding a genetic variant of rs174528 located upstream of FADS1, highlighting the biologic link between FADS1 and delta-5 desaturase activity. Multivariable MR analysis indicated that PUFAs were causally associated with acne, independent of body mass index. CONCLUSIONS Our study indicates that high DHA levels and their ratios to total fatty acids have causal protective effects against acne, while high LA levels and omega-6 : omega-3 ratio are associated with increased acne risk. This association was largely attributable to the influence of genetic variants related to FADS1.
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Affiliation(s)
- Bo Ri Kim
- Department of Dermatology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
- Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Gahyun Kim
- Precision Medicine Center, Future Innovation Research Division, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Seon-Pil Jin
- Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Dermatology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Chong Won Choi
- Department of Dermatology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
- Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jinho Kim
- Precision Medicine Center, Future Innovation Research Division, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
- Department of Genomic Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
- Department of Laboratory Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
| | - Hyunsun Park
- Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Dermatology, Seoul National University Hospital, Seoul, Republic of Korea
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Liu S, Zhu J, Zhang H, Zhong H, Wong HTH, Wang L, Wu L. Causal Relationship Between Blood Metabolites and Prostate Cancer Risk: A Two-Sample Mendelian Randomization Study. Mol Carcinog 2025. [PMID: 40387704 DOI: 10.1002/mc.23929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 04/21/2025] [Accepted: 04/27/2025] [Indexed: 05/20/2025]
Abstract
Recent research has increasingly suggested an association between changes in specific blood metabolites and prostate cancer (PCa) development. However, it remains unclear whether these observed associations represent a causal relationship. To reveal the potential causal associations between blood metabolites and PCa risk, we conducted a comprehensive two-sample Mendelian randomization (MR) analysis. We used genetic instruments for 514 and 490 metabolites from two independent comprehensive genome-wide association studies. These studies included 14,295 individuals of European ancestry from the INTERVAL/EPIC-Norfolk cohorts and 8299 individuals of European ancestry from the Canadian Longitudinal Study on Aging cohort. Summary statistics of PCa risk involving 122,188 cases and 604,640 controls of European ancestry individuals were analyzed. The associations between metabolites and PCa risk were evaluated using the inverse-variance weighted method, supplemented by sensitivity analyses including MR-Egger and MR-PRESSO tests. Additionally, we conducted a phenome-wide MR analysis to assess the potential side effects of targeting the identified metabolites for PCa intervention. Our analysis revealed 107 unique blood metabolites significantly associated with PCa risk, with 43 of these associations consistently replicated using instruments from two independent data sets. This study provides novel insights into the potential role of specific metabolites in the etiology of PCa, which warrants further investigations.
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Affiliation(s)
- Shuai Liu
- Population Sciences in the Pacific Program, Cancer Epidemiology Division, University of Hawai'i Cancer Center, University of Hawai'i at Mānoa, Honolulu, Hawaii, USA
| | - Jingjing Zhu
- Department of Quantitative Health Sciences, John A. Burns School of Medicine, University of Hawai'i at Mānoa, Honolulu, Hawaii, USA
| | - Huizhen Zhang
- Population Sciences in the Pacific Program, Cancer Epidemiology Division, University of Hawai'i Cancer Center, University of Hawai'i at Mānoa, Honolulu, Hawaii, USA
| | - Hua Zhong
- Population Sciences in the Pacific Program, Cancer Epidemiology Division, University of Hawai'i Cancer Center, University of Hawai'i at Mānoa, Honolulu, Hawaii, USA
| | - Hoi Tung Hilton Wong
- Population Sciences in the Pacific Program, Cancer Epidemiology Division, University of Hawai'i Cancer Center, University of Hawai'i at Mānoa, Honolulu, Hawaii, USA
- Biochemistry Program, Department of Chemistry, Colleges of Arts and Sciences, University of Hawai'i at Mānoa, Honolulu, Hawaii, USA
| | - Liang Wang
- Department of Tumor Microenvironment and Metastasis, Moffitt Cancer Center, Tampa, Florida, USA
| | - Lang Wu
- Population Sciences in the Pacific Program, Cancer Epidemiology Division, University of Hawai'i Cancer Center, University of Hawai'i at Mānoa, Honolulu, Hawaii, USA
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Xu T, Xiao W, Li W, Xu X, Zhang H, Zhang X. Exploring the causal relationship between immune factors and chondrosarcoma: a Mendelian randomization study. Discov Oncol 2025; 16:801. [PMID: 40382743 PMCID: PMC12086138 DOI: 10.1007/s12672-025-02654-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Accepted: 05/09/2025] [Indexed: 05/20/2025] Open
Abstract
BACKGROUND Previous studies have investigated the potential role of immune factors in chondrosarcoma (CHS). However, the causal relationship is unknown. METHODS A two-sample Mendelian randomization (MR) was used to explore potential correlations between 731 immunocyte phenotypes, 91 inflammatory proteins, and CHS. The data were derived from published summary statistics of genome-wide association studies. Inverse-variance weighted was employed as the primary method. Furthermore, a range of analytical methods, including MR-Egger, weighted mode, and weighted median was used to enhance the robustness of the results. A two-step MR was used to assess the mediating effects of inflammatory proteins. Subsequently, sensitivity and MR Steiger directionality tests were performed. RESULTS MR analyses showed that 12 immunocyte phenotypes were positively correlated with CHS (P < 0.05, OR > 1), and 11 immunocyte phenotypes were negatively correlated with CHS (P < 0.05, OR < 1). Five inflammatory proteins were positively associated with CHS (P < 0.05, OR > 1). No heterogeneous or horizontal pleiotropy was found. The MR Steiger analysis found no statistically significant evidence of reverse causation. Mediation analysis did not identify any potential mediating effects. CONCLUSION Our study underscores the pivotal role of immune factors in CHS and offers insights that can inform future research.
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Affiliation(s)
- Taichuan Xu
- Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China
| | - Wentao Xiao
- Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China
| | - Wenjie Li
- Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China
| | - Xianfa Xu
- Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China
| | - Haiwen Zhang
- Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China
| | - Xian Zhang
- Department of Spine, Wuxi Affiliated Hospital of Nanjing University of Chinese Medicine, Wuxi, 214072, Jiangsu, China.
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Zhang X, Zhu Z, Shen C, Tang G. The causal effects of systemic antioxidant capacity on male infertility: A two-sample mendelian randomization analysis. Sci Rep 2025; 15:17009. [PMID: 40379801 PMCID: PMC12084361 DOI: 10.1038/s41598-025-02243-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 05/12/2025] [Indexed: 05/19/2025] Open
Abstract
The present research aimed to assess the potential causal relationship between systemic antioxidant capacity and male infertility using a two-sample Mendelian randomization approach. The primary MR analysis utilized the inverse variance weighted (IVW)method, supplemented by complementary analyses including MR-Egger, weighted mode, simple mode, and weighted median methods. For male infertility, the available summarized data were gained from the open database (IEU OPEN GWAS PROJECT), which includes a total of 680 male patients with infertility and 72,799 controls of European population.10 biomarkers related to systemic antioxidant capacity were examined to investigate their potential association with male infertility, including glutathione S-transferase (GST), superoxide dismutase(SOD), glutathione peroxidase(GPX), catalase (CAT), total bilirubin, albumin, α-tocopherol, ascorbate, retinol, and uric acid. MR analyses using IVW mode revealed that genetically determined systemic antioxidant capacity biomarkers had no causal effects on male infertility risk, including GST(OR = 1.08, 95%CI: 0.91-1.29, P = 0.35), SOD(OR = 0.83, 95%CI: 0.66-1.04, P = 0.11), GPX(OR = 1.12, 95%CI: 0.92-1.36,P = 0.26), CAT(OR = 1.04, 95%CI: 0.83-1.29, P = 0.75), total bilirubin(OR = 0.98, 95%CI: 0.94-1.01, P = 0.18), albumin(OR = 1.14, 95%CI: 0.73-1.76, P = 0.57), α-tocopherol(OR = 0.56, 95%CI: 0.03-9.38, P = 0.69), ascorbate(OR = 1.06, 95%CI: 0.24-4.60, P = 0.94), retinol(OR = 1.29, 95%CI: 0.34-4.96, P = 0.71), and uric acid (OR = 0.88, 95% CI : 0.67-1.17, P = 0.39). The current study found no significantly causal link between systemic antioxidant capacity and male infertility. Further research with larger sample sizes and data from different ethnicities is needed.
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Affiliation(s)
- Xiaolong Zhang
- Department of Urology, Shaoxing People's Hospital(The First Affiliated Hospital, Shaoxing University), 568 Zhongxing North Road, 312000, Shaoxing, Zhejiang, China
| | - Zhirong Zhu
- Department of Urology, Shaoxing People's Hospital(The First Affiliated Hospital, Shaoxing University), 568 Zhongxing North Road, 312000, Shaoxing, Zhejiang, China
| | - Chaodong Shen
- Department of Urology, Shaoxing People's Hospital(The First Affiliated Hospital, Shaoxing University), 568 Zhongxing North Road, 312000, Shaoxing, Zhejiang, China
| | - Guiliang Tang
- Department of Urology, Shaoxing People's Hospital(The First Affiliated Hospital, Shaoxing University), 568 Zhongxing North Road, 312000, Shaoxing, Zhejiang, China.
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Lin S, Zhou D, Zhu H, Huang G, Yu M, Chen S, Wang J, Xia W. Genetic association between coffee consumption and multiple myeloma mediated by plasma metabolites: a Mendelian randomization study. Food Funct 2025. [PMID: 40375831 DOI: 10.1039/d4fo05696e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/18/2025]
Abstract
Background: Multiple myeloma (MM) is a hematologic malignancy closely associated with diets and metabolic disorders, showing an increasing incidence trend. Genome-wide association studies (GWAS) contribute to exploring the causal relationships between diets, metabolites, and MM, thereby revealing biological mechanisms underlying cancer progression. Methods: This study included large-scale GWAS data for two diets, four metabolomics, and MM. The two-sample Mendelian randomization (MR) analysis was conducted to assess causalities between these dietary patterns, metabolites, and MM. The MR analysis primarily employed the inverse variance weighted (IVW) method, supported by multiple sensitivity analysis and reverse MR analysis to validate significant associations. Mediation analysis identified specific metabolites mediating the causal relationships between diets and MM. Results: Univariate MR analysis suggested that coffee consumption (ORIVW = 2.72; 95% CI: 1.21-6.10; PIVW = 0.015, P_fdr = 0.022), decaffeinated coffee consumption (ORIVW = 7.10; 95% CI: 1.33-37.87; PIVW = 0.022, P_fdr = 0.022), ground coffee consumption (ORIVW = 4.04; 95% CI: 1.25-13.02; PIVW = 0.019, P_fdr = 0.022), instant coffee consumption (ORIVW = 6.13; 95% CI: 1.95-19.34; PIVW = 0.002, P_fdr = 0.008), and coffee max liking (ORIVW = 2.94; 95% CI: 1.23-7.03; PIVW = 0.015, P_fdr = 0.035) were associated with increased MM risk. Metabolomic MR analysis identified 19 plasma metabolites, 1 blood and urine biomarker, and 4 plasma lipids with significant association with MM. Mediation analysis indicated that hippurate and cinnamoylglycine mediated 35.55% (P < 0.001) and 21.85% (P = 0.002) of the genetically predicted effect of coffee consumption on MM risk, respectively. Cinnamoylglycine contributed 12.63% (P = 0.042) to the total causal effect of ground coffee consumption on MM. Hippurate (21.43%, P < 0.001), 3-hydroxyhippurate (4.39%, P = 0.031), and cinnamoylglycine (8.79%, P = 0.010) mediated the genetically predicted impact of instant coffee consumption on MM risk. Metabolic pathway analysis suggested that glutathione metabolism significantly contributes to MM pathogenesis (P = 0.002, FDR < 0.05). Conclusions: Our findings support the adverse causal effects of various coffee consumption on MM risk, identifying hippurate, 3-hydroxyhippurate, and cinnamoylglycine as key mediators, driving the relationship potentially through the glutathione metabolism pathway.
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Affiliation(s)
- Shichong Lin
- School of Smart Health Care (School of Health & Medical), Zhejiang Dongfang Polytechnic, Zhejiang, China
- The First Affiliated Hospital, Wenzhou Medical University, Wenzhou 325000, People's Republic of China
| | - Dan Zhou
- School of Smart Health Care (School of Health & Medical), Zhejiang Dongfang Polytechnic, Zhejiang, China
| | - Hua Zhu
- School of Smart Health Care (School of Health & Medical), Zhejiang Dongfang Polytechnic, Zhejiang, China
| | - Gaoxiang Huang
- School of Smart Health Care (School of Health & Medical), Zhejiang Dongfang Polytechnic, Zhejiang, China
| | - Menglu Yu
- Department of Pediatric Surgery, Jinhua Central Hospital, Jinhua, China
| | - Shaomin Chen
- School of Smart Health Care (School of Health & Medical), Zhejiang Dongfang Polytechnic, Zhejiang, China
| | - Junjie Wang
- Department of Cardiovascular Medicine, The Third Affiliated Hospital of Wenzhou Medical University (Ruian People's Hospital), Wenzhou, China
| | - Weiqiang Xia
- Department of Gastroenterology, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou 325200, China.
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Wang T, Huang X, Zhang X, Li N, Lu K, Zeng Y. Unveiling taurine's protective role in ischemic stroke: insights from bidirectional Mendelian randomization and LC-MS/MS analysis. GENES & NUTRITION 2025; 20:10. [PMID: 40361025 PMCID: PMC12076942 DOI: 10.1186/s12263-025-00769-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 04/25/2025] [Indexed: 05/15/2025]
Abstract
Ischemic stroke remains a leading cause of mortality and disability globally, emphasizing the urgent need for innovative preventative and therapeutic strategies. Taurine, a critical amino sulfonic acid, has garnered attention for its neuroprotective effects, yet its precise role in ischemic stroke remains elusive. This study utilized a bidirectional Mendelian Randomization (MR) approach to explore the causal relationship between plasma taurine levels and ischemic stroke risk, employing genome-wide association study (GWAS) datasets. In parallel, a novel high-sensitivity liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to quantify plasma taurine levels in ischemic stroke patients and healthy controls. Our findings reveal a significant inverse association between taurine levels and stroke risk, with IVW analysis showing beta = -0.001 and P = 0.0085. Furthermore, LC-MS/MS analysis demonstrated that plasma taurine levels in patients with ischemic stroke were notably lower at 36.07 ± 5.37 μmol/L compared to controls at 108.66 ± 25.11 μmol/L, confirming taurine's potential as a protective factor. These results suggest taurine as a promising biomarker and therapeutic target for stroke prevention and recovery. This study not only highlights the importance of taurine in cerebrovascular health but also provides a foundation for personalized intervention strategies.
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Affiliation(s)
- Tianyi Wang
- Beijing Institute of Heart, Lung, and Blood Vessel Disease, Anzhen Hospital, Capital Medical University, Beijing, China
| | - Xuyang Huang
- Department of Neurology Central Hospital Affiliated to Shenyang Medical College, Liaoning, China
| | - Xinyue Zhang
- Department of Pediatrics, Liaoning Provincial People's Hospital, Liaoning, China
| | - Na Li
- Mass Spectrometry Research Institute, Beijing Gobroad Hospital, Beijing, China
| | - Kaizhi Lu
- Mass Spectrometry Research Institute, Beijing Gobroad Hospital, Beijing, China
| | - Yong Zeng
- Beijing Institute of Heart, Lung, and Blood Vessel Disease, Anzhen Hospital, Capital Medical University, Beijing, China.
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Wang F, Liu Y, Jia J, Bai X, Zhang M, Ye X, Wang L, Bai Y. Causality between 22 personal traits and cervical cancer: a two-sample Mendelian randomization study. J Affect Disord 2025; 385:119364. [PMID: 40368145 DOI: 10.1016/j.jad.2025.05.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Revised: 03/31/2025] [Accepted: 05/04/2025] [Indexed: 05/16/2025]
Abstract
Previous research has indicated that certain personal traits are closely related to cervical cancer; however, owing to the limitations of observational studies, causality remains unclear. This pioneering study employs Mendelian Randomization (MR) analysis to explore the genetic links between personal traits and the risk of cervical cancer. We analyzed 22 personal traits and cervical cancer data from genome-wide association study (GWAS) databases. Utilizing instrumental variables identified from significant single nucleotide polymorphism (SNP) associations, we employed the Inverse Variance Weighted (IVW) method, along with the Weighted Median (WM) method and MR-Egger regression. A sensitivity analysis was conducted to confirm the robustness of the findings. Moreover, risk factor analyses were performed to explore potential mediators. Our results demonstrate positive causal relationships for smoking status (OR = 1.006, 95%CI 1.003-1.009, P < 0.001), smoking initiation (OR = 1.002, 95%CI 1.001-1.003, P = 0.02), past tobacco smoking (OR = 0.998, 95%CI 0.996-0.999, P = 0.023), age at first birth (OR = 0.999, 95%CI 0.998-0.999, P < 0.001), time spent watching television (OR = 1.005, 95%CI 1.002-1.007, P = 0.001), and duration of moderate to vigorous physical activity (OR = 0.997, 95%CI 0.995-0.999, P = 0.003). Smoking status, smoking initiation, and time spent watching television emerged as risk factors for cervical cancer, whereas past tobacco smoking, age at first birth, and duration of moderate to vigorous physical activity were identified as protective factors. No causal relationships were found between the remaining 16 personal traits and cervical cancer. This study establishes significant causal relationships between several personal traits and cervical cancer, providing valuable insights for cervical cancer prevention strategies and guiding future research directions. Moreover, it further explores the potential links between personal traits and cervical cancer.
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Affiliation(s)
- Fei Wang
- School of Clinical Medicine, Qinghai University, Xining, Qinghai Province, China
| | - Yuqin Liu
- Department of Gynaecology and Obstetrics, Qinghai Red Cross Hospital, Xining, Qinghai Province, China
| | - Jia Jia
- Department of Gynaecology and Obstetrics, Qinghai Red Cross Hospital, Xining, Qinghai Province, China
| | - Xue Bai
- Department of Gynaecology and Obstetrics, Qinghai Red Cross Hospital, Xining, Qinghai Province, China
| | - Maoyu Zhang
- Department of Gynaecology and Obstetrics, Qinghai Red Cross Hospital, Xining, Qinghai Province, China
| | - Xi Ye
- School of Clinical Medicine, Qinghai University, Xining, Qinghai Province, China
| | - Liehong Wang
- School of Clinical Medicine, Qinghai University, Xining, Qinghai Province, China; Department of Gynaecology and Obstetrics, Qinghai Red Cross Hospital, Xining, Qinghai Province, China.
| | - Yufang Bai
- School of Clinical Medicine, Qinghai University, Xining, Qinghai Province, China; Department of Gynaecology and Obstetrics, Qinghai University Affiliated Hospital, , Xining, Qinghai Province 810000, China.
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Jiesisibieke ZL, Schooling CM. Body Mass Index as an Example of a Negative Confounder: Evidence and Solutions. Genes (Basel) 2025; 16:564. [PMID: 40428387 PMCID: PMC12110786 DOI: 10.3390/genes16050564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2025] [Revised: 05/02/2025] [Accepted: 05/08/2025] [Indexed: 05/29/2025] Open
Abstract
Background: Adequate control for confounding is key to many observational study designs. Confounders are often identified based on subject matter knowledge from empirical investigations. Negative confounders, which typically generate type 2 error, i.e., false nulls, can be elusive. Such confounders can be identified comprehensively by using Mendelian randomization (MR) to search the wealth of publicly available data systematically. Here, to demonstrate the concept, we examined whether a common positive confounder, body mass index (BMI), is also a negative confounder of any common physiological exposures on health outcomes, overall and specifically by sex. Methods: We used an MR study, based on the largest overall and sex-specific genome-wide association studies of BMI (i.e., from the Genetic Investigation of ANthropometric Traits and the UK Biobank) and of relevant exposures likely affected by BMI, to assess, overall and sex-specifically, whether BMI is a negative confounder potentially obscuring effects of harmful physiological exposures. Inverse variance weighting was the main method. We assessed sex differences using a z-test. Results: BMI was a potential negative confounder for apolipoprotein B and total testosterone in men, and for both sexes regarding low-density lipoprotein cholesterol, choline, linoleic acid, polyunsaturated fatty acids, and cholesterol. Conclusions: Using BMI as an illustrative example, we demonstrate that negative confounding is an easily overlooked bias. Given negative confounding is not always obvious or known, using MR systematically to identify potential negative confounders in relevant studies may be helpful.
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Affiliation(s)
- Zhu Liduzi Jiesisibieke
- School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China;
| | - C. Mary Schooling
- School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China;
- Graduate School of Public Health and Health Policy, City University of New York, New York, NY 10027, USA
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Wang Y, Cheng S, Que H. A Bidirectional Two-Sample Mendelian Randomization Study of Genetic Causality Between Vitamin D Levels and Pemphigus. Clin Cosmet Investig Dermatol 2025; 18:1167-1176. [PMID: 40370580 PMCID: PMC12077410 DOI: 10.2147/ccid.s523136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2025] [Accepted: 05/05/2025] [Indexed: 05/16/2025]
Abstract
Background Pemphigus, a B-cell-mediated autoimmune disease, has been hypothesized to involve vitamin D due to its immunomodulatory effects on B-cell activity. However, observational studies on this association remain inconclusive due to confounding factors. This study used genome-wide association study (GWAS) data for bidirectional two-sample Mendelian randomization (MR) analysis to clarify causality. Materials and Methods Genetic instruments for serum vitamin D levels (61 SNPs) and pemphigus (3 SNPs) were analyzed via inverse variance weighting (IVW), weighted median, and MR-Egger regression. Forward MR analysis revealed no causal effect of vitamin Don pemphigus risk [IVW OR=0.835 (95% CI:0.318-2.189), P=0.623], consistent across sensitivity analyses. Conversely, reverse MR showed pemphigus did not influence vitamin D levels [IVW OR=1.000 (95% CI:0.993-1.006), P=0.867]. Heterogeneity (Cochran Q test) and pleiotropy (MR-Egger intercept) tests confirmed robustness of results. Results Our findings challenge the presumed causal link between vitamin D and pemphigus, suggesting observed associations may arise from confounding factors. This underscores the need for mechanistic studies to explore alternative pathways in pemphigus pathogenesis.
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Affiliation(s)
- Yanchun Wang
- College of Clinical Medicine, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi Province, People’s Republic of China
| | - Shiping Cheng
- Department of Dermatology, the Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, Jiangxi Province, People’s Republic of China
| | - Huafa Que
- Traditional Chinese Medicine Surgery, Longhua Hospital Affiliated to Shanghai University of Chinese Medicine, Shanghai, People’s Republic of China
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Chen G, Luo Q, Wu C, Xie M. Identification of Shared Genetic Loci Associated With Inflammatory Bowel Disease, Ischemic Heart Disease, and Atrial Fibrillation and Flutter. Clin Genet 2025. [PMID: 40343385 DOI: 10.1111/cge.14749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Revised: 03/25/2025] [Accepted: 03/27/2025] [Indexed: 05/11/2025]
Abstract
The occurrence of ischemic heart disease (IHD), atrial fibrillation, and flutter demonstrates certain associations with inflammatory bowel disease (IBD), warranting further exploration at the genetic architecture level. This study focused on genome-wide association study (GWAS) data of IHD, atrial fibrillation and flutter, and IBD, analyzing from two dimensions: genetic correlation and shared locus identification. Initially, linkage disequilibrium score regression and genetic covariance analyzer were utilized to assess the overall genetic correlations. Subsequently, the association patterns of local genomic regions were determined using Local Ancestry Variance Association (LAVA) analysis. Mendelian randomization (MR) was employed to assess causal effects. The genetic overlap among different traits was analyzed based on the statistical framework of conditional/conjunctional false discovery rate (cond/conjFDR). Finally, shared loci across these traits were identified by integrating conjFDR analysis with GWAS multi-trait analysis (MTAG). At the genomic level, significant overall correlations were observed among IHD, atrial fibrillation and flutter, and IBD and Crohn's disease (CD), while associations with ulcerative colitis appeared less pronounced. At the local level, IHD and IBD (including subtypes) showed significant associations in multiple regions. However, atrial fibrillation and flutter exhibited local associations only in the context of CD. Through conjFDR analysis, the genetic overlap across these diseases was validated. Additionally, several shared genetic loci were identified by integrating conjFDR and MTAG analyses, with genes confirmed in both IHD and IBD (including subtypes), such as SMAD3, PLCG2, ZNF831, PTPN22, RP11-136O12.2, and RP11-449I17.5. Moreover, six common genes were identified in the analysis between atrial fibrillation and flutter and IBD (including subtypes), such as ZMIZ1, MTHFS, ERAP2, GNA12, and RP1-15D23.2. This study offers empirical evidence of the genetic association between IHD, atrial fibrillation and flutter, and IBD comorbidity, providing new insights for cases where IBD co-occurs with IHD or atrial fibrillation and flutter.
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Affiliation(s)
- Guojian Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qinghua Luo
- Clinical Medical College, Jiangxi University of Chinese Medicine, Nanchang, China
| | - Chengcheng Wu
- Department of Anorectal Surgery, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, China
| | - Mingjun Xie
- Department of Digestive System, Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, China
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Liu M, Sun Z, Tan P, Xie D, Liu Y, Feng W, Ren C, Du S. Associations between psoriasis and risk of 33 cancers: a Mendelian randomization study. BMC Cancer 2025; 25:837. [PMID: 40335896 PMCID: PMC12057250 DOI: 10.1186/s12885-025-14243-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 04/29/2025] [Indexed: 05/09/2025] Open
Abstract
BACKGROUND Several observational studies have reported epidemiologic associations between psoriasis and risk of some cancers, but systematic evidence is lacking. Our aim was to comprehensively estimate the association between psoriasis and the risk of 33 common cancers using systematical Mendelian randomization based on genetic data. METHOD Forty-nine independent single-nucleotide polymorphisms (SNPs) significantly associated with psoriasis were extracted as instrumental variables from a large-scale meta-analysis study of genome-wide association study (GWAS) for psoriasis. Outcome GWAS data were obtained from the FinnGen consortium (n = 500,348), UK Biobank (n = 420,531), and other large-scale cancer datasets. The inverse-variance weighted (IVW) was used as the primary method to infer the association between psoriasis and risk of cancer, and finally the results from multiple databases were pooled by meta-analysis. RESULTS In the UK Biobank, genetically predicted psoriasis had a suggestive association with colon (OR = 1.055, 95%CI: 1.001-1.113, P = 0.046) and uterine corpus cancer (OR = 0.922, 95%CI: 0.852-0.997, P = 0.042). In the FinnGen consortium, psoriasis had a suggestive association with vulvar cancer (OR = 1.182, 95%CI: 1.023-1.366, P = 0.024), uterine corpus cancer (OR = 0.937, 95%CI: 0.883-0.993, P = 0.028), and prostate cancer (OR = 0.973, 95%CI: 0.948-0.999, P = 0.045). In an additional large-scale cancer dataset, psoriasis also showed a suggestive association with prostate cancer (OR = 0.968, 95%CI:0.942-0.995, P = 0.020). The meta-analysis confirmed the suggestive association of psoriasis with uterine corpus (OR = 0.931, 95% CI: 0.889-0.976, P = 0.003) and prostate cancer (OR = 0.976, 95% CI: 0.955-0.997, P = 0.023). Whereas the effect of psoriasis on colon and vulvar cancer was not in the same direction across different populations. Furthermore, no association between genetically predicted psoriasis and other cancers were observed. CONCLUSIONS This comprehensive MR study suggests that psoriasis may be a potential protective factor for uterine corpus cancer in women and prostate cancer in men.
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Affiliation(s)
- Mengsi Liu
- Guangdong Cardiovascular Institute, Guangzhou, China
- Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Zhen Sun
- State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Peixin Tan
- Department of Radiation Oncology, Guangdong Provincial People's Hospital, Southern Medical University, No. 106, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080, China
| | - Dehuan Xie
- Department of Radiation Oncology, Guangdong Provincial People's Hospital, Southern Medical University, No. 106, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080, China
| | - Yantan Liu
- Department of Radiation Oncology, Guangdong Provincial People's Hospital, Southern Medical University, No. 106, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080, China
| | - Wenqing Feng
- Department of Radiation Oncology, Guangdong Provincial People's Hospital, Southern Medical University, No. 106, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080, China
| | - Chen Ren
- Department of Radiation Oncology, Guangdong Provincial People's Hospital, Southern Medical University, No. 106, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080, China.
| | - Shasha Du
- Guangdong Cardiovascular Institute, Guangzhou, China.
- Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
- Department of Radiation Oncology, Guangdong Provincial People's Hospital, Southern Medical University, No. 106, Zhongshan 2nd Road, Yuexiu District, Guangzhou, 510080, China.
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Liu YC, Liu YH, Pan HF, Wang W. Unveiling new insights into migraine risk stratification using machine learning models of adjustable risk factors. J Headache Pain 2025; 26:103. [PMID: 40329184 PMCID: PMC12057085 DOI: 10.1186/s10194-025-02049-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2025] [Accepted: 04/25/2025] [Indexed: 05/08/2025] Open
Abstract
BACKGROUND Migraine ranks as the second-leading cause of global neurological disability, affecting approximately 1.1 billion individuals worldwide with severe quality-of-life impairments. Although adjustable risk factors-including environmental exposures, sleep disturbances, and dietary patterns-are increasingly implicated in pathogenesis of migraine, their causal roles remain insufficiently characterized, and the integration of multimodal evidence lags behind epidemiological needs. METHODS We developed a three-step analytical framework combining causal inference, predictive modeling, and burden projection to systematically evaluate modifiable factors associated with migraine. First, two-sample mendelian randomization (MR) assessed causality between five domains (metabolic profiles, body composition, cardiovascular markers, behavioral traits, and psychological states) and the risk of migraine. Second, we trained ensemble machine learning (ML) algorithms that incorporated these factors, with Shapley Additive exPlanations (SHAP) value analysis quantifying predictor importance. Finally, spatiotemporal burden mapping synthesized global incidence, prevalence, and disability-adjusted life years (DALYs) data to project region-specific risk and burden trajectories through 2050. RESULTS MR analyses identified significant causal associations between multiple adjustable factors (including overweight, obesity class 2, type 2 diabetes [T2DM], hip circumference [HC], body mass index [BMI], myocardial infarction, and feeling miserable) and the risk of migraine (P < 0.05, FDR-q < 0.05). The Random Forest (RF)-based model achieved excellent discrimination (Area under receiver operating characteristic curve [AUROC] = 0.927), identifying gender, age, HC, waist circumference [WC], BMI, and systolic blood pressure [SBP] as the predictors. Burden mapping projected a global decline in migraine incidence by 2050, yet persistently high prevalence and DALYs burdens underscored the urgency of timely interventions to maximize health gains. CONCLUSIONS Integrating causal inference, predictive modeling, and burden projection, this study establishes hierarchical evidence for adjustable migraine determinants and translates findings into scalable prevention frameworks. These findings bridge the gap between biological mechanisms, clinical practice, and public health policy, providing a tripartite framework that harmonizes causal inference, individualized risk prediction, and global burden mapping for migraine prevention.
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Affiliation(s)
- Yu-Chen Liu
- Department of Otolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, 230031, People's Republic of China
| | - Ye-Hai Liu
- Department of Otolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Hai-Feng Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, 230031, People's Republic of China.
| | - Wei Wang
- Headache Center, Department of Neurology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
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Cai L, Yang C. The Relationship Between Serum Uric Acid and Gynecologic Cancer Risk: A Mendelian Randomization Study. Int J Womens Health 2025; 17:1237-1245. [PMID: 40351332 PMCID: PMC12065537 DOI: 10.2147/ijwh.s493564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 04/25/2025] [Indexed: 05/14/2025] Open
Abstract
Aim High serum uric acid (UA) levels have been linked to cancer development through chronic inflammation and oxidative damage. Traditional epidemiological studies have shown inconsistent results regarding the relationship between uric acid and gynecological cancers. This study uses Mendelian randomization (MR) to explore the potential association between serum UA levels and various gynecological cancers. Methods In this two-sample MR study, summary statistical data of the genome-wide association studies (GWASs) on serum UA levels were extracted from the UK Biobank (UKB), and those on gynecological cancers were obtained from the FinnGen consortium, the Epidemiology of Endometrial Cancer Consortium (E2C2), and the Ovarian Cancer Association Consortium (OCAC). Inverse variance weighted (IVW), weighted median, MR-Egger, weighted mode, MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO), and MR-Radial methods were utilized to investigate the bidirectional causal associations of serum UA levels with gynecological cancers. The evaluation indexes were odds ratios (ORs) and confidence intervals (CIs). Tests for horizontal pleiotropism and heterogeneity of instrumental variables (IVs) were performed, respectively using MR-Egger test and Cochran's Q statistics. In addition, leave-one-out and MR scatter plots were employed for sensitivity analyses. Results IVW estimates suggested that serum UA levels elevated 1 unit had a potential causal association with higher odds of both cervical cancer (CC) (OR=1.147, 95% CI: 1.020-1.290) and invasive mucinous ovarian cancer (IMOC) (OR=1.199, 95% CI: 1.033-1.393). Also, endometrial carcinoma (EC) had a potential causal association with it (OR=1.012, 95% CI: 1.000-1.024). Additionally, sensitivity analyses showed the potential causal associations between UA and CC/IMOC were relatively robust. Conclusion An elevated serum UA level had potential associations with CC and IMOC, whereas patients with EC should pay attention to it in clinical practice, which may reduce the potential risk of gynecological cancers. However, further evidence is needed to clarify the true relationships between UA and gynecological cancers.
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Affiliation(s)
- Lei Cai
- Department of Obstetrics and Gynecology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200023, People’s Republic of China
| | - Chenmin Yang
- Department of Obstetrics and Gynecology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200023, People’s Republic of China
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Bao W, Bi H, Chao L, Jiang Y, Yu X, Ruan F, Wu D, Chen Z, Le K. Identifying the mediating role of brain atrophy on the relationship between DNA damage repair pathway and Alzheimer's disease: A Mendelian randomization analysis and mediation analysis. J Alzheimers Dis 2025:13872877251333811. [PMID: 40313062 DOI: 10.1177/13872877251333811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2025]
Abstract
BackgroundDNA damage and repair (DDR) and structural atrophies in different brain regions were recognized as critical factors in the onset of Alzheimer's disease (AD).ObjectiveWe utilized Mendelian randomization (MR) to examine the causal effects of the DDR-related molecular traits on AD and the potential mediating roles of different brain region volumes.MethodsIn primary analysis, we utilized public genome-wide association studies of AD and summary data from existing molecular traits datasets, including gene expression, DNA methylation, and protein levels quantitative trait loci (eQTL, mQTL, and pQTL) in both blood and brain to examine their causal associations by summary-data-based MR analysis and additional five two-sample MR methods. Subsequently, mediation analysis explored the potential mediate roles of 13 imaging-derived brain volume phenotypes in the associations between the DDR pathways and AD through a network MR design.ResultsWe found that the volumes of the right thalamus proper and global cerebral white matter mediated the causal pathways from EGFR to AD and relatively weak mediation effects of the right lateral ventricle volume in the causal pathways involving CHRNE, DNTT, and AD.ConclusionsWe identified causal relationships among DDR pathways, specific brain region volumes, and AD. Monitoring the molecular traits of these DDR-related genes and developing targeted drugs may help detect and interrupt the early progression of AD.
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Affiliation(s)
- Wei Bao
- Department of Rehabilitation Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, China
- Department of Pediatrics, The First Affiliated Hospital of Nanchang University, Jiangxi Medical College, Nanchang, Jiangxi Province, China
| | - Haidi Bi
- Department of Rehabilitation Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, China
| | - Lishuo Chao
- Department of Affective Disorders, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, Guangdong Province, China
| | - Yaqing Jiang
- Department of Rehabilitation Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, China
| | - Xiaoping Yu
- Department of Rehabilitation Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, China
| | - Fei Ruan
- Department of Rehabilitation Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, China
| | - Di Wu
- Department of Rehabilitation Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, China
- Department of Pediatrics, The First Affiliated Hospital of Nanchang University, Jiangxi Medical College, Nanchang, Jiangxi Province, China
| | - Zhaoyan Chen
- Department of Rehabilitation Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, China
| | - Kai Le
- Department of Rehabilitation Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, China
- Department of Rehabilitation Sciences, Faculty of Health and Social Sciences, Hong Kong Polytechnic University, Hong Kong S.A.R., China
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Leng J, Jin Z, Deng J, Ji Z. Assessing the causal relationship between psoriasis vulgaris and urolithiasis: A two-sample Mendelian randomization study. Medicine (Baltimore) 2025; 104:e42220. [PMID: 40324280 PMCID: PMC12055045 DOI: 10.1097/md.0000000000042220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 04/01/2025] [Accepted: 04/04/2025] [Indexed: 05/07/2025] Open
Abstract
Psoriasis has been suggested to be associated with urolithiasis. However, the existing literature is based on observational studies, which provide limited evidence for the causal relationship between these two conditions. This research aims to evaluate the causal association between psoriasis vulgaris and urolithiasis using 2-sample Mendelian Randomization (MR) analysis. Exposures and outcomes were sourced from genome-wide association study data. The psoriasis vulgaris dataset included 5072 patients and 4,78,102 controls. The urolithiasis dataset included 5347 patients and 2,13,445 controls. We used the inverse-variance weighted (IVW) method as our primary analytical strategy, augmented by MR-Egger regression and the weighted median method. Cochran Q test, MR-Egger regression, leave-one-out analysis and Steiger filtering were also conducted to evaluated the stability and credibility of the results. The IVW analysis showed a significant association between psoriasis vulgaris and urolithiasis (odds ratio [OR] = 1.073, 95% confidence interval [CI] = 1.017-1.131, P = .010). The results of weighted median analysis (OR = 1.071, 95% CI = 1.013-1.133, P = .017) and MR-Egger regression (OR = 1.072, 95% CI = 0.992-1.158, P = .12) indicated a consistent directional causality with the IVW analysis. There was no significant horizontal pleiotropy or heterogeneity in the analysis. Steiger filtering further confirmed the accuracy of the directional causality. In conclusion, this MR study supports a causal association between psoriasis vulgaris and urolithiasis.
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Affiliation(s)
- Junsheng Leng
- Department of Urology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences (CAMS), Beijing, China
| | - Zhaoheng Jin
- Department of Urology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences (CAMS), Beijing, China
| | - Jianhua Deng
- Department of Urology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences (CAMS), Beijing, China
| | - Zhigang Ji
- Department of Urology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences (CAMS), Beijing, China
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Jia P, Hao Z, Yiu K, Tsoi K. Causal Effects Between Blood Pressure Variability and Alzheimer's Disease: A Two-Sample Mendelian Randomization Study. J Clin Hypertens (Greenwich) 2025; 27:e70066. [PMID: 40346856 PMCID: PMC12064930 DOI: 10.1111/jch.70066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 04/10/2025] [Accepted: 04/21/2025] [Indexed: 05/12/2025]
Abstract
Alzheimer's disease (AD), an escalating global public health concern, demonstrates complex pathogenesis involving both genetic predisposition and vascular components. Blood pressure variability (BPV) has been implicated in neurodegenerative diseases, but its causal relationship with AD remains unclear. This study aims to explore the causal relationship between BPV and AD by applying Mendelian randomization (MR) to genome-wide association study (GWAS) summary data. Genetic instruments were selected from BPV GWAS based on UK Biobank data, ensuring relevance and significance(p < 5 × 10⁻⁶). Genetic estimates on exposure were obtained from three databases: The The International Genomic of Alzheimer's Project (IGAP); Maternal family history of AD from UK Biobank (MFH-UKBB), and Paternal family history of AD from UK Biobank (PFH-UKBB). Proxy SNPs were manually selected if SNPs were not available in the exposure GWAS. Data harmonization was performed to ensure consistency in effect and reference alleles. Three MR statistical methods were employed to assess causal effects, including inverse variance weighting (IVW) with random or fixed effect, MR-Egger regression, and the Weighted Median Method. Sensitivity analyses to evaluate robustness were also employed. Six SNPs associated with systolic BPV and six SNPs associated with diastolic BPV were included. Significant causal effects of SBPV on AD were found on the PFH-UKBB dataset in all four methods. The odds ratios for AD per 10-unit increment in SBPV were 1.028, 1.015, and 1.015 for MR-Egger, IVW-MR, and weighted median, respectively. In contrast, only IVW methods found significant results for DBPV in the MFH-UKBB dataset. SBPV is a possible causal risk factor for AD, while the evidence for DBPV needs further study. BPV control should be an important treatment target in preventing dementia.
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Affiliation(s)
- Pingping Jia
- JC School of Public Health and Primary CareThe Chinese University of Hong KongHong KongHong Kong SAR
- Center for Clinical and Epidemiologic ResearchBeijing Anzhen Hospital, Capital Medical UniversityBeijingChina
- Lung and Blood Vessel DiseasesBeijing Institute of HeartBeijingChina
| | - Ziyu Hao
- JC School of Public Health and Primary CareThe Chinese University of Hong KongHong KongHong Kong SAR
- Stanley Ho Big Data Decision Analytics Research CentreThe Chinese University of Hong KongHong KongHong Kong SAR
| | - Karen Yiu
- Lung and Blood Vessel DiseasesBeijing Institute of HeartBeijingChina
| | - Kelvin Tsoi
- JC School of Public Health and Primary CareThe Chinese University of Hong KongHong KongHong Kong SAR
- Lung and Blood Vessel DiseasesBeijing Institute of HeartBeijingChina
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45
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Ma K, Wang H, Du Y, Chen T, Yang D, Li Y, Li D. Mendelian Randomization Assessment of the Genetic Effects of Lipid-Lowering Drugs on Digestive System Cancers. Food Sci Nutr 2025; 13:e70293. [PMID: 40443776 PMCID: PMC12121511 DOI: 10.1002/fsn3.70293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 04/30/2025] [Accepted: 05/06/2025] [Indexed: 06/02/2025] Open
Abstract
The relationship between lipid-lowering drugs and the risk of digestive system cancers remains unclear. This study aims to assess the risk association between lipid-lowering drugs and digestive system cancers through mendelian randomization (MR) analysis. We utilized genetic instruments to substitute for the exposure to lipid-lowering drugs, including expression quantitative trait loci (eQTL) for HMGCR, PCSK9, and NPC1L1, as well as genetic variants associated with low-density lipoprotein (LDL) from the Global Lipids Genetics Consortium's genome-wide association study (GWAS) data for target genes. We used MR and SMR methods to assess the risk estimates of lipid-lowering drug target genes on digestive system tumors. The MR analysis indicated a negative association between HMGCR-mediated LDL and hepatocellular carcinoma (OR = 0.06, 95% CI: 0.00-0.81, p = 0.03), and a positive association between NPC1L1-mediated LDL and gastric cancer risk (OR = 15.45, 95% CI: 5.96-40.56, p < 0.01). In the SMR analysis, it was observed that HMGCR expression decreased the risk of hepatocellular carcinoma (OR = 0.11, 95% CI: 0.02-0.68, p = 0.02), while NPC1L1 expression increased the risk of gastric cancer (OR = 1.33, 95% CI: 1.08-1.64, p < 0.01). Our study results suggested a potential risk association between HMGCR inhibitors and NPC1L1 with hepatocellular carcinoma and gastric cancer.
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Affiliation(s)
- Keru Ma
- Department of Breast SurgeryHarbin Medical University Cancer HospitalHarbinChina
| | - Hao Wang
- Department of Breast SurgeryHarbin Medical University Cancer HospitalHarbinChina
| | - Yubo Du
- Department of Breast SurgeryHarbin Medical University Cancer HospitalHarbinChina
| | - Tianyu Chen
- Department of Breast SurgeryHarbin Medical University Cancer HospitalHarbinChina
| | - Dongxu Yang
- Department of Breast SurgeryHarbin Medical University Cancer HospitalHarbinChina
| | - Yue Li
- Department of Medical OncologyHarbin Medical University Cancer HospitalHarbinChina
| | - Dalin Li
- Department of Breast SurgeryHarbin Medical University Cancer HospitalHarbinChina
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Lei X, Qu Y, Huang J. Evaluating the Causal Relationship Between Human Blood Metabolites and the Susceptibility to Alopecia Areata. J Cosmet Dermatol 2025; 24:e70248. [PMID: 40391686 PMCID: PMC12090336 DOI: 10.1111/jocd.70248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 05/02/2025] [Accepted: 05/09/2025] [Indexed: 05/22/2025]
Abstract
BACKGROUND Alopecia areata, a common autoimmune disease, is not fully understood in terms of its cause. However, research suggests that an imbalance in specific blood metabolites may trigger immune system dysfunction, leading to an attack on hair follicles and ultimately resulting in alopecia areata. METHODS Two-sample MR analysis was conducted to investigate the causal relationship between plasma metabolites and alopecia areata using various methods. Heterogeneity and pleiotropy were assessed, robustness of findings evaluated, and reverse MR performed for effect analysis. RESULTS The MR analysis found a positive causal relationship between alpha-ketoglutarate, propionylcarnitine (c3) and other metabolites with alopecia areata risk. Conversely, xylose 3-(3-hydroxyphenyl)propionate, glycochenodeoxycholate glucuronide (1) along with other metabolites, showed a protective effect against alopecia areata development. Both BWMR and MR-PRESSO confirmed the accuracy of the above results. Reverse MR revealed no reverse causality between plasma metabolites and AA. The robustness of the results was confirmed using the leave-one-out method, which demonstrated no influential instrumental variables affecting the outcomes while accounting for heterogeneity and eliminating horizontal gene pleiotropy effects on estimating causal effects. CONCLUSION This study establishes a causal relationship between plasma metabolism and alopecia areata, enhancing our understanding of its underlying mechanisms. These findings also provide valuable references for future screening and prevention strategies.
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Affiliation(s)
- Xiaoli Lei
- The First Clinical Medical CollegeShandong University of Traditional Chinese MedicineJinanChina
| | - Yi Qu
- The First Clinical Medical CollegeShandong University of Traditional Chinese MedicineJinanChina
| | - Jiaxi Huang
- Department of PharmacyHuoqiu County First People's HospitalLuanChina
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Chen Z, Sui G, Yang C, Lv Z, Wang F. Association of depression with longitudinal changes in brain structure across the lifespan: A Mendelian randomization study. Clin Anat 2025; 38:464-470. [PMID: 39487740 DOI: 10.1002/ca.24237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 10/11/2024] [Indexed: 11/04/2024]
Abstract
Understanding the impact of depression on brain aging benefits the prognosis of this disease and of the risk that other age-related brain disorders will develop in the same population. The aim of the present study was to explore the genetic effect of depression on longitudinal changes in brain structure throughout the lifespan using a Mendelian randomization approach. Summary data from a genome-wide association study of 195,321 to 377,277 participants in the FinnGen consortium were used to predict depression, anxiety disorders, mood disorders, and antidepressant use genetically. Data from 15,640 participants in the ENIGMA consortium were included to predict changes in 15 brain structures throughout the lifespan. The causal relationship between these depressive traits and the brain structure parameters was assessed by two-sample Mendelian randomization (including inverse-variance weighted). Sensitivity analyses were conducted for quality control. Depression slowed the decrease of cortical gray matter volume significantly throughout the lifespan (p = 0.001). Depression, anxiety, and mood disorders nominally decreased the rates of change of volume in the cerebellum gray matter, lateral ventricles, and cortical gray matter throughout the lifespan (p = 0.048, p = 0.021, p = 0.038, respectively). Antidepressants did not affect these rates of change significantly (p > 0.05). Sensitivity analyses confirmed the reliability of this study. Depression and its main symptoms have a slight effect on longitudinal changes in a few brain structures throughout the lifespan at the genetic level. These findings do not support the notion that depression affects macro-aging in the brain crucially.
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Affiliation(s)
| | - Guanghong Sui
- Department of Child and Adolescent Psychology, Tianjin Anding Hospital, Tianjin, China
| | - Caixia Yang
- Department of Rehabilitation, Tianjin Anding Hospital, Tianjin, China
| | - Zongshun Lv
- Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin, China
| | - Feng Wang
- Department of Gastroenterology, Tianjin Medical University General Hospital, Tianjin, China
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Li Y, Lin X, Zou K, Du J, Li Q, Zhong L, Jiang S. Blood biochemical landscape and new insights into clinical decision-making for polycystic ovary syndrome in Chinese women: a prospective cohort study. Front Endocrinol (Lausanne) 2025; 16:1534733. [PMID: 40375948 PMCID: PMC12078145 DOI: 10.3389/fendo.2025.1534733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 04/03/2025] [Indexed: 05/18/2025] Open
Abstract
Introduction The Polycystic ovary syndrome (PCOS), a prevalent endocrine disorder affecting women's reproductive and metabolic health, faces diagnostic challenges due to heterogeneous clinical presentations and the absence of reliable biomarkers. This study investigates the role of Glucosaminyl (N-acetyl) transferase 2 (GCNT2) in modulating sex hormone-binding globulin (SHBG) and its potential as a therapeutic target in PCOS pathophysiology. Methods A prospective cohort of 103 PCOS patients treated with oral contraceptives (2021-2024) was established. Bidirectional Mendelian randomization (MR) was employed to assess genetic associations and causal relationships between PCOS and SHBG. Molecular docking studies evaluated cryptotanshinone's binding affinity to key proteins (COL1A1, COL4A2, COL6A2) in the PI3K/Akt pathway. GCNT2's regulatory effects on collagen synthesis and extracellular matrix pathways. Pharmacokinetic profiling validated therapeutic viability. Results Bidirectional MR revealed significant genetic associations (P < 0.001) and causal links between PCOS and SHBG, implicating GCNT2 as a key modulator. Cryptotanshinone exhibited strong binding affinity to PI3K/Akt signaling pathway proteins and favorable pharmacokinetic properties. Enrichment analyses highlighted GCNT2's role in collagen biosynthesis (FDR < 0.05) and extracellular matrix regulation. Discussion This study identifies GCNT2 as a critical mediator of PCOS pathophysiology through SHBG modulation and collagen remodeling. Cryptotanshinone emerges as a promising therapeutic candidate, targeting PI3K/Akt signaling pathway with high specificity. These findings advance the understanding of PCOS mechanisms and provide a foundation for biomarker-driven diagnostics and precision therapeutics. Further validation in clinical trials is warranted to translate these insights into practice.
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Affiliation(s)
- Yutong Li
- The First Clinical College, Guangdong Medical University, Zhanjiang, Guangdong, China
- Department of General Surgery, Zhongshan City People’s Hospital, Zhongshan, Guangdong, China
| | - Xiufeng Lin
- Reproductive Center, Boai Hospital of Zhongshan, Zhongshan, Guangdong, China
| | - Ke Zou
- The First Clinical College, Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Jing Du
- Reproductive Center, Boai Hospital of Zhongshan, Zhongshan, Guangdong, China
| | - Qingni Li
- Reproductive Center, Boai Hospital of Zhongshan, Zhongshan, Guangdong, China
| | - Linkun Zhong
- Department of General Surgery, Zhongshan City People’s Hospital, Zhongshan, Guangdong, China
| | - Shan Jiang
- Reproductive Center, Boai Hospital of Zhongshan, Zhongshan, Guangdong, China
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Jing Y, Zhu H, Yao P, Chen Y, Lai X, He Q, Yu L, Lin Y, Kang D. IgD-CD38-B Cell Partially Mediates the Protective Effect of Higher Serum Triacylglycerol (53:4) Levels Against Parkinson's Disease. J Neurochem 2025; 169:e70067. [PMID: 40302204 DOI: 10.1111/jnc.70067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 02/17/2025] [Accepted: 03/24/2025] [Indexed: 05/02/2025]
Abstract
Emerging evidence suggests that dysregulated lipid metabolism contributes to Parkinson's disease (PD) risk, with chronic inflammation in the central nervous system (CNS) also playing a pivotal role. Although correlations between inflammatory responses, serum lipid metabolism, and PD risk are established, a causal relationship remains unclear. Building on previous findings linking higher serum triacylglycerol (51:4) levels to reduced PD risk, this study explores the potential causal associations between 38 triacylglycerol isoforms and PD risk using Mendelian randomization (MR). We utilized summary-level data from genome-wide association studies (GWAS) on PD, circulating immune cells, inflammatory proteins, and serum lipidomes-including 38 triacylglycerol isoforms, 15 sterol ester isoforms, and 46 phosphatidylcholine isoforms-to assess the relationship between serum lipid profiles and PD. Our analysis revealed that higher levels of serum triacylglycerol (51:4) and triacylglycerol (53:4) were associated with a reduced PD risk, whereas lower levels of phosphatidylcholine (17:0_18:1) and sterol ester (27:1/20:2) were linked to higher PD risk. Notably, multivariable MR analysis confirmed a robust causal association between increased serum triacylglycerol (53:4) and a 24% reduction in PD risk (1 SD higher triacylglycerol (53:4) leading to a 24% [95% CI, 0.54-0.97] risk reduction, p = 0.005). Mediation analysis suggested that circulating immune cells, rather than inflammatory proteins, may mediate the relationship between triacylglycerol (53:4) levels and PD risk. These findings establish a causal link between triacylglycerol (53:4) and PD risk, highlighting the potential role of immune modulation in PD pathogenesis.
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Affiliation(s)
- Yajun Jing
- Department of Neurosurgery, Neurosurgery Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Honglin Zhu
- Department of Neurosurgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Peisen Yao
- Department of Neurosurgery, Neurosurgery Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Medical Laboratory, College of Medical Technology and Engineering, Fujian Medical University, Fuzhou, China
- Fujian Provincial Institutes of Brain Disorders and Brain Sciences, First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Yiming Chen
- Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Xuemiao Lai
- Department of Neurosurgery, Neurosurgery Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Qiu He
- Department of Immunology, Northwestern University, Evanston, Illinois, USA
| | - Lianghong Yu
- Department of Neurosurgery, Neurosurgery Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Medical Laboratory, College of Medical Technology and Engineering, Fujian Medical University, Fuzhou, China
| | - Yuanxiang Lin
- Department of Neurosurgery, Neurosurgery Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Medical Laboratory, College of Medical Technology and Engineering, Fujian Medical University, Fuzhou, China
- Fujian Provincial Institutes of Brain Disorders and Brain Sciences, First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Dezhi Kang
- Department of Neurosurgery, Neurosurgery Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Medical Laboratory, College of Medical Technology and Engineering, Fujian Medical University, Fuzhou, China
- Fujian Provincial Institutes of Brain Disorders and Brain Sciences, First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Institute of Neurology, First Affiliated Hospital, Fujian Medical University, Fuzhou, China
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Lei K, Lei Y, Wang Z, Ye Z, Liu J, Chen W, Zhou C, Tan J, Chen S, Zhang Y, Tan J. Integrative multi-omics and Mendelian randomization analysis reveal SPP1 + tumor-associated macrophage-driven prognostic signature for hepatocellular carcinoma. Front Mol Biosci 2025; 12:1594610. [PMID: 40376263 PMCID: PMC12078150 DOI: 10.3389/fmolb.2025.1594610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2025] [Accepted: 04/21/2025] [Indexed: 05/18/2025] Open
Abstract
Background The SPP1+ tumor-associated macrophages (TAMs) have been implicated in tumor metastasis and immune evasion. However, the prognostic significance of SPP1+ TAMs in hepatocellular carcinoma (HCC) remains largely unexplored. This study aimed to identify SPP1+ TAMs-related genes and construct a model to predict overall survival (OS) in HCC patients. Methods Single-cell RNA sequencing (scRNA-seq) datasets from HCC patients were analyzed to identify SPP1+ TAMs. SPP1+ TAMs-related risk score (STRS) was developed using Mendelian randomization (MR) analysis and Least Absolute Shrinkage and Selection Operator (LASSO) regression. HCC patients from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cohorts were stratified into high- and low-STRS groups based on STRS. Kaplan-Meier survival analysis, receiver operating characteristic (ROC) curve analysis, and functional enrichment analysis were performed to assess the prognostic value of STRS. Results SPP1+ TAMs exhibited strong associations with immunosuppressive functions. 16 SPP1+ TAMs-related genes were used to construct STRS. Patients in the high-STRS group had significantly worse OS than those in the low-STRS group (p < 0.001). ROC analysis demonstrated robust predictive power, with AUC values ranging from 0.685 to 0.748 for 1-year OS, 0.717 to 0.739 for 2-year OS, and 0.719 to 0.738 for 3-year OS. The STRS model also exhibited strong predictive capability for the distinction of drug resistance. Conclusion This study identified SPP1+ TAMs-related genes as key prognostic indicators in HCC. The STRS model provides an effective tool for predicting patient survival and may facilitate personalized treatment strategies for HCC. These findings enhance the understanding of TAMs-driven immune modulation in HCC and highlight potential therapeutic targets for improving patient outcomes.
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Affiliation(s)
- Kai Lei
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yichun Lei
- School of Nursing, Jiangxi University of Chinese Medicine, Nanchang, Jiangxi, China
| | - Zeyao Wang
- Department of General Surgery, Hui Ya Hospital of The First Affiliated Hospital, Sun Yat-sen University, Huizhou, Guangdong, China
| | - Zhixin Ye
- Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jiawei Liu
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Wenhao Chen
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Caihong Zhou
- Division of Hepatobiliopancreatic Surgery, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jinmei Tan
- Department of Intensive Care Unit, Wuchuan People’s Hospital, Zhanjiang, Guangdong, China
| | - Shuxian Chen
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yifan Zhang
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jiehui Tan
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
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