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Karadayı Ataş P. A novel clustered-based binary grey wolf optimizer to solve the feature selection problem for uncovering the genetic links between non-Hodgkin lymphomas and rheumatologic diseases. Health Inf Sci Syst 2025; 13:34. [PMID: 40321894 PMCID: PMC12048384 DOI: 10.1007/s13755-025-00350-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 04/05/2025] [Indexed: 05/08/2025] Open
Abstract
The growing incidence of Non-Hodgkin lymphomas (NHL) in recent times has brought attention to the need for thorough investigations of their genetic associations with autoimmune and rheumatologic conditions, such as systemic lupus, celiac disease, and Sjögren's syndrome. Our study is the first of its type in this field since it uses machine learning to investigate these relationships in great detail. Firstly, we have developed a new genetic dataset, specifically designed to uncover the genetic intricacies of NHL and rheumatologic diseases, offering unprecedented insights into their molecular mechanisms. Following this, we introduced the Clustered-Based Binary Grey Wolf Optimizer (CB-BGWO), a novel method that significantly revolutionizes the feature selection process in genetic analysis. This optimizer significantly improves the accuracy and efficiency of identifying important genetic variables affecting the interaction between rheumatologic and NHL illnesses. This methodological advance not only increases the analytical power but also creates a new standard for genetic research methods. Our findings address a significant gap in the literature and offer valuable insights that could positively support future treatment strategies and research paths. By illuminating the complex genetic connections between NHL and significant rheumatologic conditions, this work contributes to a better understanding and treatment of these complex diseases.
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Zhang Z, Zhang J, Yan X, Wang J, Huang H, Teng M, Liu Q, Han S. Dissecting the genetic basis and mechanisms underlying the associations between multiple extrahepatic factors and autoimmune liver diseases. J Transl Autoimmun 2025; 10:100260. [PMID: 39741931 PMCID: PMC11683281 DOI: 10.1016/j.jtauto.2024.100260] [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: 09/18/2024] [Revised: 11/02/2024] [Accepted: 11/03/2024] [Indexed: 01/03/2025] Open
Abstract
Background Autoimmune liver diseases (AILDs) encompass autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). The onset of these diseases is fundamentally influenced by genetic susceptibility. Although various extrahepatic factors are potentially linked to AILDs, the genetic underpinnings and mechanisms of these associations remain unclear. Methods Utilizing large-scale genome-wide association study (GWAS) data, this study systematically investigated the relationships between extrahepatic autoimmune diseases (EHAIDs), immune cells, and various triggering factors with AILDs. Mendelian randomization (MR) was employed to assess the causal effects of these extrahepatic factors on AILDs, complemented by linkage disequilibrium score (LDSC) regression to uncover shared genetic architecture and causal effects underlying the associations between autoimmune diseases. We employed colocalization, enrichment analysis, and protein-protein interaction (PPI) network to identify the functions of shared loci. Additionally, we proposed that activated immune cells in the circulation may contribute to liver and biliary tract inflammation via migration, mediating the impact of extrahepatic factors on AILDs. This hypothesis was tested using two mediation analysis methods: two-step MR (TSMR) and multivariable MR (MVMR). Results Causal associations between multiple extrahepatic factors and AILDs were identified. Notably, CD27+ B cells were found to be a risk factor for PBC, while PSC progression was associated with CD28+ CD8+ T cells exhaustion and increased levels of CD28- CD8+ T cells. Mediation analyses revealed 64 pathways via TSMR and 15 pathways via MVMR, indicating that the effects of extrahepatic factors on AILDs may be mediated by circulating immune cells. The shared genetic architecture also contributed to these associations. Analysis of shared loci and gene functions identified ATXN2 as being shared between PBC and 9 EHAIDs, while SH2B3 and PSMG1 were shared with 6 and 5 EHAIDs, respectively, in PSC. Conclusions Our research compared three distinct AILDs, enhancing the understanding of their etiology and providing new evidence on risk factors, diagnostic markers, and potential therapeutic targets.
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Affiliation(s)
- Zheng Zhang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Jiayi Zhang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Xinyang Yan
- Department of Neurosurgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Jiachen Wang
- Department of Joint Surgery, HongHui Hospital, Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Haoxiang Huang
- Department of urology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Menghao Teng
- Department of Orthopedics, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Qingguang Liu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Shaoshan Han
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
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Kolkova Z, Suroviakova S, Grendar M, Havlicekova Z, Hornakova A, Holubekova V, Halasova E, Banovcin P. Altered miRNA expression in duodenal tissue of celiac patients and the impact of a gluten-free diet: a preliminary study. Mol Biol Rep 2025; 52:441. [PMID: 40304865 PMCID: PMC12043776 DOI: 10.1007/s11033-025-10534-y] [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: 03/04/2025] [Accepted: 04/22/2025] [Indexed: 05/02/2025]
Abstract
BACKGROUND MicroRNAs (miRNAs) are crucial regulators of gene expression, impacting a wide range of biological processes. Their dysregulation can result in pathological changes and contribute to the development of various disorders. This study aims to evaluate the expression of selected miRNAs in duodenal tissue of paediatric patients with active celiac disease (CD), investigate the role of dysregulated miRNAs in disease pathogenesis and assess the changes in their expression profile in response to a gluten-free diet (GFD). METHODS AND RESULTS The study included newly diagnosed celiac patients (n = 20), celiac patients adhering to a GFD (n = 17) and a control group (n = 29). The miRNA expression in duodenal samples was quantified by real-time PCR. Dysregulated miRNAs were analysed for functional enrichment in molecular pathways. Our results identified 8 dysregulated miRNAs in celiac patients: miR-155-5p (upregulated) and hsa-miR-22-5p, hsa-miR-192-5p, hsa-miR-338-3p, hsa-miR-31-5p, hsa-miR-31-3p, hsa-miR-215-5p and hsa-miR-378d (downregulated). Pathway analysis implicated these miRNAs in regulating various signaling pathways related to inflammation, immune response and intercellular junctions, all of which are relevant to the pathogenesis of CD. Moreover, miR-31-3p was upregulated in CD patients on a GFD, exhibiting a negative correlation with the duration of GFD. For other miRNAs, the level of expression in CD patients adhering to a GFD was restored to levels similar to those observed in the control group. CONCLUSION This preliminary study reveals significant changes in miRNA expression in duodenal biopsies from paediatric CD patients and how these patterns shift with dietary intervention. Understanding the interactions among dysregulated miRNAs may lead to novel therapeutic strategies for managing CD.
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Affiliation(s)
- Zuzana Kolkova
- Laboratory of Genomics and Prenatal Diagnostics, Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Stanislava Suroviakova
- Department of Pediatrics, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia.
- Department of Pediatrics, University Hospital Martin, Martin, Slovakia.
| | - Marian Grendar
- Laboratory of Bioinformatics and Biostatistics, Biomedical Center in Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Zuzana Havlicekova
- Department of Pediatrics, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
- Department of Pediatrics, University Hospital Martin, Martin, Slovakia
| | - Andrea Hornakova
- Laboratory of Genomics and Prenatal Diagnostics, Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Veronika Holubekova
- Laboratory of Genomics and Prenatal Diagnostics, Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Erika Halasova
- Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Peter Banovcin
- Department of Pediatrics, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
- Department of Pediatrics, University Hospital Martin, Martin, Slovakia
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Lim S, Wu J, Kim YW, Lim SW, Shin J, Shin HJ, Kim SR, Kim DW. Celiac Disease Increases the Risk of Multiple Sclerosis: Evidence from Mendelian Randomization and the Role of CCL19. Exp Neurobiol 2025; 34:63-76. [PMID: 40229195 PMCID: PMC12069928 DOI: 10.5607/en25009] [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: 02/27/2025] [Revised: 03/05/2025] [Accepted: 03/06/2025] [Indexed: 04/16/2025] Open
Abstract
Celiac disease (CeD) is an autoimmune disorder triggered by gluten, primarily affecting the small intestine but potentially impacting other systems, including the nervous system through the gut-brain axis. This study employed Mendelian randomization (MR) to explore the causal relationships between CeD and several neurological disorders, with a particular focus on multiple sclerosis (MS). Utilizing genetic data from the OpenGWAS and Finngen databases, we applied various MR methods, including Inverse Variance Weighted (IVW), IVW-multiplicative random effects (MRE), weighted median (WM), MR-Egger, and robust adjusted profile score (RAPS), to investigate these associations. The analysis revealed no significant causal relationship between CeD and several other neurological disorders, but a significant positive association with MS was found (IVW OR=1.1919, 95% CI: 1.0851~1.3092, p=0.0002). Further analysis indicated that the mediator CCL19 plays a significant role in the pathway from CeD to MS, suggesting that CCL19 may be a key factor in the immune response linking these conditions. This mediation effect highlights the potential mechanism through which CeD increases the risk of developing MS. These findings emphasize the complexity of the relationship between CeD and MS, indicating the need for further research to understand these connections better and their clinical implications.
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Affiliation(s)
- Seongjin Lim
- Department of Oral Anatomy & Developmental Biology, Kyung Hee University College of Dentistry, Seoul 02447, Korea
| | - Junhua Wu
- Department of Neurology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Yeon Woo Kim
- Department of Oral Anatomy & Developmental Biology, Kyung Hee University College of Dentistry, Seoul 02447, Korea
| | - Sun Woo Lim
- Department of Oral Anatomy & Developmental Biology, Kyung Hee University College of Dentistry, Seoul 02447, Korea
| | - Juhee Shin
- Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon 34824, Korea
| | - Hyo Jung Shin
- Department Biochemistry, Eulji University School of Medicine, Daejeon 34824, Korea
| | - Sang Ryong Kim
- School of Life Sciences, Kyungpook National University, Daegu 41566, Korea
| | - Dong Woon Kim
- Department of Oral Anatomy & Developmental Biology, Kyung Hee University College of Dentistry, Seoul 02447, Korea
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Argue BMR, Casten LG, McCool S, Alrfooh A, Richards JG, Wemmie JA, Magnotta VA, Williams AJ, Michaelson J, Fiedorowicz JG, Scroggins SM, Gaine ME. Immune dysregulation in bipolar disorder. J Affect Disord 2025; 374:587-597. [PMID: 39818340 PMCID: PMC11830520 DOI: 10.1016/j.jad.2025.01.062] [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: 08/02/2024] [Revised: 12/21/2024] [Accepted: 01/13/2025] [Indexed: 01/18/2025]
Abstract
BACKGROUND Bipolar disorder is a debilitating mood disorder associated with a high risk of suicide and characterized by immune dysregulation. In this study, we used a multi-faceted approach to better distinguish the pattern of dysregulation of immune profiles in individuals with BD. METHODS We analyzed peripheral blood mononuclear cells (bipolar disorder N = 39, control N = 30), serum cytokines (bipolar disorder N = 86, control N = 58), whole blood RNA (bipolar disorder N = 25, control N = 25), and whole blood DNA (bipolar disorder N = 104, control N = 66) to identify immune-related differences in participants diagnosed with bipolar disorder compared to controls. RESULTS Flow cytometry revealed a higher proportion of monocytes in participants with bipolar disorder together with a lower proportion of T helper cells. Additionally, the levels of 18 cytokines were significantly elevated, while two were reduced in participants with bipolar disorder. Most of the cytokines altered in individuals with bipolar disorder were proinflammatory. Forty-nine genes were differentially expressed in our bipolar disorder cohort and further analyses uncovered several immune-related pathways altered in these individuals. Genetic analysis indicated variants associated with inflammatory bowel disease also influences bipolar disorder risk. DISCUSSION Our findings indicate a significant immune component to bipolar disorder pathophysiology and genetic overlap with inflammatory bowel disease. This comprehensive study supports existing literature, whilst also highlighting novel immune targets altered in individuals with bipolar disorder. Specifically, multiple lines of evidence indicate differences in the peripheral representation of monocytes and T cells are hallmarks of bipolar disorder.
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Affiliation(s)
- Benney M R Argue
- Department of Pharmaceutical Sciences and Experimental Therapeutics (PSET), College of Pharmacy, University of Iowa, Iowa City, IA, USA
| | - Lucas G Casten
- Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Shaylah McCool
- Department of Pharmaceutical Sciences and Experimental Therapeutics (PSET), College of Pharmacy, University of Iowa, Iowa City, IA, USA
| | - Aysheh Alrfooh
- Department of Pharmaceutical Sciences and Experimental Therapeutics (PSET), College of Pharmacy, University of Iowa, Iowa City, IA, USA
| | | | - John A Wemmie
- Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA, USA; Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA; Department of Veterans Affairs Medical Center, Iowa City, IA, USA
| | - Vincent A Magnotta
- Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA, USA; Department of Radiology, University of Iowa, Iowa City, IA, USA; Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA
| | - Aislinn J Williams
- Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA, USA; Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA
| | - Jacob Michaelson
- Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA, USA; Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA
| | - Jess G Fiedorowicz
- Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA, USA; University of Ottawa Brain and Mind Research Institute, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Sabrina M Scroggins
- Department of Obstetrics and Gynecology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA; Department of Biomedical Sciences, University of Minnesota School of Medicine, University of Minnesota Duluth, Duluth, MN, USA
| | - Marie E Gaine
- Department of Pharmaceutical Sciences and Experimental Therapeutics (PSET), College of Pharmacy, University of Iowa, Iowa City, IA, USA; Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA, USA; Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA.
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6
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Qiu J, Hu Y, Li L, Erzurumluoglu AM, Braenne I, Whitehurst C, Schmitz J, Arora J, Bartholdy BA, Gandhi S, Khoueiry P, Mueller S, Noyvert B, Ding Z, Jensen JN, de Jong J. Deep representation learning for clustering longitudinal survival data from electronic health records. Nat Commun 2025; 16:2534. [PMID: 40087274 PMCID: PMC11909183 DOI: 10.1038/s41467-025-56625-z] [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: 04/17/2024] [Accepted: 01/21/2025] [Indexed: 03/17/2025] Open
Abstract
Precision medicine requires accurate identification of clinically relevant patient subgroups. Electronic health records provide major opportunities for leveraging machine learning approaches to uncover novel patient subgroups. However, many existing approaches fail to adequately capture complex interactions between diagnosis trajectories and disease-relevant risk events, leading to subgroups that can still display great heterogeneity in event risk and underlying molecular mechanisms. To address this challenge, we implemented VaDeSC-EHR, a transformer-based variational autoencoder for clustering longitudinal survival data as extracted from electronic health records. We show that VaDeSC-EHR outperforms baseline methods on both synthetic and real-world benchmark datasets with known ground-truth cluster labels. In an application to Crohn's disease, VaDeSC-EHR successfully identifies four distinct subgroups with divergent diagnosis trajectories and risk profiles, revealing clinically and genetically relevant factors in Crohn's disease. Our results show that VaDeSC-EHR can be a powerful tool for discovering novel patient subgroups in the development of precision medicine approaches.
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Affiliation(s)
- Jiajun Qiu
- Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riβ, Germany
| | - Yao Hu
- Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riβ, Germany
| | - Li Li
- Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riβ, Germany
| | - Abdullah Mesut Erzurumluoglu
- Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riβ, Germany
| | - Ingrid Braenne
- Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riβ, Germany
| | - Charles Whitehurst
- Immunology & Respiratory Diseases, Boehringer-Ingelheim, Ridgefield, CT, USA
| | - Jochen Schmitz
- Immunology & Respiratory Diseases, Boehringer-Ingelheim, Ridgefield, CT, USA
| | - Jatin Arora
- Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riβ, Germany
| | - Boris Alexander Bartholdy
- Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riβ, Germany
| | - Shrey Gandhi
- Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riβ, Germany
| | - Pierre Khoueiry
- Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riβ, Germany
| | - Stefanie Mueller
- Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riβ, Germany
| | - Boris Noyvert
- Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riβ, Germany
| | - Zhihao Ding
- Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riβ, Germany
| | - Jan Nygaard Jensen
- Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riβ, Germany
| | - Johann de Jong
- Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riβ, Germany.
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Deng N, Agila R, He Q, You C, Zheng S. Comprehensive causal analysis between autoimmune diseases and glioma: A Mendelian randomization study. Medicine (Baltimore) 2025; 104:e41815. [PMID: 40068088 PMCID: PMC11902947 DOI: 10.1097/md.0000000000041815] [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: 12/13/2024] [Revised: 02/17/2025] [Accepted: 02/21/2025] [Indexed: 03/14/2025] Open
Abstract
The causal association between the autoimmune disease and the development of glioma and its subtypes remains unclear. We performed a comprehensive Mendelian randomization (MR) to clarify their causal association from genetic perspective. We obtained the summary-level datasets for autoimmune diseases from recently published genome-wide association studies in the UK Biobank (UKB) and the FinnGen consortium. Additionally, we collected summary statistics datasets related to glioma and its subtypes from a comprehensive meta-analysis genome-wide association study, which included 12,488 cases and 18,169 controls. We primarily used inverse variance weighting method, supplemented by Bonferroni correction to account for multiple tests to reduce the probability of false positive results. We also performed sensitivity analyses to address potential pleiotropy and strengthen the reliability of the results. After meta-analysis, pernicious anemia may decrease the risk of glioblastoma (GBM) (UKB: odds ratio (OR) = 0.01, 95% confidence interval (CI) = 0.01-0.02, P = 1.01E-12; FinnGen: OR = 0.86, 95% CI = 0.79-0.93, P = .0002; Meta: OR = 0.04, 95% CI = 0.03-0.04). In reverse MR analysis, GBM decreased the risk of celiac disease (UKB: OR = 0.96, 95% CI = 0.95-0.98, P = .0000; FinnGen: OR = 0.89, 95% CI = 0.84-0.94, P = .0001; Meta: OR = 0.95, 95% CI = 0.94-0.97). Heterogeneity and pleiotropy analyses, and reverse analysis, confirmed the robustness of these results. From the genetic perspective, our MR study uncovered that pernicious anemia may decrease the risk of GBM. Conversely, GBM appeared to mitigate the risk of celiac disease. Future studies are required to validate the causal association and illuminate the underlying mechanisms.
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Affiliation(s)
- Ni Deng
- Department of Respiratory Therapy, West China Hospital, Sichuan University, Chengdu, China
| | - Rafeq Agila
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Qiang He
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Chao You
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Songping Zheng
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Kim T, Song J, Joo JWJ. MARSweb: a fully automated web service for set-based association testing. BMC Genomics 2025; 26:193. [PMID: 39994572 PMCID: PMC11853308 DOI: 10.1186/s12864-025-11356-9] [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: 10/03/2024] [Accepted: 02/11/2025] [Indexed: 02/26/2025] Open
Abstract
BACKGROUND Despite the successes in GWAS, there is still a large gap between the known heritability and the part explained by the SNPs identified by GWAS. Set-based analysis is one of the approaches that has tried to identify associations between multiple variants in a locus a trait, leveraging allelic heterogeneity to increase power in association testing. MARS is a set-based analysis method that integrates likelihood ratio test with a recently developed fine mapping technique to accurately account for causal status of variants in a risk locus. Unfortunately, due to its complex running process, time complexity, and the requirement of high-performance computing resources, it is not widely used. RESULTS To address these issues, we proposed a fully automated web-based analysis service, MARSweb. By providing a web service, we minimized the effort required for initial configuration. Additionally, users can perform analyses by simply uploading their data without needing to familiarize themselves with intricate analysis procedures. Furthermore, it facilitates easier interpretation of results by integrating advanced visualization tools. We confirmed the performance of MARSweb by detecting eGenes and performing pathway analysis of the genes using a Yeast Dataset. CONCLUSIONS MARSweb is a web-based analysis service that fully automates set-based analysis. It offers an intuitive user interface, making complex analyses more accessible while significantly reducing processing time for enhanced efficiency. MARSweb is available for use at http://cblab.dongguk.edu/MARSweb and its source code is available at https://github.com/DGU-CBLAB/MARSweb .
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Affiliation(s)
- Taegun Kim
- Division of AI Software Convergence, Dongguk University-Seoul, Seoul, 04620, South Korea
- Department of Computer Science and Engineering, Dongguk University-Seoul, Seoul, 04620, South Korea
| | - Jaeseung Song
- Department of Life Science, Dongguk University-Seoul, Seoul, 04620, South Korea
| | - Jong Wha J Joo
- Division of AI Software Convergence, Dongguk University-Seoul, Seoul, 04620, South Korea.
- Department of Computer Science and Engineering, Dongguk University-Seoul, Seoul, 04620, South Korea.
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Bascuñán KA, Araya M, Rodríguez JM, Roncoroni L, Elli L, Alvarez JDPL, Valenzuela R. Interplay of n-3 Polyunsaturated Fatty Acids, Intestinal Inflammation, and Gut Microbiota in Celiac Disease Pathogenesis. Nutrients 2025; 17:621. [PMID: 40004950 PMCID: PMC11858531 DOI: 10.3390/nu17040621] [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: 01/03/2025] [Revised: 01/31/2025] [Accepted: 02/08/2025] [Indexed: 02/27/2025] Open
Abstract
Celiac disease (CD) is a chronic autoimmune disorder driven by both genetic and environmental factors, with the HLA DQ2/DQ8 genotypes playing a central role in its development. Despite the genetic predisposition, only a small percentage of individuals carrying these genotypes develop the disease. Gluten, a protein found in wheat, rye, and barley, is the primary environmental trigger, but other factors, such as the intestinal microbiota, may also contribute to disease progression. While the gluten-free diet (GFD) remains the cornerstone of treatment, many CD patients experience persistent inflammation and gut dysbiosis, leading to ongoing symptoms and complications. This chronic inflammation, which impairs nutrient absorption, increases the risk of malnutrition, anemia, and other autoimmune disorders. Recent studies have identified an altered gut microbiota in CD patients, both on and off the GFD, highlighting the potential role of the microbiota in disease pathogenesis. An emerging area of interest is the supplementation of n-3 polyunsaturated fatty acids (PUFAs), known for their anti-inflammatory properties, as a potential therapeutic strategy. n-3 PUFAs, found in fish oil and certain plant oils, modulate the immune cell function and cytokine production, making them a promising intervention for controlling chronic inflammation in CD. This review explores the current understanding of n-3 PUFAs' effects on the gut microbiota's composition and inflammation in CD, with the goal of identifying new avenues for complementary treatments to improve disease management.
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Affiliation(s)
- Karla A. Bascuñán
- Department of Nutrition, Faculty of Medicine, University of Chile, Santiago 8380453, Chile; (K.A.B.); (J.D.P.L.A.)
| | - Magdalena Araya
- Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago 7830490, Chile (J.M.R.)
| | - Juan Manuel Rodríguez
- Institute of Nutrition and Food Technology (INTA), University of Chile, Santiago 7830490, Chile (J.M.R.)
| | - Leda Roncoroni
- Center for Prevention and Diagnosis of Celiac Disease, Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (L.R.); (L.E.)
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy
| | - Luca Elli
- Center for Prevention and Diagnosis of Celiac Disease, Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (L.R.); (L.E.)
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy
| | | | - Rodrigo Valenzuela
- Department of Nutrition, Faculty of Medicine, University of Chile, Santiago 8380453, Chile; (K.A.B.); (J.D.P.L.A.)
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10
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Wang H, Concannon P, Ge Y. Roles of TULA-family proteins in T cells and autoimmune diseases. Genes Immun 2025; 26:54-62. [PMID: 39558087 DOI: 10.1038/s41435-024-00300-8] [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: 07/09/2024] [Revised: 09/28/2024] [Accepted: 10/01/2024] [Indexed: 11/20/2024]
Abstract
The T cell Ubiquitin Ligand (TULA) protein family contains two members, UBASH3A and UBASH3B, that display similarities in protein sequence and domain structure. Both TULA proteins act to repress T cell activation via a combination of overlapping and nonredundant functions. UBASH3B acts mainly as a phosphatase that suppresses proximal T cell receptor (TCR) signaling. In contrast, UBASH3A acts primarily as an adaptor protein, interacting with other proteins (including UBASH3B) in T cells upon TCR stimulation and resulting in downregulation of TCR signaling and NF-κB signaling. Human genetic and functional studies have revealed another notable distinction between UBASH3A and UBASH3B: numerous genome-wide association studies have identified statistically significant associations between genetic variants in and around the UBASH3A gene and at least seven different autoimmune diseases, suggesting a key role of UBASH3A in autoimmunity. However, the evidence for an independent role of UBASH3B in autoimmune disease is limited. This review summarizes key findings regarding the roles of TULA proteins in T cell biology and autoimmunity, highlights the commonalities and differences between UBASH3A and UBASH3B, and speculates on the individual and joint effects of TULA proteins on T cell signaling.
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Affiliation(s)
- Hua Wang
- International Center for Genetic Engineering and Biotechnology, China Regional Research Center, Taizhou, Jiangsu Province, China
| | - Patrick Concannon
- Genetics Institute, University of Florida, Gainesville, FL, USA
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, USA
| | - Yan Ge
- International Center for Genetic Engineering and Biotechnology, China Regional Research Center, Taizhou, Jiangsu Province, China.
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11
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Vafadar A, Vosough P, Alashti SK, Taghizadeh S, Savardashtaki A. Biosensors for the detection of celiac disease. Clin Chim Acta 2025; 567:120092. [PMID: 39681227 DOI: 10.1016/j.cca.2024.120092] [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: 10/28/2024] [Revised: 12/11/2024] [Accepted: 12/11/2024] [Indexed: 12/18/2024]
Abstract
Celiac disease (CeD) is an autoimmune disorder triggered by sensitivity to gluten, a protein complex found in wheat, barley, and rye. Gliadins, a component of gluten, are proteins that trigger an immune response in individuals with CeD, primarily affecting the small intestine's inner lining. Despite a 1-1.5% prevalence, only 24% of cases are diagnosed due to non-specific symptoms. Screening is advised for high-risk groups, including first-degree relatives and type 1 diabetes patients. The accurate diagnosis of this condition and the assessment of the patient's response to the current treatment - a lifelong gluten-free diet - necessitate using dependable, swift, sensitive, specific, uncomplicated, and affordable analytical methods. Detecting CeD biomarkers in whole blood, serum, or plasma provides a non-invasive approach that serves as an ideal initial diagnostic step. Biosensors offer a novel and alternative way for CeD detection, began emerging in 2007, and hold promise for clinical and point-of-care applications. This review explores the use of biomarker-based diagnostic approaches for CeD, with a focus on biosensors. It delves into the progress of biosensors for CeD diagnosis, identifying trends and challenges in this evolving field. Key biomarkers are highlighted, offering insights into the evolving landscape of biosensors in CeD detection.
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Affiliation(s)
- Asma Vafadar
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Parisa Vosough
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shayan Khalili Alashti
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran; Epilepsy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saeed Taghizadeh
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran; Pharmaceutical Science Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Amir Savardashtaki
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran; Infertility Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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12
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Ti Y, Xu D, Qin X, Hu Y, Xu Y, Zhao Q, Bu P, Li J. Mendelian randomization analysis does not support a causal influence between lipoprotein(A) and immune-mediated inflammatory diseases. Sci Rep 2025; 15:3834. [PMID: 39885280 PMCID: PMC11782540 DOI: 10.1038/s41598-025-88375-9] [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: 08/08/2024] [Accepted: 01/28/2025] [Indexed: 02/01/2025] Open
Abstract
Observational studies have reported an association between lipoprotein(a) (Lp(a)) and immune-mediated inflammatory diseases (IMIDs). This study used Mendelian Randomization (MR) and multivariable MR (MVMR) to explore the causal relationship between lipoprotein(a) [Lp(a)] and immune-mediated inflammatory diseases (IMIDs). We performed a bidirectional two-sample mendelian randomization analyses based on genome-wide association study (GWAS) summary statistics of Lp(a) and nine IMIDs, specifically celiac disease (CeD), Crohn's disease (CD), ulcerative colitis (UC), inflammatory bowel disease (IBD), multiple sclerosis (MS), psoriasis (Pso), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), and summary-level data for lipid traits. Furthermore, we performed MVMR to examine the independence of relationship between Lp(a) and IMIDs after controlling other lipid traits, namely high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG). We didn't observe a causal association between Lp(a) and the risk of IMIDs in univariable and multivariable MR analysis, challenging previous observational studies. However, genetically predicted lipid traits HDL-C was associated with increased risk of Type 1 diabetes (T1D). The identification of potential mechanisms underlying the observed associations in observational studies necessitates further investigation.
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Affiliation(s)
- Yun Ti
- State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Dan Xu
- Department of General Practice, Qilu Hospital of Shandong University, Jinan, China
| | - Xiaoning Qin
- State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Yang Hu
- State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Yuru Xu
- State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Qingzhao Zhao
- State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Peili Bu
- State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
| | - Jingyuan Li
- State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province; Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China.
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13
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Aitella E, Cozzolino D, Ginaldi L, Romano C. Celiac Disease: A Transitional Point of View. Nutrients 2025; 17:234. [PMID: 39861364 PMCID: PMC11767334 DOI: 10.3390/nu17020234] [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: 11/25/2024] [Revised: 01/03/2025] [Accepted: 01/04/2025] [Indexed: 01/27/2025] Open
Abstract
Celiac disease (CeD) is a chronic, lifelong, multifactorial, polygenic, and autoimmune disorder, characteristically triggered by exposure to the exogenous factor "gluten" in genetically predisposed individuals, with resulting duodenal inflammation and enteropathy, as well as heterogeneous multisystemic and extraintestinal manifestations. The immunopathogenesis of CeD is complex, favored by a peculiar human leukocyte antigen (HLA) genetic predisposition, leading to gluten presentation by antigen-presenting cells to CD4+ T helper (Th) cells, T cell-B cell interactions, and production of specific antibodies, resulting in the immune-mediated killing of enterocytes and, macroscopically, in duodenal inflammation. Here, the most relevant correlations between cellular and molecular aspects and clinical manifestations of this complex disease are reviewed, with final considerations on nutritional aspects for disease management.
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Affiliation(s)
- Ernesto Aitella
- Department of Clinical Medicine, Public Health, Life and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (E.A.); (L.G.)
- Allergy and Clinical Immunology Unit, “G. Mazzini” Hospital, ASL Teramo, 64100 Teramo, Italy
| | - Domenico Cozzolino
- Division of Internal Medicine, Department of Precision Medicine, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy;
| | - Lia Ginaldi
- Department of Clinical Medicine, Public Health, Life and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (E.A.); (L.G.)
- Allergy and Clinical Immunology Unit, “G. Mazzini” Hospital, ASL Teramo, 64100 Teramo, Italy
| | - Ciro Romano
- Clinical Immunology Outpatient Clinic, Division of Internal Medicine, Department of Advanced Medical and Surgical Sciences, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy
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14
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Chen S, Zhang N, Zhang R, Zhang L, Luo D, Li J, Liu Y, Wang Y, Duan X, Tian X, Wang T. The causal relationship between systemic lupus erythematosus and juvenile myoclonic epilepsy: A Mendelian randomization study and mediation analysis. IBRAIN 2025; 11:98-105. [PMID: 40103704 PMCID: PMC11911104 DOI: 10.1002/ibra.12191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 12/11/2024] [Accepted: 12/18/2024] [Indexed: 03/20/2025]
Abstract
This study aimed to investigate the causal relationship between systemic lupus erythematosus (SLE) and juvenile myoclonic epilepsy (JME). Univariable and reverse Mendelian randomization (MR) analyses were performed to investigate the potential causal associations between SLE, systemic autoimmune disorders (SADs), and JME. Two-step mediation MR analysis was further performed to explore indirect factors that may influence the relationship between SLE and JME. Summary data on SADs were extracted from the Integrative Epidemiology Unit Open genome-wide association study database, and summary statistics for JME were acquired from the International League Against Epilepsy Consortium. The inverse-variance weighted (IVW) method was used for primary analysis, supplemented by MR-Egger and weighted median. In the univariable MR analysis, IVW results indicated a causal relationship between SLE and an increased risk of JME (odds ratio = 1.0030, 95% confidence interval, 1.0004-1.0057; p = 0.023). The subsequent mediation MR analysis showed that inflammatory cytokines may not be the mediating factors between SLE and JME, while the inverse MR analysis found no significant relationship. Our study indicated that genetic susceptibility to SLE was causally linked to JME. However, subsequent mediation analysis failed to identify the potential mediators that could influence this relationship. Moreover, evidence suggested that other SADs were not causally associated with JME. This study may provide guidance for screening risk factors for seizures and exploring potential treatments in SLE and JME, and even all SADs and JME.
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Affiliation(s)
- Sirui Chen
- The Second Hospital & Clinical Medical School Lanzhou University Lanzhou China
| | - Ningning Zhang
- The Second Hospital & Clinical Medical School Lanzhou University Lanzhou China
| | - Ruirui Zhang
- The Second Hospital & Clinical Medical School Lanzhou University Lanzhou China
| | - Lan Zhang
- The Second Hospital & Clinical Medical School Lanzhou University Lanzhou China
| | - Dadong Luo
- The Second Hospital & Clinical Medical School Lanzhou University Lanzhou China
| | - Junqiang Li
- Department of Neurology, Epilepsy Center, The Second Hospital & Clinical Medical School Lanzhou University Lanzhou China
| | - Yaqing Liu
- Department of Neurology, Epilepsy Center, The Second Hospital & Clinical Medical School Lanzhou University Lanzhou China
| | - Yunan Wang
- The First Clinical Medical College Chongqing Medical University Chongqing China
| | - Xinyue Duan
- The First Clinical Medical College Chongqing Medical University Chongqing China
| | - Xin Tian
- Department of Neurology The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology Chongqing China
- Key Laboratory of Major Brain Disease and Aging Research (Ministry of Education) Chongqing Medical University Chongqing China
| | - Tiancheng Wang
- Department of Neurology, Epilepsy Center, The Second Hospital & Clinical Medical School Lanzhou University Lanzhou China
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15
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Fatoba A, Simpson C. Assessing the causal association between celiac disease and autism spectrum disorder: A two-sample Mendelian randomization approach. Autism Res 2025; 18:195-201. [PMID: 39587862 PMCID: PMC11849517 DOI: 10.1002/aur.3257] [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: 06/21/2024] [Accepted: 10/19/2024] [Indexed: 11/27/2024]
Abstract
The association between celiac disease (CD) and autism spectrum disorder (ASD) remains inconclusive. Reports from different observational studies have become controversial, necessitating exploration of the causal relationship between CD and ASD. To assess true causality, this study used a two-sample Mendelian randomization (MR) analysis to determine the causal association between CD and ASD. Summary-level data from a genome-wide association study (GWAS) of the European population were used to select instrument variables (IVs) at genome-wide significance (p < 5 × 10-8). The strength of IVs was also evaluated with F-statistics. The inverse variance weighted method (IVW) was the primary MR analysis, supported by other MR tests such as the weighted median method and weighted mode. The presence of horizontal pleiotropy was tested with MR-Egger and MR-PRESSO while other sensitivity analyses such as heterogeneity, leave-one-out analysis, and scatterplot were used to assess the validity of our MR results. Our study did not show an association between CD and ASD (OR, 0.994; 95% CI, 0.935-1.057; p = 0.859). There was also no evidence of horizontal pleiotropy (MR-Egger intercept = 0.015; p-value = 0.223) and heterogeneity (Q = 14.029; p-value = 0.051). These results were also complemented by the leave-one-out analyses, forest plot, and scatter plot, which showed that none of the SNPs influenced the result. The result of this study shows that CD is not causally associated with ASD.
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Affiliation(s)
- Abiodun Fatoba
- Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Centers, Memphis, Tennessee, USA
| | - Claire Simpson
- Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Centers, Memphis, Tennessee, USA
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16
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Liu RL, Song QC, Liu LM, Yang YF, Zhu WH. Mood instability and risk of gastrointestinal diseases - a univariable and multivariable mendelian randomization study. Ann Gen Psychiatry 2024; 23:50. [PMID: 39702383 DOI: 10.1186/s12991-024-00537-7] [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: 06/06/2024] [Accepted: 12/13/2024] [Indexed: 12/21/2024] Open
Abstract
BACKGROUND Mood instability, characterized by sudden and unpredictable mood shifts, is prevalent in psychiatric disorders and as a personality trait. Its association with gastrointestinal diseases has been recognized but remains poorly understood in terms of causality. METHODS This study aims to investigate the causal relationship between mood instability and a spectrum of gastrointestinal diseases by univariable and multivariable mendelian randomization analysis. The exposure and outcome data were retrieved from the IEU open GWAS database, the UK biobank and the FinnGen study. Instrumental variables were selected to meet relevance, independence, and exclusion restriction criteria. GWAS datasets for mood instability and 28 gastrointestinal diseases were utilized, incorporating diverse populations and genders. Univariable and multivariable Mendelian randomization analyses were conducted using R software. MR statistics from different datasets for the same disease were meta-analyzed to maximize the study population. RESULTS In univariable MR analysis, genetic predisposition to mood instability showed significant associations with increased risk for several gastrointestinal diseases, including: gastroesophageal reflux disease, gastric ulcer, acute gastritis, irritable bowel syndrome, internal hemorrhoids, cirrhosis, cholecystitis, cholelithiasis, acute pancreatitis, chronic pancreatitis. In multivariable MR analysis, after adjusting for major depression, bipolar disorder, anxiety disorder, and schizophrenia, associations with the following gastrointestinal diseases remained statistically significant: internal hemorrhoids, cirrhosis, acute pancreatitis, chronic pancreatitis. CONCLUSION This study provides compelling evidence for a potential causal relationship between mood instability and certain gastrointestinal diseases underscoring the importance of considering mood instability as a potential risk factor for gastrointestinal diseases as well as the positive role of maintaining mood stability in the prevention of gastrointestinal disorders.
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Affiliation(s)
- Rui-Lin Liu
- Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Central South University, Changsha, China
| | - Qing-Chun Song
- Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Central South University, Changsha, China
| | - Li-Ming Liu
- Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Central South University, Changsha, China
| | - Yi-Feng Yang
- Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Central South University, Changsha, China.
| | - Wei-Hong Zhu
- Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Central South University, Changsha, China.
- Department of Ultrasound, Chen Zhou No.1 People's Hospital, ChenZhou, China.
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17
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Du Y, Hu Y, Sheng Y, Zhu T, Liu S, Ding H, Guan Y. Primary ovarian insufficiency consequence of autoimmune diseases: a bidirectional two-sample Mendelian randomization study. Front Endocrinol (Lausanne) 2024; 15:1417896. [PMID: 39717103 PMCID: PMC11663653 DOI: 10.3389/fendo.2024.1417896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 11/20/2024] [Indexed: 12/25/2024] Open
Abstract
Background Observational studies suggest the risk of primary ovarian insufficiency (POI) is increased in autoimmune disorders (AIDs), but it is unclear whether there is a causal relationship. Therefore, we aimed to investigate the bidirectional causality between 20 AIDs and POI using Mendelian randomization (MR) analysis. Methods A bidirectional two-sample MR investigation was designed by using publicly accessible summary-level data from genome-wide association studies (GWAS). The inverse variance weighted (IVW) method was performed as the main analysis, supplemented by several sensitivity analyses. Cochran Q test was used to evaluate SNP estimate heterogeneity. MR-Egger and MR-PRESSO methods were utilized to detect horizontal pleiotropy. Results The MR analyses revealed that genetically determined coeliac disease (CeD) (OR = 1.124, 95% CI 1.033-1.224, P = 0.007), vitiligo (OR = 1.092, 95% CI 1.003-1.188; P = 0.042), systemic lupus erythematosus (SLE) (OR = 1.122, 95% CI 1.030-1.223, P = 0.008), and selective immunoglobulin A deficiency (SIgAD) (OR = 0.866, 95% CI: 0.776-0.967, P = 0.011) exhibited significant causal relationships with POI. We also found suggestive evidence of positive effect of Addison's disease (AD) towards POI (OR5e-6 = 1.076, 95% CI 1.002-1.154, P = 0.043). Conclusion This comprehensive MR analysis indicated that SLE, CeD, vitiligo, and AD caused an increased risk of POI, SIgAD was associated with a decreased risk of POI. These insights carry profound clinical implications, particularly emphasizing the early intervention for women with AIDs/POI who wish to preserve their reproductive potential or plan for future pregnancies.
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Affiliation(s)
- Yongming Du
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Yichao Hu
- Department of Urology, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Yuehua Sheng
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Tianhong Zhu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Shenping Liu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Huiqing Ding
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Yutao Guan
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Ningbo University, Ningbo, China
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Chen Z, Zheng Z, Jiang B, Xu Y. Genetic association between celiac disease and chronic kidney disease: a two-sample Mendelian randomization study. Ren Fail 2024; 46:2357246. [PMID: 38832490 DOI: 10.1080/0886022x.2024.2357246] [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: 10/17/2023] [Accepted: 05/14/2024] [Indexed: 06/05/2024] Open
Abstract
OBJECTIVE A two-sample Mendelian randomization (MR) analysis was performed to elucidate the causal impact of celiac disease on the risk of chronic kidney disease (CKD). METHODS The study comprised data from three genome-wide association studies involving individuals of European ancestry. The study groups included participants with celiac disease (n = 24,269), CKD (n = 117,165), and estimated glomerular filtration rate levels based on serum creatinine (eGFRcrea, n = 133,413). We employed four widely recognized causal inference algorithms: MR-Egger, inverse variance weighted (IVW), weighted median, and weighted mode. To address potential issues related to pleiotropy and overall effects, MR-Egger regression and the MR-PRESSO global test were performed. Heterogeneity was assessed using Cochran's Q test. RESULTS We identified 14 genetic variants with genome-wide significance. The MR analysis provided consistent evidence across the various methodologies, supporting a causal relationship between celiac disease and an elevated risk of CKD (odds ratio (OR)IVW = 1.027, p = 0.025; ORweighted median = 1.028, P = 0.049; ORweighted mode = 1.030, p = 0.044). Furthermore, we observed a causal link between celiac disease and a decreased eGFRcrea (ORIVW = 0.997, P = 2.94E-06; ORweighted median = 0.996, P = 1.68E-05; ORweighted mode = 0.996, P = 3.11E-04; ORMR Egger = 0.996, P = 5.00E-03). We found no significant evidence of horizontal pleiotropy, heterogeneity, or bias based on MR-Egger regression, MR-PRESSO, and Cochran's Q test. CONCLUSION The results of this study indicate a causal relationship between celiac disease and an increased risk of CKD.
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Affiliation(s)
- Zhimin Chen
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Zigui Zheng
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Bingjing Jiang
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Yanfang Xu
- Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Research Center for Metabolic Chronic Kidney Disease, the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
- Department of Nephrology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China
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Li T, Feng Y, Wang C, Shi T, Huang X, Abuduhadeer M, Abudurexiti A, Zhang M, Gao F. Causal relationships between autoimmune diseases and celiac disease: A Mendelian randomization analysis. Biotechnol Genet Eng Rev 2024; 40:4611-4626. [PMID: 37219596 DOI: 10.1080/02648725.2023.2215039] [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: 03/30/2023] [Accepted: 05/14/2023] [Indexed: 05/24/2023]
Abstract
The aim of this study was to investigate the causal relationship between autoimmune disorders and celiac disease (CeD) through Mendelian randomization (MR). Single nucleotide polymorphisms (SNPs) significantly associated with 13 autoimmune diseases were extracted from the summary statistics of European genome-wide association studies (GWAS), and their effects were examined by Inverse variance-weighted (IVW) in a large European GWAS on CeD. Finally, reverse MR was performed to investigate the causal effects of CeD on autoimmune traits. Following the application of Bonferroni correction for multiple testing, genetically determined seven autoimmune diseases are causally associated with CeD: Crohn's disease (CD) (OR [95%CI] = 1.156 [1.106 ± 1.208], P = 1.27E-10), primary biliary cholangitis (PBC) (1.229 [1.143 ± 1.321], P = 2.53E-08), primary sclerosing cholangitis (PSC) (1.688 [1.466 ± 1.944], P = 3.56E-13), rheumatoid arthritis (RA) (1.231 [1.154 ± 1.313], P = 2.74E-10), systemic lupus erythematosus (SLE) (1.127 [1.081 ± 1.176], P = 2.59E-08), type 1 diabetes (T1D) (1.41 [1.238 ± 1.606], P = 2.24E-07), and asthma (1.414 [1.137 ± 1.758], P = 1.86E-03). The IVW analysis indicated that CeD increased the risk for seven diseases: CD (1.078 [1.044 ± 1.113], P = 3.71E-06), Graves' disease (GD) (1.251 [1.127 ± 1.387], P = 2.34E-05), PSC (1.304 [1.227 ± 1.386], P = 8.56E-18), psoriasis (PsO) (1.12 [1.062 ± 1.182], P = 3.38E-05), SLE (1.301[1.22 ± 1.388], P = 1.25E-15), T1D (1.3[1.228 ± 1.376], P = 1.57E-19), and asthma (1.045 [1.024 ± 1.067], P = 1.82E-05). The sensitivity analyses deemed the results reliable without pleiotropy. There are positive genetic correlations between various autoimmune diseases and CeD, and the latter also affects the predisposition to multiple autoimmune disorders in the European population.
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Affiliation(s)
- Ting Li
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
| | - Yan Feng
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
| | - Chun Wang
- Department of Pathology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
| | - Tian Shi
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
| | - Xiaoling Huang
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
| | - Mireayi Abuduhadeer
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
| | - Adilai Abudurexiti
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
| | - Mengxia Zhang
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
| | - Feng Gao
- Department of Gastroenterology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, Xinjiang, China
- Xinjiang Clinical Research Center for Digestive Disease, Urumqi, Xinjiang, China
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20
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Yuan S, Chen J, Li X, Leffler DA, Larsson SC, Ludvigsson JF. No association between celiac disease and female infertility: evidence from Mendelian randomization analysis. Fertil Steril 2024; 122:1144-1146. [PMID: 38977120 DOI: 10.1016/j.fertnstert.2024.07.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Revised: 06/27/2024] [Accepted: 07/01/2024] [Indexed: 07/10/2024]
Affiliation(s)
- Shuai Yuan
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
| | - Jie Chen
- School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China
| | - Xue Li
- School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China
| | - Daniel A Leffler
- The Celiac Center at Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Susanna C Larsson
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Jonas F Ludvigsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Pediatrics, Orebro University Hospital, Orebro, Sweden; Department of Medicine, Celiac Disease Center at Columbia University Medical Center, New York, New York
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21
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Lyu C, Wang Y, Xu R. Mendelian randomization analysis reveals causal effects of inflammatory bowel disease and autoimmune hyperthyroidism on diffuse large B-cell lymphoma risk. Sci Rep 2024; 14:29163. [PMID: 39587169 PMCID: PMC11589711 DOI: 10.1038/s41598-024-79791-4] [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: 12/06/2023] [Accepted: 11/12/2024] [Indexed: 11/27/2024] Open
Abstract
The clinical phenomenon whereby diffuse large B-cell lymphoma (DLBCL) occurs in patients with a history of autoimmune disease (AD) has been noted, but it remains controversial. This study aimed to evaluate the causal associations between nine ADs and DLBCL via a Mendelian randomization (MR) study. Single-nucleotide polymorphism (SNP) obtained from published genome-wide association studies (GWAS) was chosen as instrumental variable (IV). A total of nine ADs of European ancestry including asthma (56,167 cases and 352,255 controls), psoriasis (4,510 cases and 212,242 controls), autoimmune hyperthyroidism (962 cases and 172,976 controls), inflammatory bowel disease (31,665 cases and 33,977 controls), type 1 diabetes (6,683 cases and 12,173 controls), multiple sclerosis (14,498 cases and 24,091 controls), sarcoidosis (2,046 cases and 215,712 controls), ankylosing spondylitis (9,069 cases and 1,550 controls), and celiac disease (12,041 cases and 12,228 controls), were set as the exposure and DLBCL (209 cases and 218,583 controls) of European ancestry as the outcome. Inverse-variance weighted (IVW) was used as the primary analysis method, and the weighted median and MR-Egger method were used as supplementary methods. The sensitivity analyses employed in this study include the MR-Egger intercept, MR-PRESSO global test, Cochran's Q test, leave-one-out analysis, and funnel plot. IVW showed that inflammatory bowel disease (OR = 1.241, 95% CI 1.009-1.526, P = 0.040) and autoimmune hyperthyroidism (OR = 1.464, 95% CI 1.103-1.942, P = 0.008) increased the risk of DLBCL without significant heterogeneity or horizontal pleiotropy, and the results remained stable according to the leave-one-out analysis. The IVW results revealed no associations between the other seven ADs and DLBCL: asthma (OR = 0.782, 95% CI 0.395-1.546, P = 0.159), psoriasis (OR = 0.842, 95% CI 0.669-1.060, P = 0.143), type 1 diabetes (OR = 1.071, 95% CI 0.860-1.334, P = 0.537), multiple sclerosis (OR = 1.331, 95% CI 0.941-1.883, P = 0.105), sarcoidosis (OR = 1.324, 95% CI 0.861-2.038, P = 0.200), ankylosing spondylitis (OR = 1.884, 95% CI 0.776-4.573, P = 0.161), and celiac disease (OR = 1.003, 95% CI 0.854-1.178, P = 0.969). Although no significant heterogeneity or horizontal pleiotropy was detected in these seven ADs and DLBCL, these results did not pass the leave-one-out analysis; therefore, the results need to be interpreted with caution. Inflammatory bowel disease and autoimmune hyperthyroidism may increase the onset of DLBCL. The risk of DLBCL should be considered in specific types of ADs.
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Affiliation(s)
- Chunyi Lyu
- Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
| | - Yan Wang
- Key Laboratory of Integrated Traditional Chinese and Western Medicine for Hematology, Health Commission of Shandong Province; Institute of Hematology, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China.
- Department of Hematology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China.
| | - Ruirong Xu
- Key Laboratory of Integrated Traditional Chinese and Western Medicine for Hematology, Health Commission of Shandong Province; Institute of Hematology, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China.
- Department of Hematology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China.
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22
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Duan L, Li S, Chen D, Shi Y, Zhou X, Feng Y. Causality between autoimmune diseases and schizophrenia: a bidirectional Mendelian randomization study. BMC Psychiatry 2024; 24:817. [PMID: 39550571 PMCID: PMC11568594 DOI: 10.1186/s12888-024-06287-w] [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: 11/13/2023] [Accepted: 11/11/2024] [Indexed: 11/18/2024] Open
Abstract
BACKGROUND Observational studies have shown a link between autoimmune diseases and schizophrenia, with conflicting conclusions. Due to the existence of confounding factors, the causal link between autoimmune diseases and schizophrenia is still unknown. METHOD We conducted a comprehensive Mendelian randomization (MR) analysis of schizophrenia and ten common autoimmune diseases in individuals of European descent using genome-wide association studies (GWASs). To evaluate the relationships between autoimmune diseases and schizophrenia, inverse variance weighted, MR-RAPS, Bayesian weighted MR, constrained maximum likelihood, debiased IVW, MR-Egger, and weighted median were utilized. Several sensitivity analyses were performed to ensure the reliability of the study's results. RESULTS Our findings reveal that genetically predicted ankylosing spondylitis is related to an increased risk of schizophrenia, whereas celiac disease, type 1 diabetes, and systemic lupus erythematosus are associated with a lower risk of schizophrenia. In the reverse MR analysis, our study indicated that genetically predicted schizophrenia is linked to higher risks of ankylosing spondylitis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, and psoriasis. Neither multiple sclerosis nor rheumatoid arthritis have been linked to schizophrenia, and vice versa. CONCLUSION Despite contradicting some other observational reports, this study showed support for a causal link between autoimmune diseases and schizophrenia. To gain a better understanding of the mechanisms underlying the development of immune-mediated schizophrenia, additional research is required to identify potential mechanisms identified in observational studies.
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Affiliation(s)
- Lincheng Duan
- Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shiyin Li
- Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Dongnan Chen
- Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yue Shi
- Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xianhua Zhou
- Meishan Hospital of Traditional Chinese Medicine, Affiliated Meishan Hospital of Chengdu University of Traditional Chinese Medicine, Meishan, China.
| | - Yue Feng
- Chengdu University of Traditional Chinese Medicine, Chengdu, China.
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23
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Tanigawa Y, Kellis M. Hypometric genetics: Improved power in genetic discovery by incorporating quality control flags. Am J Hum Genet 2024; 111:2478-2493. [PMID: 39442521 PMCID: PMC11568753 DOI: 10.1016/j.ajhg.2024.09.008] [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: 05/02/2024] [Revised: 09/26/2024] [Accepted: 09/27/2024] [Indexed: 10/25/2024] Open
Abstract
Balancing the tradeoff between quantity and quality of phenotypic data is critical in omics studies. Measurements below the limit of quantification (BLQ) are often tagged in quality control fields, but these flags are currently underutilized in human genetics studies. Extreme phenotype sampling is advantageous for mapping rare variant effects. We hypothesize that genetic drivers, along with environmental and technical factors, contribute to the presence of BLQ flags. Here, we introduce "hypometric genetics" (hMG) analysis and uncover a genetic basis for BLQ flags, indicating an additional source of genetic signal for genetic discovery, especially from phenotypic extremes. Applying our hMG approach to n = 227,469 UK Biobank individuals with metabolomic profiles, we reveal more than 5% heritability for BLQ flags and report biologically relevant associations, for example, at APOC3, APOA5, and PDE3B loci. For common variants, polygenic scores trained only for BLQ flags predict the corresponding quantitative traits with 91% accuracy, validating the genetic basis. For rare coding variant associations, we find an asymmetric 65.4% higher enrichment of metabolite-lowering associations for BLQ flags, highlighting the impact of putative loss-of-function variants with large effects on phenotypic extremes. Joint analysis of binarized BLQ flags and the corresponding quantitative metabolite measurements improves power in Bayesian rare variant aggregation tests, resulting in an average of 181% more prioritized genes. Our approach is broadly applicable to omics profiling. Overall, our results underscore the benefit of integrating quality control flags and quantitative measurements and highlight the advantage of joint analysis of population-based samples and phenotypic extremes in human genetics studies.
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Affiliation(s)
- Yosuke Tanigawa
- Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
| | - Manolis Kellis
- Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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24
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Goode EC, Fachal L, Panousis N, Moutsianas L, McIntyre RE, Bai BYH, Kawasaki N, Wittmann A, Raine T, Rushbrook SM, Anderson CA. Fine-mapping and molecular characterisation of primary sclerosing cholangitis genetic risk loci. Nat Commun 2024; 15:9594. [PMID: 39505854 PMCID: PMC11541731 DOI: 10.1038/s41467-024-53602-w] [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: 08/22/2023] [Accepted: 10/17/2024] [Indexed: 11/08/2024] Open
Abstract
Genome-wide association studies of primary sclerosing cholangitis have identified 23 susceptibility loci. The majority of these loci reside in non-coding regions of the genome and are thought to exert their effect by perturbing the regulation of nearby genes. Here, we aim to identify these genes to improve the biological understanding of primary sclerosing cholangitis, and nominate potential drug targets. We first build an eQTL map for six primary sclerosing cholangitis-relevant T-cell subsets obtained from the peripheral blood of primary sclerosing cholangitis and ulcerative colitis patients. These maps identify 10,459 unique eGenes, 87% of which are shared across all six primary sclerosing cholangitis T-cell types. We then search for colocalisations between primary sclerosing cholangitis loci and eQTLs and undertake Bayesian fine-mapping to identify disease-causing variants. In this work, colocalisation analyses nominate likely primary sclerosing cholangitis effector genes and biological mechanisms at five non-coding (UBASH3A, PRKD2, ETS2 and AP003774.1/CCDC88B) and one coding (SH2B3) primary sclerosing cholangitis loci. Through fine-mapping we identify likely causal variants for a third of all primary sclerosing cholangitis-associated loci, including two to single variant resolution.
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Affiliation(s)
- Elizabeth C Goode
- Wellcome Sanger Institute, Hinxton, Cambridge, UK
- University of Cambridge, Cambridge, UK
- Norfolk and Norwich University Hospital, Norwich, UK
| | - Laura Fachal
- Wellcome Sanger Institute, Hinxton, Cambridge, UK
| | | | | | | | - Benjamin Yu Hang Bai
- Wellcome Sanger Institute, Hinxton, Cambridge, UK
- University of Cambridge, Cambridge, UK
| | | | | | - Tim Raine
- University of Cambridge, Cambridge, UK
| | - Simon M Rushbrook
- Norfolk and Norwich University Hospital, Norwich, UK
- Norwich Medical School, University of East Anglia, Norwich, UK
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25
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Gilglioni EH, Li A, St-Pierre-Wijckmans W, Shen TK, Pérez-Chávez I, Hovhannisyan G, Lisjak M, Negueruela J, Vandenbempt V, Bauzá-Martinez J, Herranz JM, Ezeriņa D, Demine S, Feng Z, Vignane T, Otero Sanchez L, Lambertucci F, Prašnická A, Devière J, Hay DC, Encinar JA, Singh SP, Messens J, Filipovic MR, Sharpe HJ, Trépo E, Wu W, Gurzov EN. PTPRK regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity. Nat Commun 2024; 15:9522. [PMID: 39496584 PMCID: PMC11535053 DOI: 10.1038/s41467-024-53733-0] [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: 02/13/2024] [Accepted: 10/22/2024] [Indexed: 11/06/2024] Open
Abstract
Fat accumulation, de novo lipogenesis, and glycolysis are key drivers of hepatocyte reprogramming and the consequent metabolic dysfunction-associated steatotic liver disease (MASLD). Here we report that obesity leads to dysregulated expression of hepatic protein-tyrosine phosphatases (PTPs). PTPRK was found to be increased in steatotic hepatocytes in both humans and mice, and correlates positively with PPARγ-induced lipogenic signaling. High-fat-fed PTPRK knockout male and female mice have lower weight gain and reduced hepatic fat accumulation. Phosphoproteomic analysis in primary hepatocytes and hepatic metabolomics identified fructose-1,6-bisphosphatase 1 and glycolysis as PTPRK targets in metabolic reprogramming. Mechanistically, PTPRK-induced glycolysis enhances PPARγ and lipogenesis in hepatocytes. Silencing PTPRK in liver cancer cell lines reduces colony-forming capacity and high-fat-fed PTPRK knockout mice exposed to a hepatic carcinogen develop smaller tumours. Our study defines the role of PTPRK in the regulation of hepatic glycolysis, lipid metabolism, and tumour development in obesity.
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Affiliation(s)
- Eduardo H Gilglioni
- Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, B-1070, Brussels, Belgium
| | - Ao Li
- Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, B-1070, Brussels, Belgium
| | | | - Tzu-Keng Shen
- Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, B-1070, Brussels, Belgium
- VIB-VUB Center for Structural Biology, Vlaams Instituut voor Biotechnologie, B-1050, Brussels, Belgium
- Structural Biology Brussels, Vrije Universiteit Brussel, B-1050, Brussels, Belgium
- Brussels Center for Redox Biology, Vrije Universiteit Brussel, B-1050, Brussels, Belgium
| | - Israel Pérez-Chávez
- Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, B-1070, Brussels, Belgium
- VIB-VUB Center for Structural Biology, Vlaams Instituut voor Biotechnologie, B-1050, Brussels, Belgium
- Structural Biology Brussels, Vrije Universiteit Brussel, B-1050, Brussels, Belgium
- Brussels Center for Redox Biology, Vrije Universiteit Brussel, B-1050, Brussels, Belgium
| | - Garnik Hovhannisyan
- Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, B-1070, Brussels, Belgium
| | - Michela Lisjak
- Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, B-1070, Brussels, Belgium
| | - Javier Negueruela
- Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, B-1070, Brussels, Belgium
| | - Valerie Vandenbempt
- Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, B-1070, Brussels, Belgium
| | - Julia Bauzá-Martinez
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CH, Utrecht, The Netherlands
- Netherlands Proteomics Centre, 3584 CH, Utrecht, The Netherlands
| | - Jose M Herranz
- Hepatology Program, CIMA, University of Navarra, 31009, Pamplona, Spain
| | - Daria Ezeriņa
- VIB-VUB Center for Structural Biology, Vlaams Instituut voor Biotechnologie, B-1050, Brussels, Belgium
- Structural Biology Brussels, Vrije Universiteit Brussel, B-1050, Brussels, Belgium
- Brussels Center for Redox Biology, Vrije Universiteit Brussel, B-1050, Brussels, Belgium
| | - Stéphane Demine
- Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, B-1070, Brussels, Belgium
| | - Zheng Feng
- Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, B-1070, Brussels, Belgium
| | - Thibaut Vignane
- Leibniz Institute for Analytical Sciences, ISAS e.V., 44139, Dortmund, Germany
| | - Lukas Otero Sanchez
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Hôpital Universitaire de Bruxelles, B-1070, Brussels, Belgium
- Laboratory of Experimental Gastroenterology, Université libre de Bruxelles, B-1070, Brussels, Belgium
| | - Flavia Lambertucci
- Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, B-1070, Brussels, Belgium
| | - Alena Prašnická
- Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, B-1070, Brussels, Belgium
| | - Jacques Devière
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Hôpital Universitaire de Bruxelles, B-1070, Brussels, Belgium
- Laboratory of Experimental Gastroenterology, Université libre de Bruxelles, B-1070, Brussels, Belgium
| | - David C Hay
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh, EH16 4UU, UK
| | - Jose A Encinar
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDIBE), 03202, Elche, Spain
| | - Sumeet Pal Singh
- IRIBHM, Université libre de Bruxelles, B-1070, Brussels, Belgium
| | - Joris Messens
- VIB-VUB Center for Structural Biology, Vlaams Instituut voor Biotechnologie, B-1050, Brussels, Belgium
- Structural Biology Brussels, Vrije Universiteit Brussel, B-1050, Brussels, Belgium
- Brussels Center for Redox Biology, Vrije Universiteit Brussel, B-1050, Brussels, Belgium
| | - Milos R Filipovic
- Leibniz Institute for Analytical Sciences, ISAS e.V., 44139, Dortmund, Germany
| | - Hayley J Sharpe
- Signalling Programme, Babraham Institute, Cambridge, CB22 3AT, UK
| | - Eric Trépo
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Hôpital Universitaire de Bruxelles, B-1070, Brussels, Belgium
- Laboratory of Experimental Gastroenterology, Université libre de Bruxelles, B-1070, Brussels, Belgium
| | - Wei Wu
- Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CH, Utrecht, The Netherlands
- Netherlands Proteomics Centre, 3584 CH, Utrecht, The Netherlands
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, 138648, Singapore
- Department of Pharmacy & Pharmaceutical Sciences, National University of Singapore, Singapore, 117543, Singapore
| | - Esteban N Gurzov
- Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, B-1070, Brussels, Belgium.
- WELBIO Department, WEL Research Institute, B-1300, Wavre, Belgium.
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26
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Willis TW, Gkrania-Klotsas E, Wareham NJ, McKinney EF, Lyons PA, Smith KGC, Wallace C. Leveraging pleiotropy identifies common-variant associations with selective IgA deficiency. Clin Immunol 2024; 268:110356. [PMID: 39241920 DOI: 10.1016/j.clim.2024.110356] [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: 06/27/2024] [Revised: 08/22/2024] [Accepted: 08/31/2024] [Indexed: 09/09/2024]
Abstract
Selective IgA deficiency (SIgAD) is the most common inborn error of immunity (IEI). Unlike many IEIs, evidence of a role for highly penetrant rare variants in SIgAD is lacking. Previous SIgAD studies have had limited power to identify common variants due to their small sample size. We overcame this problem first through meta-analysis of two existing GWAS. This identified four novel common-variant associations and enrichment of SIgAD-associated variants in genes linked to Mendelian IEIs. SIgAD showed evidence of shared genetic architecture with serum IgA and a number of immune-mediated diseases. We leveraged this pleiotropy through the conditional false discovery rate procedure, conditioning our SIgAD meta-analysis on large GWAS of asthma and rheumatoid arthritis, and our own meta-analysis of serum IgA. This identified an additional 18 variants, increasing the number of known SIgAD-associated variants to 27 and strengthening the evidence for a polygenic, common-variant aetiology for SIgAD.
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Affiliation(s)
- Thomas W Willis
- Medical Research Council Biostatistics Unit, University of Cambridge, Cambridge, UK; Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, UK.
| | - Effrossyni Gkrania-Klotsas
- Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, UK; Department of Infectious Diseases, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK
| | - Nicholas J Wareham
- Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, UK
| | - Eoin F McKinney
- Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, UK; Department of Medicine, University of Cambridge, Cambridge, UK
| | - Paul A Lyons
- Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, UK; Department of Medicine, University of Cambridge, Cambridge, UK
| | - Kenneth G C Smith
- Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Department of Medical Biology, University of Melbourne, Melbourne, Australia
| | - Chris Wallace
- Medical Research Council Biostatistics Unit, University of Cambridge, Cambridge, UK; Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, UK; Department of Medicine, University of Cambridge, Cambridge, UK
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27
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Eurén A, Lynch K, Lindfors K, Parikh H, Koletzko S, Liu E, Akolkar B, Hagopian W, Krischer J, Rewers M, Toppari J, Ziegler A, Agardh D, Kurppa K. Risk of celiac disease autoimmunity is modified by interactions between CD247 and environmental exposures. Sci Rep 2024; 14:25463. [PMID: 39462122 PMCID: PMC11567144 DOI: 10.1038/s41598-024-75496-w] [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: 02/14/2024] [Accepted: 10/07/2024] [Indexed: 10/28/2024] Open
Abstract
Season of birth, viral infections, HLA haplogenotypes and non-HLA variants are implicated in the development of celiac disease and celiac disease autoimmunity, suggesting a combined role of genes and environmental exposures. The aim of the study was to further decipher the biological pathways conveying the season of birth effect in celiac disease autoimmunity to gain novel insights into the early pathogenesis of celiac disease. Interactions between season of birth, genetics, and early-life environmental factors on the risk of celiac autoimmunity were investigated in the multicenter TEDDY birth cohort study. Altogether 6523 genetically predisposed children were enrolled to long-term follow-up with prospective sampling and data collection at six research centers in the USA, Germany, Sweden and Finland. Celiac disease autoimmunity was defined as positive tissue transglutaminase antibodies in two consecutive serum samples. There was a significant season of birth effect on the risk of celiac autoimmunity. The effect was dependent on polymorphisms in CD247 gene encoding for CD3ζ chain of TCR-CD3 complex. In particular, children with major alleles for SNP rs864537A > G, in CD247 (AA genotype) had an excess risk of celiac autoimmunity when born March-August as compared to other months. The interaction of CD247 with season of birth on autoimmunity risk was accompanied by interactions with febrile infections between the ages of 3-6 months. Considering the important role of TCR-CD3 complex in the adaptive immune response and our findings here, CD247 variants and their possible effect of subgroups in autoimmunity development could be of interest in the design of future gene-environment studies of celiac disease. ClinicalTrials.gov Identifier: NCT00279318.
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Affiliation(s)
- Anna Eurén
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Kristian Lynch
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Katri Lindfors
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Hemang Parikh
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Sibylle Koletzko
- Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, LMU Munich, Munich, Germany
- Department of Pediatrics, Gastroenterology and Nutrition, School of Medicine Collegium Medicum University of Warmia and Mazury, Olsztyn, Poland
| | - Edwin Liu
- Digestive Health Institute, Children's Hospital, Anschutz Medical Campus, University of Colorado, Denver, CO, USA
| | - Beena Akolkar
- National Institute of Diabetes & Digestive & Kidney Diseases, Bethesda, MD, USA
| | - William Hagopian
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jeffrey Krischer
- Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Marian Rewers
- Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver, CO, USA
| | - Jorma Toppari
- Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Centre for Population Health Research, University of Turku, Turku, Finland
- Department of Pediatrics, Turku University Hospital, 20520, Turku, Finland
| | - Anette Ziegler
- Institute of Diabetes Research, Helmholtz Zentrum München, Munich, Germany
- Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
- Forschergruppe Diabetes e.V., Neuherberg -Munich, Germany
| | | | - Kalle Kurppa
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
- Faculty of Medicine and Health Technology, Tampere Center for Child, Adolescent, and Maternal Health Research, Tampere University and Tampere University Hospital, Arvo Ylpön Katu 34, 33520, Tampere, Finland.
- Seinäjoen yliopistokeskus, Seinäjoki, Finland.
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Wu Y, Li Q, Lou Y, Zhou Z, Huang J. Cysteine cathepsins and autoimmune diseases: A bidirectional Mendelian randomization. Medicine (Baltimore) 2024; 103:e40268. [PMID: 39470488 PMCID: PMC11521024 DOI: 10.1097/md.0000000000040268] [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: 08/30/2024] [Revised: 10/07/2024] [Accepted: 10/09/2024] [Indexed: 10/30/2024] Open
Abstract
Cysteine cathepsins are proteolytic enzymes crucial in various physiological and pathological processes, primarily operating within lysosomes. Their functions include protein degradation, immune system regulation, and involvement in various diseases. While some cysteine cathepsins play important roles in the immune system, their connection to autoimmune diseases remains unclear. This study proposes using Mendelian randomization to explore the causal relationship between cysteine cathepsins and autoimmune diseases. Single nucleotide polymorphisms (SNPs) for cysteine cathepsins were obtained from a publicly available genome-wide association study (GWAS) dataset, while outcome SNP data were sourced from 10 separate GWAS datasets. Mendelian randomization (MR) analysis employed the Wald ratio (WR) and inverse variance weighted (IVW) approach as primary methods, supplemented by the weighted median and MR-Egger methods. Heterogeneity was assessed using Cochran Q test, and sensitivity analysis was conducted using the MR-PRESSO method. The association strength between exposure and outcome was evaluated using odds ratios (OR) with 95% confidence intervals (CI). The study identified a potential positive correlation between elevated cathepsin B and psoriasis (Wald ratio OR = 1.449, 95% CI: 1.053-1.993, P = .0227). Elevated cathepsin F was potentially linked to ulcerative colitis (WR OR = 1.073, 95% CI: 1.021-1.127, P = .0056), ankylosing spondylitis (WR OR = 1.258, 95% CI: 1.082-1.463, P = .0029), and primary biliary cholangitis(PBC) (WR OR = 1.958, 95% CI: 1.326-2.889, P = .0007). Conversely, cathepsin H appeared protective against celiac disease (WR OR = 0.881, 95% CI: 0.838-0.926, P = 6.5e-7), though elevated levels may increase the risk of type 1 diabetes (IVW OR = 1.121, 95% CI: 1.053-1.194, P = .0003) and PBC (WR OR = 1.792, 95% CI: 1.062-3.024, P = .0288). Cathepsin Z was also associated with an increased risk of type 1 diabetes (IVW OR = 1.090, 95% CI: 1.006-1.181, P = .0349). The MR analysis suggests potential risks of cathepsin B with psoriasis, cathepsin F with ulcerative colitis, ankylosing spondylitis, and PBC, and cathepsin Z with type 1 diabetes. Conversely, cathepsin H may protect against celiac disease but could increase the risk of type 1 diabetes and PBC.
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Affiliation(s)
- Yetong Wu
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qiaoqiao Li
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yake Lou
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Zhongzheng Zhou
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jing Huang
- Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Daga N, Servaas NH, Kisand K, Moonen D, Arnold C, Reyes-Palomares A, Kaleviste E, Kingo K, Kuuse R, Ulst K, Steinmetz L, Peterson P, Nakic N, Zaugg JB. Integration of genetic and chromatin modification data pinpoints autoimmune-specific remodeling of enhancer landscape in CD4 + T cells. Cell Rep 2024; 43:114810. [PMID: 39388354 DOI: 10.1016/j.celrep.2024.114810] [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: 12/23/2023] [Revised: 07/16/2024] [Accepted: 09/16/2024] [Indexed: 10/12/2024] Open
Abstract
CD4+ T cells play a crucial role in adaptive immune responses and have been implicated in the pathogenesis of autoimmune diseases (ADs). Despite numerous studies, the molecular mechanisms underlying T cell dysregulation in ADs remain incompletely understood. Here, we used chromatin immunoprecipitation (ChIP)-sequencing of active chromatin and transcriptomic data from CD4+ T cells of healthy donors and patients with systemic lupus erythematosus (SLE), psoriasis, juvenile idiopathic arthritis (JIA), and Graves' disease to investigate the role of enhancers in AD pathogenesis. By generating enhancer-based gene regulatory networks (eGRNs), we identified disease-specific dysregulated pathways and potential downstream target genes of enhancers harboring AD-associated single-nucleotide polymorphisms (SNPs), which we also validated using chromatin-capture (HiC) data and CRISPR interference (CRISPRi) in primary CD4+ T cells. Our results suggest that alterations in the regulatory landscapes of CD4+ T cells, including enhancers, contribute to the development of ADs and provide a basis for developing new therapeutic approaches.
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Affiliation(s)
- Neha Daga
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Nila H Servaas
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Kai Kisand
- Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Dewi Moonen
- Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Christian Arnold
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Armando Reyes-Palomares
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Epp Kaleviste
- Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Külli Kingo
- Department of Dermatology and Venerology, Faculty of Medicine, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia and Dermatology Clinic, Tartu University Hospital, Tartu, Estonia
| | - Reet Kuuse
- Department of Internal Medicine, Tartu University Hospital, Tartu, Estonia
| | - Katrin Ulst
- Department of Internal Medicine, Tartu University Hospital, Tartu, Estonia
| | - Lars Steinmetz
- Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany; Department of Genetics, Stanford University, Stanford, CA, USA
| | - Pärt Peterson
- Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Nikolina Nakic
- Functional Genomics, Medicinal Science and Technology, GSK R&D, Stevenage, UK
| | - Judith B Zaugg
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
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Hitomi Y, Ueno K, Aiba Y, Nishida N, Kono M, Sugihara M, Kawai Y, Kawashima M, Khor SS, Sugi K, Kouno H, Kohno H, Naganuma A, Iwamoto S, Katsushima S, Furuta K, Nikami T, Mannami T, Yamashita T, Ario K, Komatsu T, Makita F, Shimada M, Hirashima N, Yokohama S, Nishimura H, Sugimoto R, Komura T, Ota H, Kojima M, Nakamuta M, Fujimori N, Yoshizawa K, Mano Y, Takahashi H, Hirooka K, Tsuruta S, Sato T, Yamasaki K, Kugiyama Y, Motoyoshi Y, Suehiro T, Saeki A, Matsumoto K, Nagaoka S, Abiru S, Yatsuhashi H, Ito M, Kawata K, Takaki A, Arai K, Arinaga-Hino T, Abe M, Harada M, Taniai M, Zeniya M, Ohira H, Shimoda S, Komori A, Tanaka A, Ishigaki K, Nagasaki M, Tokunaga K, Nakamura M. A genome-wide association study identified PTPN2 as a population-specific susceptibility gene locus for primary biliary cholangitis. Hepatology 2024; 80:776-790. [PMID: 38652555 DOI: 10.1097/hep.0000000000000894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 02/22/2024] [Indexed: 04/25/2024]
Abstract
BACKGROUND AND AIMS Previous genome-wide association studies (GWAS) have indicated the involvement of shared (population-nonspecific) and nonshared (population-specific) susceptibility genes in the pathogenesis of primary biliary cholangitis (PBC) among European and East-Asian populations. Although a meta-analysis of these distinct populations has recently identified more than 20 novel PBC susceptibility loci, analyses of population-specific genetic architecture are still needed for a more comprehensive search for genetic factors in PBC. APPROACH AND RESULTS Protein tyrosine phosphatase nonreceptor type 2 ( PTPN2) was identified as a novel PBC susceptibility gene locus through GWAS and subsequent genome-wide meta-analysis involving 2181 cases and 2699 controls from the Japanese population (GWAS-lead variant: rs8098858, p = 2.6 × 10 -8 ). In silico and in vitro functional analyses indicated that the risk allele of rs2292758, which is a primary functional variant, decreases PTPN2 expression by disrupting Sp1 binding to the PTPN2 promoter in T follicular helper cells and plasmacytoid dendritic cells. Infiltration of PTPN2-positive T-cells and plasmacytoid dendritic cells was confirmed in the portal area of the PBC liver by immunohistochemistry. Furthermore, transcriptomic analysis of PBC-liver samples indicated the presence of a compromised negative feedback loop in vivo between PTPN2 and IFNG in patients carrying the risk allele of rs2292758. CONCLUSIONS PTPN2 , a novel susceptibility gene for PBC in the Japanese population, may be involved in the pathogenesis of PBC through an insufficient negative feedback loop caused by the risk allele of rs2292758 in IFN-γ signaling. This suggests that PTPN2 could be a potential molecular target for PBC treatment.
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Affiliation(s)
- Yuki Hitomi
- Department of Human Genetics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Kazuko Ueno
- Genome Medical Science Project, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Yoshihiro Aiba
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Nao Nishida
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
- Department of Genomic Function and Diversity, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Michihiro Kono
- Laboratory for Human Immunogenetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Mitsuki Sugihara
- Division of Biomedical Information Analysis, Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Yosuke Kawai
- Genome Medical Science Project, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | | | - Seik-Soon Khor
- Genome Medical Science Project, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
- Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, Singapore, Singapore
| | - Kazuhiro Sugi
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Hirotaka Kouno
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Hiroshi Kohno
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Atsushi Naganuma
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Satoru Iwamoto
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Shinji Katsushima
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Kiyoshi Furuta
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Toshiki Nikami
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Tomohiko Mannami
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Tsutomu Yamashita
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Keisuke Ario
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Tatsuji Komatsu
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Fujio Makita
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Masaaki Shimada
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Noboru Hirashima
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Shiro Yokohama
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Hideo Nishimura
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Rie Sugimoto
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Takuya Komura
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Hajime Ota
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Motoyuki Kojima
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Makoto Nakamuta
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Naoyuki Fujimori
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Kaname Yoshizawa
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Yutaka Mano
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Hironao Takahashi
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Kana Hirooka
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Satoru Tsuruta
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Takeaki Sato
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Kazumi Yamasaki
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Yuki Kugiyama
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | | | - Tomoyuki Suehiro
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Akira Saeki
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Kosuke Matsumoto
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Shinya Nagaoka
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Seigo Abiru
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | | | - Masahiro Ito
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
| | - Kazuhito Kawata
- Hepatology Division, Department of Internal Medicine II, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Akinobu Takaki
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Kuniaki Arai
- Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Teruko Arinaga-Hino
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Masanori Abe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Matsuyama, Japan
| | - Masaru Harada
- The Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Makiko Taniai
- Department of Medicine and Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Mikio Zeniya
- Department of Gastroenterology and Hepatology, Tokyo Jikei University School of Medicine, Tokyo, Japan
| | - Hiromasa Ohira
- Department of Gastroenterology, Fukushima Medical University, Fukushima, Japan
| | - Shinji Shimoda
- Division of Gastroenterology and Hepatology, Third Department of Internal Medicine, Kansai Medical University, Hirakata, Japan
| | - Atsumasa Komori
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
- Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Kazuyoshi Ishigaki
- Laboratory for Human Immunogenetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Masao Nagasaki
- Division of Biomedical Information Analysis, Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
- Human Biosciences Unit for the Top Global Course Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto, Japan
| | - Katsushi Tokunaga
- Genome Medical Science Project, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Minoru Nakamura
- Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
- Division of Biomedical Information Analysis, Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
- Headquarters of PBC Research in NHO Study Group for Liver Disease in Japan (NHOSLJ), Clinical Research Center, NHO Nagasaki Medical Center, Omura, Japan
- Department of Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Omura, Japan
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Chen P, Wang Y, Xiong Z, Luo T, Lai Y, Zhong H, Peng S, Zhuang R, Li K, Huang H. Association between autoimmunity-related disorders and prostate cancer: A Mendelian randomization study. CANCER PATHOGENESIS AND THERAPY 2024; 2:292-298. [PMID: 39371096 PMCID: PMC11447306 DOI: 10.1016/j.cpt.2024.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Revised: 03/12/2024] [Accepted: 03/20/2024] [Indexed: 10/08/2024]
Abstract
Background Although many epidemiological studies and meta-analyses have reported an association between autoimmune disorders and prostate cancer, none has reported a clear correlation or the direction of the association. The purpose of our study was to explore the potential relationship between autoimmunity-related disorders and prostate cancer using Mendelian randomization (MR). Methods We retrieved literature from PubMed using the keywords "autoimmune disorder" AND "prostate cancer" to find more clues on the correlation between prostate cancer and autoimmunity-related disorder. Based on this literature search, we selected 16 autoimmunity-related disorders that had genome-wide association study (GWAS) data and may be associated with prostate cancer. The inverse variance weighting (IVW) method was applied as our primary analysis for two-sample MR and multivariate MR analysis to estimate the odds ratio (OR) and 95% confidence interval (CI). We further verified the robustness of our conclusions using a series of sensitivity analyses. Results The autoimmunity-related diseases selected include rheumatoid arthritis, ankylosing spondylitis, coxarthrosis, gonarthrosis, Crohn's disease, ulcerative colitis, irritable bowel syndrome, celiac disease, primary sclerosing cholangitis, asthma, type 1 diabetes, systemic lupus erythematosus, multiple sclerosis, autoimmune hyperthyroidism, psoriatic arthropathies, and polymyalgia rheumatica. The results of inverse variance weighting (IVW suggested that six diseases were associated with the development of prostate cancer. The three diseases that may increase the risk of prostate cancer are rheumatoid arthritis (P = 0.001), coxarthrosis (P < 0.001), and gonarthrosis (P = 0.008). The three possible protective factors against prostate cancer are primary sclerosing cholangitis (P = 0.001), autoimmune hyperthyroidism (P = 0.011), and psoriatic arthropathies (P = 0.001). Horizontal pleiotropy was not observed in the MR-Egger test. Conclusions Our findings provide predictive genetic evidence for an association between autoimmune disorders and prostate cancer. Further research is needed to explore the underlying mechanisms of comorbidities at the molecular level.
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Affiliation(s)
- Peixian Chen
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China
| | - Yue Wang
- National Institutes for Food and Drug Control, Beijing 102629, China
| | - Zhi Xiong
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China
| | - Tianlong Luo
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China
| | - Yiming Lai
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China
| | - Haitao Zhong
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China
| | - Shirong Peng
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China
| | - Ruilin Zhuang
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China
| | - Kaiwen Li
- Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China
| | - Hai Huang
- Department of Urology, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong Provincial Clinical Research Center for Urological Diseases, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China
- Department of Urology, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, Guangdong 511518, China
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Bildstein T, Charbit-Henrion F, Azabdaftari A, Cerf-Bensussan N, Uhlig HH. Cellular and molecular basis of proximal small intestine disorders. Nat Rev Gastroenterol Hepatol 2024; 21:687-709. [PMID: 39117867 DOI: 10.1038/s41575-024-00962-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/28/2024] [Indexed: 08/10/2024]
Abstract
The proximal part of the small intestine, including duodenum and jejunum, is not only dedicated to nutrient digestion and absorption but is also a highly regulated immune site exposed to environmental factors. Host-protective responses against pathogens and tolerance to food antigens are essential functions in the small intestine. The cellular ecology and molecular pathways to maintain those functions are complex. Maladaptation is highlighted by common immune-mediated diseases such as coeliac disease, environmental enteric dysfunction or duodenal Crohn's disease. An expanding spectrum of more than 100 rare monogenic disorders inform on causative molecular mechanisms of nutrient absorption, epithelial homeostasis and barrier function, as well as inflammatory immune responses and immune regulation. Here, after summarizing the architectural and cellular traits that underlie the functions of the proximal intestine, we discuss how the integration of tissue immunopathology and molecular mechanisms can contribute towards our understanding of disease and guide diagnosis. We propose an integrated mechanism-based taxonomy and discuss the latest experimental approaches to gain new mechanistic insight into these disorders with large disease burden worldwide as well as implications for therapeutic interventions.
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Affiliation(s)
- Tania Bildstein
- Great Ormond Street Hospital for Children, Department of Paediatric Gastroenterology, London, UK
| | - Fabienne Charbit-Henrion
- Department of Genomic Medicine for Rare Diseases, Necker-Enfants Malades Hospital, APHP, University of Paris-Cité, Paris, France
- INSERM UMR1163, Intestinal Immunity, Institut Imagine, Paris, France
| | - Aline Azabdaftari
- Translational Gastroenterology Unit, Nuffield Department of Medicine, Oxford, UK
| | | | - Holm H Uhlig
- Translational Gastroenterology Unit, Nuffield Department of Medicine, Oxford, UK.
- Department of Paediatrics, University of Oxford, Oxford, UK.
- National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre, Oxford, UK.
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Pershad Y, Poisner H, Corty RW, Hellwege JN, Bick AG. Variance quantitative trait loci reveal gene-gene interactions which alter blood traits. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.09.18.24313883. [PMID: 39371150 PMCID: PMC11451758 DOI: 10.1101/2024.09.18.24313883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/08/2024]
Abstract
Gene-gene (GxG) interactions play an important role in human genetics, potentially explaining part of the "missing heritability" of polygenic traits and the variable expressivity of monogenic traits. Many GxG interactions have been identified in model organisms through experimental breeding studies, but they have been difficult to identify in human populations. To address this challenge, we applied two complementary variance QTL (vQTL)-based approaches to identify GxG interactions that contribute to human blood traits and blood-related disease risk. First, we used the previously validated genome-wide scale test for each trait in ~450,000 people in the UK Biobank and identified 4 vQTLs. Genome-wide GxG interaction testing of these vQTLs enabled discovery of novel interactions between (1) CCL24 and CCL26 for eosinophil count and plasma CCL24 and CCL26 protein levels and (2) HLA-DQA1 and HLA-DQB1 for lymphocyte count and risk of celiac disease, both of which replicated in ~140,000 NIH All of Us and ~70,000 Vanderbilt BioVU participants. Second, we used a biologically informed approach to search for vQTL in disease-relevant genes. This approach identified (1) a known interaction for hemoglobin between two pathogenic variants in HFE which cause hereditary hemochromatosis and alters risk of cirrhosis and (2) a novel interaction between the JAK2 46/1 haplotype and a variant on chromosome 14 which modifies platelet count, JAK2 V617F clonal hematopoiesis, and risk of polycythemia vera. This work identifies novel disease-relevant GxG interactions and demonstrates the utility of vQTL-based approaches in identifying GxG interactions relevant to human health at scale.
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Affiliation(s)
- Yash Pershad
- Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Hannah Poisner
- Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Robert W Corty
- Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Jacklyn N Hellwege
- Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Alexander G Bick
- Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
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Gaba K, Malhotra P, Kumar A, Suneja P, Dang AS. Understanding the Genetic Basis of Celiac Disease: A Comprehensive Review. Cell Biochem Biophys 2024; 82:1797-1808. [PMID: 38907939 DOI: 10.1007/s12013-024-01371-0] [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] [Accepted: 06/16/2024] [Indexed: 06/24/2024]
Abstract
Celiac disease is an immune-mediated enteropathy with typical symptoms of weight loss, abdominal bloating, diarrhea, vomiting, or constipation. Many shreds of evidence show that CeD is hereditary in origin and various biochemical pathways have been connected to its etiology. Numerous genes from different physiological pathways have been investigated in the last few decades, however a comprehensive analysis is required to address the gaps and provide a more integrated understanding of how these genetic factors contribute to the pathogenesis of disease. Present study attempts to summarize the historical and up-to-date findings to understand the role of genetics in Celiac disease. The literature was searched from sources such as PubMed and Google Scholar to analyze studies conducted on celiac disease from the years 1995 to 2024. Term maps were created to examine the frequency of studies related to various terms to understand the major focus of the studies till date. The study also concise the different genetic polymorphisms studied in a table to understand the role of genetics in celiac diseases. Early studies on celiac disease primarily focused on its pathophysiology, prevalence, and general aspects, with limited attention to genetics. However, recent studies have increasingly emphasized the genetic basis of the disease and highlighting the involvement of various pathways like inflammation, T-cell differentiation and activation, epithelial barrier function, stress and apoptosis pathways. However, present study indicate that most current research predominantly focus on cytokines, specifically the TNF alpha gene. Consequently, there is a need for additional research to gain a more comprehensive understanding of the genetics of celiac disease.
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Affiliation(s)
- Kajal Gaba
- Centre For Medical Biotechnology, Maharshi Dayanand University, Rohtak, 124001, India
| | | | - Anil Kumar
- Centre For Medical Biotechnology, Maharshi Dayanand University, Rohtak, 124001, India
| | - Pooja Suneja
- Department of Microbiology, Maharshi Dayanand University, Rohtak, 124001, India
| | - Amita Suneja Dang
- Centre For Medical Biotechnology, Maharshi Dayanand University, Rohtak, 124001, India.
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Levescot A, Cerf-Bensussan N. Loss of tolerance to dietary proteins: From mouse models to human model diseases. Immunol Rev 2024; 326:173-190. [PMID: 39295093 DOI: 10.1111/imr.13395] [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] [Indexed: 09/21/2024]
Abstract
The critical importance of the immunoregulatory mechanisms, which prevent adverse responses to dietary proteins is demonstrated by the consequences of their failure in two common but distinct human pathological conditions, food allergy and celiac disease. The mechanisms of tolerance to dietary proteins have been extensively studied in mouse models but the extent to which the results in mice can be extrapolated to humans remains unclear. Here, after summarizing the mechanisms known to control oral tolerance in mouse models, we discuss how the monogenic immune disorders associated with food allergy on the one hand, and celiac disease, on the other hand, represent model diseases to gain insight into the key immunoregulatory pathways that control immune responses to food antigens in humans. The spectrum of monogenic disorders, in which the dysfunction of a single gene, is strongly associated with TH2-mediated food allergy suggests an important overlap between the mechanisms that regulate TH2 and IgE responses to food antigens in humans and mice. In contrast, celiac disease provides a unique example of the link between autoimmunity and loss of tolerance to a food antigen.
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Affiliation(s)
- Anais Levescot
- Laboratory of Intestinal Immunity, INSERM UMR 1163 and Imagine Institute, Université Paris Cité, Paris, France
| | - Nadine Cerf-Bensussan
- Laboratory of Intestinal Immunity, INSERM UMR 1163 and Imagine Institute, Université Paris Cité, Paris, France
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Rigo FF, Oliveira ECSD, Quaglio AEV, Moutinho BD, Di Stasi LC, Sassaki LY. Expression of MicroRNAs in Adults with Celiac Disease: A Narrative Review. Int J Mol Sci 2024; 25:9412. [PMID: 39273359 PMCID: PMC11395070 DOI: 10.3390/ijms25179412] [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: 07/06/2024] [Revised: 08/07/2024] [Accepted: 08/28/2024] [Indexed: 09/15/2024] Open
Abstract
Celiac disease (CD) is an immune-mediated enteropathy triggered by the ingestion of proline- and glutamine-rich proteins, widely termed "gluten", in genetically susceptible individuals. CD induces an altered immune response that leads to chronic inflammation and duodenal mucosal damage. Currently, there are no specific tests for the accurate diagnosis of CD, and no drugs are available to treat this condition. The only available treatment strategy is lifelong adherence to a gluten-free diet. However, some studies have investigated the involvement of microRNAs (miRNAs) in CD pathogenesis. miRNAs are small noncoding ribonucleic acid molecules that regulate gene expression. Despite the growing number of studies on the role of miRNAs in autoimmune disorders, data on miRNAs and CD are scarce. Therefore, this study aimed to perform a literature review to summarize CD, miRNAs, and the potential interactions between miRNAs and CD in adults. This review shows that miRNA expression can suppress or stimulate pathways related to CD pathogenesis by regulating cell proliferation and differentiation, regulatory T-cell development, innate immune response, activation of the inflammatory cascade, focal adhesion, T-cell commitment, tissue transglutaminase synthesis, and cell cycle. Thus, identifying miRNAs and their related effects on CD could open new possibilities for diagnosis, prognosis, and follow-up of biomarkers.
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Affiliation(s)
- Francielen Furieri Rigo
- Department of Internal Medicine, Medical School, São Paulo State University (UNESP), Botucatu 18618-687, SP, Brazil
| | | | | | - Bruna Damásio Moutinho
- Department of Gastroenterology, Division of Clinical Gastroenterology and Hepatology, University of São Paulo School of Medicine (USP), São Paulo 01246-903, SP, Brazil
| | - Luiz Claudio Di Stasi
- Laboratory of Phytomedicines, Pharmacology and Biotechnology (PhytoPharmaTec), Department of Biophysics and Pharmacology, Institute of Biosciences, São Paulo State University (UNESP), Botucatu 18618-689, SP, Brazil
| | - Ligia Yukie Sassaki
- Department of Internal Medicine, Medical School, São Paulo State University (UNESP), Botucatu 18618-687, SP, Brazil
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Ge YM, Peng SL, Wang Q, Yuan J. Causality between Celiac disease and kidney disease: A Mendelian Randomization Study. Medicine (Baltimore) 2024; 103:e39465. [PMID: 39213254 PMCID: PMC11365674 DOI: 10.1097/md.0000000000039465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 08/03/2024] [Accepted: 08/06/2024] [Indexed: 09/04/2024] Open
Abstract
Celiac disease, characterized as an autoimmune disorder, possesses the capacity to affect multiple organs and systems. Earlier research has indicated an increased risk of kidney diseases associated with celiac disease. However, the potential causal relationship between genetic susceptibility to celiac disease and the risk of kidney diseases remains uncertain. We conducted Mendelian randomization analysis using nonoverlapping European population data, examining the link between celiac disease and 10 kidney traits in whole-genome association studies. We employed the inverse variance-weighted method to enhance statistical robustness, and results' reliability was reinforced through rigorous sensitivity analysis. Mendelian randomization analysis revealed a genetic susceptibility of celiac disease to an increased risk of immunoglobulin A nephropathy (OR = 1.44; 95% confidence interval [CI] = 1.17-1.78; P = 5.7 × 10-4), chronic glomerulonephritis (OR = 1.15; 95% CI = 1.08-1.22; P = 2.58 × 10-5), and a decline in estimated glomerular filtration rate (beta = -0.001; P = 2.99 × 10-4). Additionally, a potential positive trend in the causal relationship between celiac disease and membranous nephropathy (OR = 1.37; 95% CI = 1.08-1.74; P = 0.01) was observed. Sensitivity analysis indicated the absence of pleiotropy. This study contributes novel evidence establishing a causal link between celiac disease and kidney traits, indicating a potential association between celiac disease and an elevated risk of kidney diseases. The findings provide fresh perspectives for advancing mechanistic and clinical research into kidney diseases associated with celiac disease.
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Affiliation(s)
- Ya-mei Ge
- Clinical College of Chinese Medicine, Hubei University of Chinese Medicine, Hubei, Wuhan, China
| | - Shuang-li Peng
- Department of Traditional Chinese Medicine, Renmin Hospital of Wuhan University, Hubei, Wuhan, China
| | - Qiong Wang
- Clinical College of Chinese Medicine, Hubei University of Chinese Medicine, Hubei, Wuhan, China
| | - Jun Yuan
- Department of Nephrology, Renmin Hospital of Wuhan University, Hubei, Wuhan, China
- First Clinical College, Hubei University of Chinese Medicine, Hubei, Wuhan, China
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Mack TM, Raddatz MA, Pershad Y, Nachun DC, Taylor KD, Guo X, Shuldiner AR, O'Connell JR, Kenny EE, Loos RJF, Redline S, Cade BE, Psaty BM, Bis JC, Brody JA, Silverman EK, Yun JH, Cho MH, DeMeo DL, Levy D, Johnson AD, Mathias RA, Yanek LR, Heckbert SR, Smith NL, Wiggins KL, Raffield LM, Carson AP, Rotter JI, Rich SS, Manichaikul AW, Gu CC, Chen YDI, Lee WJ, Shoemaker MB, Roden DM, Kooperberg C, Auer PL, Desai P, Blackwell TW, Smith AV, Reiner AP, Jaiswal S, Weinstock JS, Bick AG. Epigenetic and proteomic signatures associate with clonal hematopoiesis expansion rate. NATURE AGING 2024; 4:1043-1052. [PMID: 38834882 PMCID: PMC11832052 DOI: 10.1038/s43587-024-00647-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 05/08/2024] [Indexed: 06/06/2024]
Abstract
Clonal hematopoiesis of indeterminate potential (CHIP), whereby somatic mutations in hematopoietic stem cells confer a selective advantage and drive clonal expansion, not only correlates with age but also confers increased risk of morbidity and mortality. Here, we leverage genetically predicted traits to identify factors that determine CHIP clonal expansion rate. We used the passenger-approximated clonal expansion rate method to quantify the clonal expansion rate for 4,370 individuals in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) cohort and calculated polygenic risk scores for DNA methylation aging, inflammation-related measures and circulating protein levels. Clonal expansion rate was significantly associated with both genetically predicted and measured epigenetic clocks. No associations were identified with inflammation-related lab values or diseases and CHIP expansion rate overall. A proteome-wide search identified predicted circulating levels of myeloid zinc finger 1 and anti-Müllerian hormone as associated with an increased CHIP clonal expansion rate and tissue inhibitor of metalloproteinase 1 and glycine N-methyltransferase as associated with decreased CHIP clonal expansion rate. Together, our findings identify epigenetic and proteomic patterns associated with the rate of hematopoietic clonal expansion.
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Affiliation(s)
- Taralynn M Mack
- Vanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Michael A Raddatz
- Vanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, TN, USA
- Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Yash Pershad
- Vanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Daniel C Nachun
- Department of Pathology, Stanford University, Stanford, CA, USA
| | - Kent D Taylor
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Xiuqing Guo
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Alan R Shuldiner
- Department of Medicine, University of Maryland, Baltimore, Baltimore, MD, USA
| | - Jeffrey R O'Connell
- Department of Medicine, University of Maryland, Baltimore, Baltimore, MD, USA
| | - Eimear E Kenny
- Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ruth J F Loos
- The Charles Bronfman Institute of Personalized Medicine, Mount Sinai Hospital, New York City, NY, USA
- The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Susan Redline
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Brian E Cade
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Bruce M Psaty
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
- Department of Medicine, University of Washington, Seattle, WA, USA
- Department of Health Systems and Population Health, University of Washington, Seattle, WA, USA
| | - Joshua C Bis
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Jennifer A Brody
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Edwin K Silverman
- Channing Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Jeong H Yun
- Channing Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Michael H Cho
- Channing Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Dawn L DeMeo
- Channing Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Daniel Levy
- National Heart, Lung and Blood Institute, Population Sciences Branch, Framingham, MA, USA
| | - Andrew D Johnson
- National Heart, Lung and Blood Institute, Population Sciences Branch, Framingham, MA, USA
| | - Rasika A Mathias
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Lisa R Yanek
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Susan R Heckbert
- Department of Epidemiology, University of Washington, Seattle, WA, USA
- Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA, USA
| | - Nicholas L Smith
- Department of Epidemiology, University of Washington, Seattle, WA, USA
- Kaiser Permanente Washington Health Research Institute, Kaiser Permanente Washington, Seattle, WA, USA
- Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, Seattle, WA, USA
| | - Kerri L Wiggins
- Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA
| | - Laura M Raffield
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - April P Carson
- Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA
| | - Jerome I Rotter
- The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Stephen S Rich
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - Ani W Manichaikul
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
| | - C Charles Gu
- Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA
| | - Yii-Der Ida Chen
- Medical Genetics Translational Genomics and Population Sciences (TGPS), Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Wen-Jane Lee
- Department of Medical Research, Taichung Veterans General Hospital, Taichung City, Taiwan
| | - M Benjamin Shoemaker
- Division of Cardiology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Dan M Roden
- Departments of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University, Nashville, TN, USA
| | - Charles Kooperberg
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Paul L Auer
- Division of Biostatistics, Institute for Health and Equity, and Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Pinkal Desai
- Division of Hematology and Oncology, Weill Cornell Medicine, New York, NY, USA
- Englander Institute of Precision Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Thomas W Blackwell
- Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Albert V Smith
- Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Alexander P Reiner
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | | | - Joshua S Weinstock
- Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Alexander G Bick
- Vanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, TN, USA.
- Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
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Yuan S, Leffler D, Lebwohl B, Green PHR, Sun J, Carlsson S, Larsson SC, Ludvigsson JF. Coeliac disease and type 2 diabetes risk: a nationwide matched cohort and Mendelian randomisation study. Diabetologia 2024; 67:1630-1641. [PMID: 38772918 PMCID: PMC11343898 DOI: 10.1007/s00125-024-06175-8] [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: 02/14/2024] [Accepted: 04/11/2024] [Indexed: 05/23/2024]
Abstract
AIMS/HYPOTHESIS While the association between coeliac disease and type 1 diabetes is well documented, the association of coeliac disease with type 2 diabetes risk remains undetermined. We conducted a nationwide cohort and Mendelian randomisation analysis to investigate this link. METHODS This nationwide matched cohort used data from the Swedish ESPRESSO cohort including 46,150 individuals with coeliac disease and 219,763 matched individuals in the comparator group selected from the general population, followed up from 1969 to 2021. Data from 9053 individuals with coeliac disease who underwent a second biopsy were used to examine the association between persistent villous atrophy and type 2 diabetes. Multivariable Cox regression was employed to estimate the associations. In Mendelian randomisation analysis, 37 independent genetic variants associated with clinically diagnosed coeliac disease at p<5×10-8 were used to proxy genetic liability to coeliac disease. Summary-level data for type 2 diabetes were obtained from the DIAGRAM consortium (80,154 cases) and the FinnGen study (42,593 cases). RESULTS Over a median 15.7 years' follow-up, there were 6132 (13.3%) and 30,138 (13.7%) incident cases of type 2 diabetes in people with coeliac disease and comparator individuals, respectively. Those with coeliac disease were not at increased risk of incident type 2 diabetes with an HR of 1.00 (95% CI 0.97, 1.03) compared with comparator individuals. Persistent villous atrophy was not associated with an increased risk of type 2 diabetes compared with mucosal healing among participants with coeliac disease (HR 1.02, 95% CI 0.90, 1.16). Genetic liability to coeliac disease was not associated with type 2 diabetes in DIAGRAM (OR 1.01, 95% CI 0.99, 1.03) or in FinnGen (OR 1.01, 95% CI 0.99-1.04). CONCLUSIONS/INTERPRETATION Coeliac disease was not associated with type 2 diabetes risk.
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Affiliation(s)
- Shuai Yuan
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
| | - Dan Leffler
- The Celiac Center at Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Benjamin Lebwohl
- Department of Medicine, Celiac Disease Center at Columbia University Medical Center, New York, NY, USA
| | - Peter H R Green
- Departments of Medicine and Surgical Pathology, Columbia University College of Physicians and Surgeons, New York, NY, USA
| | - Jiangwei Sun
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Sofia Carlsson
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Susanna C Larsson
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Jonas F Ludvigsson
- Department of Medicine, Celiac Disease Center at Columbia University Medical Center, New York, NY, USA
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Department of Pediatrics, Orebro University Hospital, Orebro, Sweden
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Risemberg EL, Smeekens JM, Cruz Cisneros MC, Hampton BK, Hock P, Linnertz CL, Miller DR, Orgel K, Shaw GD, de Villena FPM, Burks AW, Valdar W, Kulis MD, Ferris MT. A mutation in Themis contributes to anaphylaxis severity following oral peanut challenge in CC027 mice. J Allergy Clin Immunol 2024; 154:387-397. [PMID: 38670234 PMCID: PMC11323216 DOI: 10.1016/j.jaci.2024.03.027] [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: 09/07/2023] [Revised: 03/12/2024] [Accepted: 03/22/2024] [Indexed: 04/28/2024]
Abstract
BACKGROUND The development of peanut allergy is due to a combination of genetic and environmental factors, although specific genes have proven difficult to identify. Previously, we reported that peanut-sensitized Collaborative Cross strain CC027/GeniUnc (CC027) mice develop anaphylaxis upon oral challenge to peanut, in contrast to C3H/HeJ (C3H) mice. OBJECTIVE This study aimed to determine the genetic basis of orally induced anaphylaxis to peanut in CC027 mice. METHODS A genetic mapping population between CC027 and C3H mice was designed to identify the genetic factors that drive oral anaphylaxis. A total of 356 CC027xC3H backcrossed mice were generated, sensitized to peanut, then challenged to peanut by oral gavage. Anaphylaxis and peanut-specific IgE were quantified for all mice. T-cell phenotyping was conducted on CC027 mice and 5 additional Collaborative Cross strains. RESULTS Anaphylaxis to peanut was absent in 77% of backcrossed mice, with 19% showing moderate anaphylaxis and 4% having severe anaphylaxis. There were 8 genetic loci associated with variation in response to peanut challenge-6 associated with anaphylaxis (temperature decrease) and 2 associated with peanut-specific IgE levels. There were 2 major loci that impacted multiple aspects of the severity of acute anaphylaxis, at which the CC027 allele was associated with worse outcome. At one of these loci, CC027 has a private genetic variant in the Themis gene. Consistent with described functions of Themis, we found that CC027 mice have more immature T cells with fewer CD8+, CD4+, and CD4+CD25+CD127- regulatory T cells. CONCLUSIONS Our results demonstrate a key role for Themis in the orally reactive CC027 mouse model of peanut allergy.
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Affiliation(s)
- Ellen L Risemberg
- Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Johanna M Smeekens
- Division of Allergy and Immunology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Marta C Cruz Cisneros
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Brea K Hampton
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Pablo Hock
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Colton L Linnertz
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Darla R Miller
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Kelly Orgel
- Division of Allergy and Immunology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Ginger D Shaw
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Fernando Pardo Manuel de Villena
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - A Wesley Burks
- Division of Allergy and Immunology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - William Valdar
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC.
| | - Michael D Kulis
- Division of Allergy and Immunology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC.
| | - Martin T Ferris
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC.
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Zeng X, Tong L. Genetic and causal relationship between chronic gastrointestinal diseases and erectile dysfunction: a Mendelian randomization study. Front Med (Lausanne) 2024; 11:1422267. [PMID: 39144654 PMCID: PMC11322132 DOI: 10.3389/fmed.2024.1422267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 07/17/2024] [Indexed: 08/16/2024] Open
Abstract
Background Studies based on observations have indicated potential associations between chronic gastrointestinal diseases and an increased risk of erectile dysfunction (ED). However, the causality of these connections remains ambiguous. Methods Summary data for chronic gastrointestinal diseases were extracted from public data. Summary data on ED were extracted from three distinct sources. The genetic correlations between chronic gastrointestinal diseases and ED were explored using linkage disequilibrium score regression (LDSC). The causal associations between chronic gastrointestinal diseases and ED were evaluated using Mendelian randomization (MR) analysis, followed by a meta-analysis to determine the ultimate causal effect. Results The LDSC results suggested significant genetic correlations between Crohn's disease (CD) and ED. Inflammatory bowel disease (IBD), ulcerative colitis (UC), and liver cirrhosis (LC) were found to have potential genetic correlations with ED. The combined multiple MR results indicate that IBD and CD have significant causal relationships with ED, while colorectal cancer (CRC) may have a potential causal effect on ED. Conclusion This research provided evidence supporting a causal association between IBD, CD, CRC, and ED. The impact of chronic gastrointestinal diseases on ED warrants greater attention in clinical practice.
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Affiliation(s)
- Xiaoyan Zeng
- Qinghai University, Xining, China
- Qinghai Provincial Key Laboratory of Traditional Chinese Medicine Research for Glucolipid Metabolic Diseases, Xining, China
- The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi City, China
| | - Li Tong
- Qinghai University, Xining, China
- Qinghai Provincial Key Laboratory of Traditional Chinese Medicine Research for Glucolipid Metabolic Diseases, Xining, China
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Argue BMR, Casten LG, McCool S, Alrfooh A, Gringer Richards J, Wemmie JA, Magnotta VA, Williams AJ, Michaelson J, Fiedorowicz JG, Scroggins SM, Gaine ME. Patterns of Immune Dysregulation in Bipolar Disorder. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.07.26.24311078. [PMID: 39211848 PMCID: PMC11361205 DOI: 10.1101/2024.07.26.24311078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Background Bipolar disorder is a debilitating mood disorder associated with a high risk of suicide and characterized by immune dysregulation. In this study, we used a multi-faceted approach to better distinguish the pattern of dysregulation of immune profiles in individuals with BD. Methods We analyzed peripheral blood mononuclear cells (bipolar disorder N=39, control N=30), serum cytokines (bipolar disorder N=86, control N=58), whole blood RNA (bipolar disorder N=25, control N=25), and whole blood DNA (bipolar disorder N=104, control N=66) to identify immune-related differences in participants diagnosed with bipolar disorder compared to controls. Results Flow cytometry revealed a higher proportion of monocytes in participants with bipolar disorder together with a lower proportion of T helper cells. Additionally, the levels of 18 cytokines were significantly elevated, while two were reduced in participants with bipolar disorder. Most of the cytokines altered in individuals with bipolar disorder were proinflammatory. Forty-nine genes were differentially expressed in our bipolar disorder cohort and further analyses uncovered several immune-related pathways altered in these individuals. Genetic analysis indicated variants associated with inflammatory bowel disease also influences bipolar disorder risk. Discussion Our findings indicate a significant immune component to bipolar disorder pathophysiology and genetic overlap with inflammatory bowel disease. This comprehensive study supports existing literature, whilst also highlighting novel immune targets altered in individuals with bipolar disorder. Specifically, multiple lines of evidence indicate differences in the peripheral representation of monocytes and T cells are hallmarks of bipolar disorder.
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Pushkarev O, van Mierlo G, Kribelbauer JF, Saelens W, Gardeux V, Deplancke B. Non-coding variants impact cis-regulatory coordination in a cell type-specific manner. Genome Biol 2024; 25:190. [PMID: 39026229 PMCID: PMC11256678 DOI: 10.1186/s13059-024-03333-4] [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: 10/09/2023] [Accepted: 07/09/2024] [Indexed: 07/20/2024] Open
Abstract
BACKGROUND Interactions among cis-regulatory elements (CREs) play a crucial role in gene regulation. Various approaches have been developed to map these interactions genome-wide, including those relying on interindividual epigenomic variation to identify groups of covariable regulatory elements, referred to as chromatin modules (CMs). While CM mapping allows to investigate the relationship between chromatin modularity and gene expression, the computational principles used for CM identification vary in their application and outcomes. RESULTS We comprehensively evaluate and streamline existing CM mapping tools and present guidelines for optimal utilization of epigenome data from a diverse population of individuals to assess regulatory coordination across the human genome. We showcase the effectiveness of our recommended practices by analyzing distinct cell types and demonstrate cell type specificity of CRE interactions in CMs and their relevance for gene expression. Integration of genotype information revealed that many non-coding disease-associated variants affect the activity of CMs in a cell type-specific manner by affecting the binding of cell type-specific transcription factors. We provide example cases that illustrate in detail how CMs can be used to deconstruct GWAS loci, assess variable expression of cell surface receptors in immune cells, and reveal how genetic variation can impact the expression of prognostic markers in chronic lymphocytic leukemia. CONCLUSIONS Our study presents an optimal strategy for CM mapping and reveals how CMs capture the coordination of CREs and its impact on gene expression. Non-coding genetic variants can disrupt this coordination, and we highlight how this may lead to disease predisposition in a cell type-specific manner.
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Affiliation(s)
- Olga Pushkarev
- Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
- Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland
| | - Guido van Mierlo
- Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
- Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
| | - Judith Franziska Kribelbauer
- Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
- Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland
| | - Wouter Saelens
- Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
- Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland
| | - Vincent Gardeux
- Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
- Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland
| | - Bart Deplancke
- Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
- Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
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Young KA, Wojdyla K, Lai T, Mulholland KE, Aldaz Casanova S, Antrobus R, Andrews SR, Biggins L, Mahler-Araujo B, Barton PR, Anderson KR, Fearnley GW, Sharpe HJ. The receptor protein tyrosine phosphatase PTPRK promotes intestinal repair and catalysis-independent tumour suppression. J Cell Sci 2024; 137:jcs261914. [PMID: 38904097 PMCID: PMC11298714 DOI: 10.1242/jcs.261914] [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: 12/18/2023] [Accepted: 05/28/2024] [Indexed: 06/22/2024] Open
Abstract
PTPRK is a receptor tyrosine phosphatase that is linked to the regulation of growth factor signalling and tumour suppression. It is stabilized at the plasma membrane by trans homophilic interactions upon cell-cell contact. PTPRK regulates cell-cell adhesion but is also reported to regulate numerous cancer-associated signalling pathways. However, the signalling mechanism of PTPRK remains to be determined. Here, we find that PTPRK regulates cell adhesion signalling, suppresses invasion and promotes collective, directed migration in colorectal cancer cells. In vivo, PTPRK supports recovery from inflammation-induced colitis. In addition, we confirm that PTPRK functions as a tumour suppressor in the mouse colon and in colorectal cancer xenografts. PTPRK regulates growth factor and adhesion signalling, and suppresses epithelial to mesenchymal transition (EMT). Contrary to the prevailing notion that PTPRK directly dephosphorylates EGFR, we find that PTPRK regulation of both EGFR and EMT is independent of its catalytic function. This suggests that additional adaptor and scaffold functions are important features of PTPRK signalling.
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Affiliation(s)
| | | | - Tiffany Lai
- Signalling programme, Babraham Institute, Cambridge CB22 3AT, UK
| | | | | | - Robin Antrobus
- Cambridge Institute for Medical Research, Hills Road, Cambridge CB2 0XY, UK
| | | | - Laura Biggins
- Bioinformatics, Babraham Institute, Cambridge CB22 3AT, UK
| | | | - Philippa R. Barton
- Cambridge Institute for Medical Research, Hills Road, Cambridge CB2 0XY, UK
| | - Keith R. Anderson
- Molecular biology department, Genentech, South San Francisco, CA 94080, USA
| | | | - Hayley J. Sharpe
- Signalling programme, Babraham Institute, Cambridge CB22 3AT, UK
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González-Castro AM, Fernández-Bañares F, Zabana Y, Farago-Pérez G, Ortega-Barrionuevo J, Expósito E, Guagnozzi D. Microscopic Colitis and Celiac Disease: Sharing More than a Diagnostic Overlap. Nutrients 2024; 16:2233. [PMID: 39064676 PMCID: PMC11279699 DOI: 10.3390/nu16142233] [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: 06/02/2024] [Revised: 07/01/2024] [Accepted: 07/04/2024] [Indexed: 07/28/2024] Open
Abstract
Microscopic colitis (MC) is an emergent group of chronic inflammatory diseases of the colon, and celiac disease (CD) is a chronic gluten-induced immune-mediated enteropathy affecting the small bowel. We performed a narrative review to provide an overview regarding the relationship between both disorders, analyzing the most recent studies published at the epidemiological, clinical and pathophysiological levels. In fact, MC and CD are concomitantly prevalent in approximately 6% of the cases, mainly in the subset of refractory patients. Thus, physicians should screen refractory patients with CD against MC and vice versa. Both disorders share more than a simple epidemiological association, being multifactorial diseases involving innate and adaptive immune responses to known or unknown luminal factors based on a rather common genetic ground. Moreover, autoimmunity is a shared characteristic between the patients with MC and those with CD, with autoimmunity in the latter being quite well-established. Furthermore, CD and MC share some common clinical symptoms and risk factors and overlap with other gastrointestinal diseases, but some differences exist between both disorders. More studies are therefore needed to better understand the complex mechanisms involving the common pathogenetic ground contributing to the CD and MC epidemiological association.
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Affiliation(s)
- Ana María González-Castro
- Translational Mucosal Immunology Laboratory, Vall d’Hebron Institut de Recerca, 08035 Barcelona, Spain; (A.M.G.-C.); (E.E.)
- Neuro-Immuno-Gastroenterology Laboratory, Vall d’Hebron Institut de Recerca, 08035 Barcelona, Spain
| | - Fernando Fernández-Bañares
- Gastroenterology Department, University Hospital Mútua Terrassa, 08221 Terrassa, Spain (Y.Z.)
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd, Instituto Carlos III), 28029 Madrid, Spain
| | - Yamile Zabana
- Gastroenterology Department, University Hospital Mútua Terrassa, 08221 Terrassa, Spain (Y.Z.)
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd, Instituto Carlos III), 28029 Madrid, Spain
| | - Georgina Farago-Pérez
- Translational Mucosal Immunology Laboratory, Vall d’Hebron Institut de Recerca, 08035 Barcelona, Spain; (A.M.G.-C.); (E.E.)
| | - Jonathan Ortega-Barrionuevo
- Translational Mucosal Immunology Laboratory, Vall d’Hebron Institut de Recerca, 08035 Barcelona, Spain; (A.M.G.-C.); (E.E.)
| | - Elba Expósito
- Translational Mucosal Immunology Laboratory, Vall d’Hebron Institut de Recerca, 08035 Barcelona, Spain; (A.M.G.-C.); (E.E.)
- Neuro-Immuno-Gastroenterology Laboratory, Vall d’Hebron Institut de Recerca, 08035 Barcelona, Spain
| | - Danila Guagnozzi
- Translational Mucosal Immunology Laboratory, Vall d’Hebron Institut de Recerca, 08035 Barcelona, Spain; (A.M.G.-C.); (E.E.)
- Neuro-Immuno-Gastroenterology Laboratory, Vall d’Hebron Institut de Recerca, 08035 Barcelona, Spain
- Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd, Instituto Carlos III), 28029 Madrid, Spain
- Gastroenterology Department, University Hospital Vall d’Hebron, 08035 Barcelona, Spain
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46
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Liu M, Zhao Y, Jiang L. Mendelian randomization analysis elucidates the causal relationship between celiac disease and the risk of thyroid dysfunction. Medicine (Baltimore) 2024; 103:e38474. [PMID: 38905357 PMCID: PMC11191923 DOI: 10.1097/md.0000000000038474] [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: 04/23/2024] [Accepted: 05/15/2024] [Indexed: 06/23/2024] Open
Abstract
The link between celiac disease (CeD) and thyroid dysfunction has been investigated. However, it is uncertain if CeD is causally linked to thyroid dysfunction. A 2-sample Mendelian randomization study was conducted to ascertain the causal connection between CeD and thyroid dysfunction. Using data from the FinnGen Consortium, a 2-sample Mendelian randomization study was conducted to look at the connection between thyroid dysfunction and CeD. Another replication of the data from the UK Biobank was subsequently performed to confirm our findings. Furthermore, a sequence of sensitivity analyses was performed. The inverse variance weighting technique demonstrates that genetically determined CeD is substantially linked with hypothyroidism, thyrotoxicosis, Graves' disease, and free thyroxine. However, no significant associations were found between CeD and thyroid-stimulating hormone or thyroiditis. Moreover, we achieve the same results in duplicate datasets, which increases the reliability of our findings. This study suggests that CeD and thyroid dysfunction are linked, and it gives theoretical support and new ways of thinking about how to diagnose and treat both conditions.
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Affiliation(s)
- Ming Liu
- Chengdu Integrated Traditional Chinese Medicine and Western Medicine Hospital, Chengdu First People’s Hospital, Chengdu, Sichuan, China
| | - Yueping Zhao
- Chengdu Integrated Traditional Chinese Medicine and Western Medicine Hospital, Chengdu First People’s Hospital, Chengdu, Sichuan, China
| | - Lianxue Jiang
- Chengdu Integrated Traditional Chinese Medicine and Western Medicine Hospital, Chengdu First People’s Hospital, Chengdu, Sichuan, China
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47
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Reeve MP, Vehviläinen M, Luo S, Ritari J, Karjalainen J, Gracia-Tabuenca J, Mehtonen J, Padmanabhuni SS, Kolosov N, Artomov M, Siirtola H, Olilla HM, Graham D, Partanen J, Xavier RJ, Daly MJ, Ripatti S, Salo T, Siponen M. Oral and non-oral lichen planus show genetic heterogeneity and differential risk for autoimmune disease and oral cancer. Am J Hum Genet 2024; 111:1047-1060. [PMID: 38776927 PMCID: PMC11179409 DOI: 10.1016/j.ajhg.2024.04.020] [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: 02/29/2024] [Revised: 04/23/2024] [Accepted: 04/25/2024] [Indexed: 05/25/2024] Open
Abstract
Lichen planus (LP) is a T-cell-mediated inflammatory disease affecting squamous epithelia in many parts of the body, most often the skin and oral mucosa. Cutaneous LP is usually transient and oral LP (OLP) is most often chronic, so we performed a large-scale genetic and epidemiological study of LP to address whether the oral and non-oral subgroups have shared or distinct underlying pathologies and their overlap with autoimmune disease. Using lifelong records covering diagnoses, procedures, and clinic identity from 473,580 individuals in the FinnGen study, genome-wide association analyses were conducted on carefully constructed subcategories of OLP (n = 3,323) and non-oral LP (n = 4,356) and on the combined group. We identified 15 genome-wide significant associations in FinnGen and an additional 12 when meta-analyzed with UKBB (27 independent associations at 25 distinct genomic locations), most of which are shared between oral and non-oral LP. Many associations coincide with known autoimmune disease loci, consistent with the epidemiologic enrichment of LP with hypothyroidism and other autoimmune diseases. Notably, a third of the FinnGen associations demonstrate significant differences between OLP and non-OLP. We also observed a 13.6-fold risk for tongue cancer and an elevated risk for other oral cancers in OLP, in agreement with earlier reports that connect LP with higher cancer incidence. In addition to a large-scale dissection of LP genetics and comorbidities, our study demonstrates the use of comprehensive, multidimensional health registry data to address outstanding clinical questions and reveal underlying biological mechanisms in common but understudied diseases.
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Affiliation(s)
- Mary Pat Reeve
- Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
| | - Mari Vehviläinen
- Department of Oral and Maxillofacial Diseases, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Shuang Luo
- Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
| | - Jarmo Ritari
- Finnish Red Cross Blood Service, Helsinki, Finland
| | - Juha Karjalainen
- Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
| | - Javier Gracia-Tabuenca
- Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
| | - Juha Mehtonen
- Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
| | - Shanmukha Sampath Padmanabhuni
- Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
| | - Nikita Kolosov
- Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland; Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA; Ohio State University College of Medicine, Columbus, OH, USA
| | - Mykyta Artomov
- Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland; Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA; Ohio State University College of Medicine, Columbus, OH, USA
| | - Harri Siirtola
- TAUCHI Research Center, Tampere University, Tampere, Finland
| | - Hanna M Olilla
- Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Daniel Graham
- Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | | | - Ramnik J Xavier
- Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Mark J Daly
- Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytical and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Samuli Ripatti
- Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
| | - Tuula Salo
- Research Unit of Population Health, Department of Oral Pathology, University of Oulu and Oulu University Hospital, Oulu, Finland; Medical Research Center, Oulu University Hospital, Oulu, Finland; Department of Oral and Maxillofacial Diseases, and Translational Immunology Program (TRIMM), University of Helsinki, Helsinki, Finland
| | - Maria Siponen
- Institute of Dentistry, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland; Odontology Education Unit, and Oral and Maxillofacial Diseases Clinic, Kuopio University Hospital, Kuopio, Finland
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48
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Abadie V, Han AS, Jabri B, Sollid LM. New Insights on Genes, Gluten, and Immunopathogenesis of Celiac Disease. Gastroenterology 2024; 167:4-22. [PMID: 38670280 PMCID: PMC11283582 DOI: 10.1053/j.gastro.2024.03.042] [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: 12/12/2023] [Revised: 03/10/2024] [Accepted: 03/11/2024] [Indexed: 04/28/2024]
Abstract
Celiac disease (CeD) is a gluten-induced enteropathy that develops in genetically susceptible individuals upon consumption of cereal gluten proteins. It is a unique and complex immune disorder to study as the driving antigen is known and the tissue targeted by the immune reaction can be interrogated. This review integrates findings gained from genetic, biochemical, and immunologic studies, which together have revealed mechanisms of gluten peptide modification and HLA binding, thereby enabling a maladapted anti-gluten immune response. Observations in human samples combined with experimental mouse models have revealed that the gluten-induced immune response involves CD4+ T cells, cytotoxic CD8+ T cells, and B cells; their cross-talks are critical for the tissue-damaging response. The emergence of high-throughput technologies is increasing our understanding of the phenotype, location, and presumably function of the gluten-specific cells, which are all required to identify novel therapeutic targets and strategies for CeD.
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Affiliation(s)
- Valérie Abadie
- Department of Medicine, University of Chicago, Chicago, Illinois; Section of Gastroenterology, Nutrition and Hepatology, University of Chicago, Chicago, Illinois; Committee on Immunology, University of Chicago, Chicago, Illinois.
| | - Arnold S Han
- Columbia Center for Translational Immunology, Columbia University, New York, New York; Department of Microbiology and Immunology, Columbia University, New York, New York; Department of Medicine, Digestive and Liver Diseases, Columbia University, New York, New York
| | - Bana Jabri
- Department of Medicine, University of Chicago, Chicago, Illinois; Section of Gastroenterology, Nutrition and Hepatology, University of Chicago, Chicago, Illinois; Committee on Immunology, University of Chicago, Chicago, Illinois; Department of Pathology, University of Chicago, Chicago, Illinois; Department of Pediatrics, University of Chicago, Chicago, Illinois
| | - Ludvig M Sollid
- Norwegian Coeliac Disease Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Immunology, Oslo University Hospital-Rikshospitalet, Oslo, Norway
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49
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Malamut G, Soderquist CR, Bhagat G, Cerf-Bensussan N. Advances in Nonresponsive and Refractory Celiac Disease. Gastroenterology 2024; 167:132-147. [PMID: 38556189 DOI: 10.1053/j.gastro.2024.02.048] [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: 11/10/2023] [Revised: 02/04/2024] [Accepted: 02/20/2024] [Indexed: 04/02/2024]
Abstract
Nonresponsive celiac disease (CeD) is relatively common. It is generally attributed to persistent gluten exposure and resolves after correction of diet errors. However, other complications of CeD and disorders clinically mimicking CeD need to be excluded. Novel therapies are being evaluated to facilitate mucosal recovery, which might benefit patients with nonresponsive CeD. Refractory CeD (RCeD) is rare and is divided into 2 types. The etiology of type I RCeD is unclear. A switch to gluten-independent autoimmunity is suspected in some patients. In contrast, type II RCeD represents a low-grade intraepithelial lymphoma. Type I RCeD remains a diagnosis of exclusion, requiring ruling out gluten intake and other nonmalignant causes of villous atrophy. Diagnosis of type II RCeD relies on the demonstration of a clonal population of neoplastic intraepithelial lymphocytes with an atypical immunophenotype. Type I RCeD and type II RCeD generally respond to open-capsule budesonide, but the latter has a dismal prognosis due to severe malnutrition and frequent progression to enteropathy-associated T-cell lymphoma; more efficient therapy is needed.
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Affiliation(s)
- Georgia Malamut
- Department of Gastroenterology, Assistance Publique-Hôpitaux de Paris Centre-Université Paris Cité, Hôpital Cochin, Paris, France; Laboratory of Intestinal Immunity, INSERM UMR 1163-Institut Imagine, Université Paris Cité, Paris, France.
| | - Craig R Soderquist
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
| | - Govind Bhagat
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
| | - Nadine Cerf-Bensussan
- Laboratory of Intestinal Immunity, INSERM UMR 1163-Institut Imagine, Université Paris Cité, Paris, France.
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50
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El-Fadeal NMA, Saad MA, Mehanna ET, Atwa H, Abo-elmatty DM, Hosny N. Association of CIITA (rs8048002) and CLEC2D (rs2114870) gene variants and type 1 diabetes mellitus. J Diabetes Metab Disord 2024; 23:1151-1162. [PMID: 38932894 PMCID: PMC11196453 DOI: 10.1007/s40200-024-01402-w] [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: 11/21/2023] [Accepted: 02/13/2024] [Indexed: 06/28/2024]
Abstract
Background Type I diabetes mellitus (T1DM) is a significant health challenge, especially for children, owing to its chronic autoimmune nature. Although the exact etiology of T1DM remains elusive, the interplay of genetic predisposition, immune responses, and environmental factors are postulated. Genetic factors control immune reactivity against β-cells. Given the pivotal roles of CIITA and CLEC2D genes in modulating a variety of immune pathologies, we hypothesized that genetic variations in CIITA and CLEC2D genes may impact T1DM disease predisposition. This study was designed to explore the association between gene polymorphisms in CIITA (rs8048002) and CLEC2D (rs2114870) and type 1 diabetes (T1DM), with a focus on analyzing the functional consequence of those gene variants. Methods The study enlisted 178 healthy controls and 148 individuals with type 1 diabetes (T1DM) from Suez Canal University Hospital. Genotyping for CIITA and CLEC2D was done using allelic-discrimination polymerase chain reaction (PCR). Levels of glycated hemoglobin (HbA1c) and lipid profiles were determined through automated analyzer, while fasting blood glucose and insulin serum levels were measured using the enzyme-linked immunosorbent assay (ELISA) technique. RegulomeDB was used to examine the regulatory functions of CIITA (rs8048002) and CLEC2D (rs2114870) gene variants. Results Analysis of the genotype distribution of the CIITA rs8048002 polymorphism revealed a significantly higher prevalence of the rare C allele in T1DM patients compared to the control group (OR = 1.77; P = 0.001). Both the CIITA rs8048002 heterozygote TC genotype (OR = 1.93; P = 0.005) and the rare homozygote CC genotype (OR = 3.62; P = 0.006) were significantly more frequent in children with T1DM when compared to the control group. Conversely, the rare A allele of CLEC2D rs2114870 was found to be significantly less frequent in T1DM children relative to the control group (OR = 0.58; P = 0.002). The heterozygote GA genotype (OR = 0.61; P = 0.033) and the rare homozygote AA genotype (OR = 0.25; P = 0.004) were also significantly less frequent in T1DM patients compared to the control group. Both CIITA (rs8048002) and CLEC2D (rs2114870) gene variants were predicted to have regulatory functions, indicated by a RegulomeDB score of (1f) for each. Conclusion The rare C allele of CIITA rs8048002 genetic variant was associated with an increased risk of developing T1DM, while the less common A allele of CLEC2D rs2114870 was associated with a reduced risk of T1DM. Supplementary Information The online version contains supplementary material available at 10.1007/s40200-024-01402-w.
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Affiliation(s)
- Noha M. Abd El-Fadeal
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Suez Canal University, 41522 Ismailia, Egypt
- Department of Biochemistry, Ibn Sina National College for Medical Studies, Jeddah, Saudi Arabia
- Oncology Diagnostic Unit, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
- Center of Excellence in Molecular and Cellular Medicine, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | | | - Eman T. Mehanna
- Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt
| | - Hoda Atwa
- Department of Pediatric Medicine, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Dina M. Abo-elmatty
- Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt
| | - Nora Hosny
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Suez Canal University, 41522 Ismailia, Egypt
- Center of Excellence in Molecular and Cellular Medicine, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
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