Genes and immunity最新文献_第2页

Transcriptomics and eQTLs reveal inflammatory heterogeneity in the duodenal lining in coeliac disease 转录组学和eqtl揭示了乳糜泻十二指肠内膜的炎症异质性。

IF 4.5 3区医学

Genes and immunity Pub Date : 2025-09-09 DOI: 10.1038/s41435-025-00356-0

Aarón D. Ramírez-Sánchez, Stephanie Zühlke, Raúl Aguirre-Gamboa, Martijn Vochteloo, Lude Franke, Knut E. A. Lundin, Sebo Withoff, Iris H. Jonkers

{"title":"Transcriptomics and eQTLs reveal inflammatory heterogeneity in the duodenal lining in coeliac disease","authors":"Aarón D. Ramírez-Sánchez, Stephanie Zühlke, Raúl Aguirre-Gamboa, Martijn Vochteloo, Lude Franke, Knut E. A. Lundin, Sebo Withoff, Iris H. Jonkers","doi":"10.1038/s41435-025-00356-0","DOIUrl":"10.1038/s41435-025-00356-0","url":null,"abstract":"In coeliac disease (CeD), the epithelial lining (EL) of the small intestine is severely damaged by a complex auto-inflammatory response, leading intraepithelial lymphocytes to attack epithelial cells. To understand the intestinal changes and genetic regulation in CeD, we investigated the heterogeneity in the transcriptomic profile of the duodenal EL using RNA-seq and eQTL analysis on predicted cell types. The study included duodenal biopsies from 82 patients, grouped into controls, gluten-free diet treated CeD and untreated CeD. We identified 1 862 differential expressed genes, which clustered into four sets. Two sets, one upregulated for cell cycle function (n = 366) and one downregulated for digestion, transmembrane transport, and laminin pathways (n = 543), defined three sample groups based on inflammation status: non-inflamed, mild inflammation or severe inflammation. The remaining two sets of genes were enriched for immune (n = 458) and extracellular matrix and barrier functions (n = 495) and were sufficient to classify samples into their disease conditions. Finally, deconvoluting eQTL effects from epithelial and immune cells identified 6 and 15 cell-type-mediated eQTL genes, respectively. In sum, we identified genes expressed in the duodenal EL whose expression reflect heterogeneity in CeD and that may be used as biomarkers to assess CeD condition and its mucosal and immune status.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 5","pages":"519-530"},"PeriodicalIF":4.5,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41435-025-00356-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145029594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Transcriptional regulation of Ligase IV by an intronic regulatory element directs thymocyte development 一个内含子调控元件对连接酶IV的转录调控指导胸腺细胞的发育。

IF 4.5 3区医学

Genes and immunity Pub Date : 2025-09-05 DOI: 10.1038/s41435-025-00353-3

Matthew D. Estrada, Christopher J. Gebhardt, Mariam A. Salem, Christina N. Rau, Kruthika Sharma, Rebecca A. Glynn, Craig H. Bassing, Eugene M. Oltz, Patrick L. Collins

{"title":"Transcriptional regulation of Ligase IV by an intronic regulatory element directs thymocyte development","authors":"Matthew D. Estrada, Christopher J. Gebhardt, Mariam A. Salem, Christina N. Rau, Kruthika Sharma, Rebecca A. Glynn, Craig H. Bassing, Eugene M. Oltz, Patrick L. Collins","doi":"10.1038/s41435-025-00353-3","DOIUrl":"10.1038/s41435-025-00353-3","url":null,"abstract":"Double-strand breaks represent the most dangerous form of DNA damage, and in resting cells, these breaks are sealed via the non-homologous end joining (NHEJ) factor Ligase IV (LIG4). Excessive NHEJ may be genotoxic, necessitating multiple mechanisms to control NHEJ activity. However, a clear mechanism of transcriptional control for them has not yet been identified. Here, we examine mechanisms governing Lig4 transcription in mammals, finding that most tissues maintain very low levels of LIG4 production. Select tissues upregulate LIG4, employing different strategies for genomic regulation. In developing lymphocytes, the Lig4 locus is devoid of long-range chromatin contacts; instead, its expression and role in immune development depend upon a promoter-proximal intronic regulatory element. Deletion of the Lig4 intronic regulatory element results in thymocyte-specific loss of Lig4 upregulation, defects in lymphocyte development, and altered antigen receptor rearrangement. Our findings show the NHEJ gene, Lig4, is transcriptionally controlled to support stage-specific function concurrent with programmed DSBs. Moreover, we provide an example of how DNA cis-regulatory elements very close to a promoter can have substantial transcriptional effects.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 5","pages":"509-518"},"PeriodicalIF":4.5,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41435-025-00353-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of core genes for systemic lupus erythematosus via genome-wide aggregated trans-effects analysis 通过全基因组聚合反式效应分析发现系统性红斑狼疮的核心基因。

IF 4.5 3区医学

Genes and immunity Pub Date : 2025-09-03 DOI: 10.1038/s41435-025-00352-4

Andrii Iakovliev, Olivia Castellini-Pérez, Buddhiprabha Erabadda, PRECISESADS Clinical Consortium, PRECISESADS Flow Cytometry Consortium, Javier Martín, Guillermo Barturen, Paul M. McKeigue, Elena Carnero-Montoro, Marta E. Alarcón-Riquelme, Athina Spiliopoulou

{"title":"Discovery of core genes for systemic lupus erythematosus via genome-wide aggregated trans-effects analysis","authors":"Andrii Iakovliev, Olivia Castellini-Pérez, Buddhiprabha Erabadda, PRECISESADS Clinical Consortium, PRECISESADS Flow Cytometry Consortium, Javier Martín, Guillermo Barturen, Paul M. McKeigue, Elena Carnero-Montoro, Marta E. Alarcón-Riquelme, Athina Spiliopoulou","doi":"10.1038/s41435-025-00352-4","DOIUrl":"10.1038/s41435-025-00352-4","url":null,"abstract":"The “omnigenic” hypothesis postulates that the polygenic effects of common variants on a typical complex trait coalesce on relatively few core genes through trans-effects on their expression. Our aim was to identify core genes for systemic lupus erythematosus (SLE) by testing for association with genome-wide aggregated trans-effects (GATE) scores for gene expression in a large genetic dataset (5267/4909 SLE cases/controls). SLE was strongly associated with upregulation of expression of eight interferon-stimulated genes driven by shared trans-effects. We estimate that trans-effects on interferon signaling account for 9% of the total genetic effect on SLE risk. Outside this pathway, GATE analysis detected twenty putative core genes for SLE. Direct protein measurements for these genes were strongly associated with SLE in UK Biobank. Two putative core genes (TNFRSF17, TNFRSF13B) encode receptors (BCMA, TACI) expressed on B cells; their ligands (BAFF, APRIL) are targeted by drugs licensed or in development for SLE. Four genes (PDCD1, LAG3, TNFRSF9, CD27) encode receptors that have been characterized as immune checkpoints, and three (CD5L, SIGLEC1, CXCL13) are biomarkers of SLE disease activity. These results provide genetic support for existing drug targets in SLE (interferon signaling, BAFF/APRIL signaling) and identify other possible therapeutic targets including immune checkpoint receptors.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 5","pages":"497-508"},"PeriodicalIF":4.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41435-025-00352-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

IRF3 in viral infections: more than just triggering the interferon response IRF3在病毒感染中的作用：不仅仅是触发干扰素反应。

IF 4.5 3区医学

Genes and immunity Pub Date : 2025-09-02 DOI: 10.1038/s41435-025-00354-2

Marie Bourdon, Caroline Manet, Xavier Montagutelli

引用次数: 0

An efficient framework to decipher microRNA regulatory programs applied to T cells 一个有效的框架来破译应用于T细胞的microRNA调控程序。

IF 4.5 3区医学

Genes and immunity Pub Date : 2025-08-18 DOI: 10.1038/s41435-025-00351-5

Hongya Zhu, Divya Ganapathi Sankaran, Norah L. Smith, Ciarán W. P. Daly, Kristel Yee Mon, Cybelle Tabilas, Erin M. Wissink, Brian D. Rudd, Andrew Grimson

{"title":"An efficient framework to decipher microRNA regulatory programs applied to T cells","authors":"Hongya Zhu, Divya Ganapathi Sankaran, Norah L. Smith, Ciarán W. P. Daly, Kristel Yee Mon, Cybelle Tabilas, Erin M. Wissink, Brian D. Rudd, Andrew Grimson","doi":"10.1038/s41435-025-00351-5","DOIUrl":"10.1038/s41435-025-00351-5","url":null,"abstract":"Naïve CD8 + T cells are heterogenous, with subsets exhibiting divergent kinetics and functions post-activation. MicroRNAs, important mediators of post-transcriptional regulation, contribute to specification of different naïve T cell subsets. However, the microRNA regulatory circuits mediating functional specialization of naïve subsets are poorly understood. Here, we profiled microRNA expression in diverse subsets of naïve CD8 + T cells, revealing significant differences in their microRNA expression landscapes. We developed a novel framework, miR-Inf, to decipher microRNA regulatory programs. miR-Inf features two innovative attributes: (i) an efficient approach based on intron-exon ratios to estimate gene decay rates from a compendium of RNA-seq profiles, in order to better capture microRNA regulatory effects, and (ii) identification of cell-type-specific microRNA targets by integrating decay rate data and microRNA expression data. We applied this framework to identify consequential miRNAs in naïve CD8 + T cell subsets and predicted their subset-specific targets. Our analyses revealed that miR-29, a microRNA known to be important in CD8 + T cells, likely functions by modulating transcripts encoding epigenetic factors, thereby pre-programming different naïve T cell subsets to exhibit different immune responses post-activation. Collectively, our data and broadly applicable framework defined microRNA regulatory circuits across a variety of naïve CD8 + T cell subsets.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 5","pages":"486-496"},"PeriodicalIF":4.5,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41435-025-00351-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144872888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Neutrophil extracellular traps aggravate periodontitis by disturbing regulatory T-cell differentiation 中性粒细胞胞外陷阱通过干扰调节性t细胞分化而加重牙周炎。

IF 4.5 3区医学

Genes and immunity Pub Date : 2025-08-11 DOI: 10.1038/s41435-025-00350-6

Beibei Chen, Danni Song, Tianfan Cheng, Lijian Jin, Yongming Li, Chongshan Liao

{"title":"Neutrophil extracellular traps aggravate periodontitis by disturbing regulatory T-cell differentiation","authors":"Beibei Chen, Danni Song, Tianfan Cheng, Lijian Jin, Yongming Li, Chongshan Liao","doi":"10.1038/s41435-025-00350-6","DOIUrl":"10.1038/s41435-025-00350-6","url":null,"abstract":"Excessive neutrophil extracellular traps (NETs) induce an intense inflammatory response in periodontitis. Recently, Tregs were shown to be essential for attenuating inflammation-driven bone resorption. However, the regulation of Tregs differentiation by NETs in periodontitis is still unclear and needs further investigation. In this study, a murine experimental periodontitis model was established either without or with NETs depletion via DNase I. Firstly, we revealed that NETs accumulated significantly in both periodontal tissues and sera of mice models with periodontitis, while the depletion of NETs alleviated alveolar bone resorption. Moreover, RNA sequencing and bioinformatics analysis revealed that NETs depletion regulated the immune response of gingival tissue, especially affecting T-cell differentiation, and identified potential regulatory pathways. Subsequently, we verified that inhibition of NETs promoted the infiltration of Tregs and increased expression levels of IL-10 and TGF-β in periodontal tissue. Furthermore, in vitro studies demonstrated that NETs produced by P. g-LPS-stimulated neutrophils impeded the differentiation of co-cultured naive CD4+ T cells into Tregs, which could be restored by DNase I-mediated digestion of NETs. In conclusion, excessive NETs could exacerbate alveolar bone resorption in periodontitis by interfering with the differentiation of Tregs, and DNase I provides a novel targeted strategy for the immunotherapy of periodontitis.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 5","pages":"475-485"},"PeriodicalIF":4.5,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144821274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A multi-omics approach reveals dysregulated TNF-related signaling pathways in circulating NK and T cell subsets of young children with autism 多组学方法揭示了自闭症儿童循环NK和T细胞亚群中tnf相关信号通路失调。

IF 4.5 3区医学

Genes and immunity Pub Date : 2025-07-30 DOI: 10.1038/s41435-025-00349-z

Wared Nour-Eldine, Samia M. Ltaief, Khalid Ouararhni, Nimshitha P. Abdul Manaph, Alberto de la Fuente, Ilham Bensmail, Houari B. Abdesselem, Abeer R. Al-Shammari

{"title":"A multi-omics approach reveals dysregulated TNF-related signaling pathways in circulating NK and T cell subsets of young children with autism","authors":"Wared Nour-Eldine, Samia M. Ltaief, Khalid Ouararhni, Nimshitha P. Abdul Manaph, Alberto de la Fuente, Ilham Bensmail, Houari B. Abdesselem, Abeer R. Al-Shammari","doi":"10.1038/s41435-025-00349-z","DOIUrl":"10.1038/s41435-025-00349-z","url":null,"abstract":"Peripheral immune dysregulation is frequently reported in autism spectrum disorder (ASD); however, the underlying molecular mechanisms remain unclear. We recruited a well-defined cohort of young Arab children with ASD, aged 2–4 years, along with matched controls in Qatar. Using a multimodal approach, we integrated transcriptomic, proteomic, and single-cell RNA-seq data analyses from this cohort. Targeted transcriptomic profiling identified differential expression of 50 immune-related genes in the circulating PBMCs of children with ASD, three of which (JAK3, CUL2, and CARD11) negatively correlated with ASD symptom severity. These gene signatures were validated in independent studies using blood and brain tissues from individuals with ASD. Enrichment analysis revealed involvement of these genes in immune function, particularly through TNF signaling pathway. Proteomic analysis highlighted disrupted TNF signaling and upregulated levels of TNFSF10 (TRAIL), TNFSF11 (RANKL), and TNFSF12 (TWEAK) in plasma of individuals with ASD. Single-cell RNA-seq revealed that B cells, CD4 T cells, and NK cells potentially contributed to these upregulations in ASD. Dysregulated TRAIL, RANKL, and TWEAK signaling pathways were specifically observed in CD8 T cells, CD4 T cells, and NK cells of individuals with ASD. These findings provide new insights into immune dysregulation mechanisms in ASD and highlight potential therapeutic targets.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 5","pages":"462-474"},"PeriodicalIF":4.5,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41435-025-00349-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144753199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Impact of tertiary lymphoid structure scores and their stage of maturation on prognosis of colorectal cancer patients 三级淋巴样结构评分及其成熟阶段对结直肠癌患者预后的影响。

IF 4.5 3区医学

Genes and immunity Pub Date : 2025-07-28 DOI: 10.1038/s41435-025-00346-2

Si Shen, Ran Sun, Tian Wang, Danfang Zhang, Na Che, Xiao Wang, Nan Zhao

{"title":"Impact of tertiary lymphoid structure scores and their stage of maturation on prognosis of colorectal cancer patients","authors":"Si Shen, Ran Sun, Tian Wang, Danfang Zhang, Na Che, Xiao Wang, Nan Zhao","doi":"10.1038/s41435-025-00346-2","DOIUrl":"10.1038/s41435-025-00346-2","url":null,"abstract":"Tertiary lymphoid structures (TLSs) are essential for promoting immune responses against tumours. However, the impact of TLS score and its maturation stage on the prognosis of colorectal cancer (CRC) patients has not yet been clarified. The aim of this study was to investigate the relationship between TLS score and its maturation stage and CRC prognosis through a retrospective study. In this study, firstly, high TLS score (≥0.752) was found to be a favourable prognostic factor for the survival of CRC patients using the TCGA database (HR = 0.381, 95% CI = 0.222 ~ 0.656). Secondly, CCL19, CCL21, and CXCL13 were found to be differential genes in the high and low TLS score groups in combination with several databases, and their main function was to chemotaxis TLS maturation. Subsequently, immunohistochemical staining was used to clarify the stage of TLS maturation in 76 clinical samples and to investigate its impact on patients’ survival prognosis. Finally, the validation of TNFRSF17 gene function was completed by cellular experiments. Analysis of the clinical samples showed that patients with higher early TLS (E-TLS) density had shorter survival than those with lower density (P = 0.016). High E-TLS density may be an independent risk factor for CRC (HR = 6.40, 95% CI = 1.82 ~ 22.55). However, the density of secondary follicular-like TLS did not show a significant prognostic effect in this study. In conclusion, patients with high TLS scores had longer survival, higher expression of immune checkpoint genes, and higher expression of TNFRSF17, which promotes T-cell infiltration and adhesion, but highly aggregated E-TLS may hamper patients’ survival prognosis.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 5","pages":"449-461"},"PeriodicalIF":4.5,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144729852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

N6-methyladenosine RNA modification regulates microglial phagocytosis in the APP/PS1 mouse model of Alzheimer’s disease n6 -甲基腺苷RNA修饰调控阿尔茨海默病APP/PS1小鼠模型的小胶质细胞吞噬

IF 4.5 3区医学

Genes and immunity Pub Date : 2025-07-24 DOI: 10.1038/s41435-025-00347-1

Xueqi Qu, Li Lin, Yinhu Li, Yuewen Chen, Yu Chen

{"title":"N6-methyladenosine RNA modification regulates microglial phagocytosis in the APP/PS1 mouse model of Alzheimer’s disease","authors":"Xueqi Qu, Li Lin, Yinhu Li, Yuewen Chen, Yu Chen","doi":"10.1038/s41435-025-00347-1","DOIUrl":"10.1038/s41435-025-00347-1","url":null,"abstract":"N6-methyladenosine (m6A) methylation and abnormal cellular processes are involved in neurodegenerative diseases, including Alzheimer’s disease (AD). However, the functions of molecular signatures associated with m6A modification in AD remain unclear. Here, we show that m6A abundance is elevated in the hippocampus in 6-month-old APP/PS1 mice, an AD mouse model. Comparative analysis of mRNA m6A modification profiles revealed substantial variation in m6A modifications between AD and control mice. Transcripts with differential m6A modification (either hyper- or hypomethylation) were enriched in the regulation of cellular processes, including metabolic alterations, immune responses, synaptic transmission, and responses to stimuli, in both the nervous and immune systems. Moreover, the m6A-associated immune features were involved in microglial signatures, including cytokine signaling, microglial homeostasis, and microglial phagocytosis. Importantly, we identified genes with significant enrichment of m6A modifications in AD mice. Among these, we confirmed that m6A methylation was associated with the gene expression levels of CD9 and Cebpβ. Moreover, these alterations were negatively associated with microglia-mediated phagocytosis in vitro, which in turn impaired activated microglia-induced inflammation. Taken together, these findings suggest that the alteration of m6A modification contributes to the progression of AD by regulating gene expression and microglial function.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 5","pages":"438-448"},"PeriodicalIF":4.5,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41435-025-00347-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144698353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genetic insights into the association between inflammatory bowel disease and Alzheimer’s disease 对炎症性肠病和阿尔茨海默病之间关系的遗传见解。

IF 4.5 3区医学

Genes and immunity Pub Date : 2025-07-16 DOI: 10.1038/s41435-025-00344-4

Lu Zeng, Charles C. White, David A. Bennett, Hans-Ulrich Klein, Philip L. De Jager

{"title":"Genetic insights into the association between inflammatory bowel disease and Alzheimer’s disease","authors":"Lu Zeng, Charles C. White, David A. Bennett, Hans-Ulrich Klein, Philip L. De Jager","doi":"10.1038/s41435-025-00344-4","DOIUrl":"10.1038/s41435-025-00344-4","url":null,"abstract":"Myeloid cells, including monocytes, macrophages, and microglia, play major roles in innate and adaptive immune responses. Alzheimer’s disease (AD) and inflammatory bowel disease (IBD) susceptibility loci are both enriched for genes expressed in myeloid cells, so we assessed whether these myeloid pathways may be shared. Leveraging genome-wide association study results, we investigated the causal effect of IBD (including ulcerative colitis and Crohn’s disease) variants on AD and its endophenotypes. Microglia and monocyte expression Quantitative Trait Locus (eQTLs) were used to examine the functional consequences of IBD and AD variants. Our results revealed that the sets of genes and pathways implicated in AD and IBD susceptibility are largely distinct. Specifically, AD loci were enriched for microglial eQTLs, while IBD loci were enriched for monocyte eQTLs. Nonetheless, genetically determined IBD was associated with a modest protective effect against AD (p < 0.03), whereas CD susceptibility was linked to a modest increase in amyloid accumulation (β = 7.14, p = 0.02) and AD risk. UC susceptibility, on the other hand, was associated with increased TDP-43 deposition (β = 7.58, p value = 6.11 × 10−4). Thus, the relationship between gastrointestinal inflammatory diseases and AD is complex, but there is evidence for a modest role of IBD susceptibility on AD risk that could yield valuable therapeutic insights.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 5","pages":"429-437"},"PeriodicalIF":4.5,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144649291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0