BMC Medical Genomics最新文献

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MEIS1 knockdown upregulates WNT signaling pathway genes in esophageal squamous cell carcinoma. MEIS1敲低可上调食管鳞状细胞癌中WNT信号通路基因。
IF 2.1 4区 医学
BMC Medical Genomics Pub Date : 2025-04-10 DOI: 10.1186/s12920-025-02134-3
Nayyerehalsadat Hosseini, Mohammad Mahdi Forghanifard
{"title":"MEIS1 knockdown upregulates WNT signaling pathway genes in esophageal squamous cell carcinoma.","authors":"Nayyerehalsadat Hosseini, Mohammad Mahdi Forghanifard","doi":"10.1186/s12920-025-02134-3","DOIUrl":"https://doi.org/10.1186/s12920-025-02134-3","url":null,"abstract":"<p><strong>Background: </strong>The transcription factor MEIS1 belongs to the 3-amino acid loop extension (TALE) family of homeodomain proteins which plays various functions in normal and tumor cell progression. The canonical WNT/β-catenin pathway governs a plethora of biological processes including cell proliferation, differentiation, and tumor development. In the present study, the effect of MEIS1 gene silencing was assessed on WNT pathway genes in esophageal squamous cell carcinoma (ESCC) cells.</p><p><strong>Materials and methods: </strong>Along with the packaging plasmids, the pLKO.1-MEIS1 plasmid was cotransfected into HEK293T to generate lentiviral particles, followed by transduction of a semi-confluent KYSE-30 cell culture. After total RNA extraction and cDNA synthesis, comparative real-time PCR was applied to assess the efficiency of MEIS1 knockdown and the expression of genes related to the WNT signaling pathway.</p><p><strong>Results: </strong>The results revealed effective downregulation of MEIS1 in KYSE-30 cells. Interestingly, MEIS1 silencing led to a substantial overexpression of WNT pathway key components while the expression of negative regulators of this pathway was substantially decreased.</p><p><strong>Conclusions: </strong>Our data suggest that MEIS1 gene probably induces WNT/β-catenin pathway deactivation in ESCC cells. Consequently, the inverse correlation of MEIS1 expression and WNT signaling pathway activation may introduce a new molecular linkage through ESCC progression and aggressiveness.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"69"},"PeriodicalIF":2.1,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11983858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143973657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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 analysis of four cases of Poirier Bienvenu neurodevelopmental syndrome associated with CSNK2B variant. 4例与CSNK2B变异相关的普瓦里尔-比恩弗努神经发育综合征的遗传分析。
IF 2.1 4区 医学
BMC Medical Genomics Pub Date : 2025-04-10 DOI: 10.1186/s12920-025-02132-5
Liu Yang, Daoqi Mei, Yanping Liu, Li Gao
{"title":"Genetic analysis of four cases of Poirier Bienvenu neurodevelopmental syndrome associated with CSNK2B variant.","authors":"Liu Yang, Daoqi Mei, Yanping Liu, Li Gao","doi":"10.1186/s12920-025-02132-5","DOIUrl":"10.1186/s12920-025-02132-5","url":null,"abstract":"<p><strong>Background: </strong>CSNK2B deficiency underlies the pathogenesis of Poirier-Bienvenu neurodevelopmental syndrome (POBINDS). In this study, we present four cases of pediatric seizures caused by de novo variants in CSNK2B, with the aim to reinforce the clinical and variant data pertaining to early genetic factors associated with epilepsy.</p><p><strong>Methods: </strong>Trio whole exome sequencing were used to detect variants in the proband and her family members, and bioinformatics annotation was performed for the variant. Sanger sequencing and CSNK2B cDNA sequencing were employed to ascertain the carrier status of additional family members and evaluate the potential impact of variants on splicing.</p><p><strong>Results: </strong>All four cases presented with epilepsy as the initial manifestation, accompanied by global developmental delay, particularly in language and motor developmental delay. Cases 1, 3 and 4 exhibited full-scale tonic-clonic seizures, while case 2 displayed myoclonic and typical absence seizures. Furthermore, case 2 demonstrated delayed growth and development compared to age-matched peers. No abnormality was detected in the head magnetic resonance imaging (MRI). Genetic analysis revealed novel heterozygous variants in the CSNK2B gene in all four cases, including c.175 + 1G > A, c.73-2A > G, c.291 + 1G > A and c.481delA. In case 2, reverse transcription analysis of CSNK2B mRNA revealed the retention of the 3' end sequence of Intron 2 and deletion of the 5' end sequence of Exon 3. In treatment, four case received a combination of one to three types of antiseizure medication and rehabilitation training individually. Case 1 continued to experience seizures to varying degrees, while cases 2-4 demonstrated effective seizure control. Overall motor and intellectual development improved in all four cases, however, there was slow recovery in language function.</p><p><strong>Conclusion: </strong>This study elucidates the molecular etiology of epilepsy in four cases with POBINDS and expands the mutational spectrum of pathogenic variants in the CSNK2B, highlighting their impact on splicing. The highly genetic heterogeneous phenotype of POBINDS relies on the detection of pathogenic variants in CSNK2B. Conventional antiseizure medication effectively control seizures, while rehabilitation treatment can significantly improve intelligence and motor function to varying degrees; however, language recovery tends to be relatively slow.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"68"},"PeriodicalIF":2.1,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11983931/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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 targets related to aging for the treatment of coronary artery disease. 冠状动脉疾病治疗中与衰老相关的基因靶点
IF 2.1 4区 医学
BMC Medical Genomics Pub Date : 2025-04-09 DOI: 10.1186/s12920-025-02137-0
Kai Huang, Zijun Chen, Ruting Wang, Hangfeng Ying, Jiahao Duan, Yi Zhang, Qianyuan Shi, Chun Yang, Ling Yang
{"title":"Genetic targets related to aging for the treatment of coronary artery disease.","authors":"Kai Huang, Zijun Chen, Ruting Wang, Hangfeng Ying, Jiahao Duan, Yi Zhang, Qianyuan Shi, Chun Yang, Ling Yang","doi":"10.1186/s12920-025-02137-0","DOIUrl":"https://doi.org/10.1186/s12920-025-02137-0","url":null,"abstract":"<p><strong>Background: </strong>Coronary Artery Disease (CAD) is the most common cardiovascular disease worldwide, threatening human health, quality of life and longevity. Aging is a dominant risk factor for CAD. This study aims to investigate the potential mechanisms of aging-related genes and CAD, and to make molecular drug predictions that will contribute to the diagnosis and treatment.</p><p><strong>Methods: </strong>We downloaded the gene expression profile of circulating leukocytes in CAD patients (GSE12288) from Gene Expression Omnibus database, obtained differentially expressed aging genes through \"limma\" package and GenaCards database, and tested their biological functions. Further screening of aging related characteristic genes (ARCGs) using least absolute shrinkage and selection operator and random forest, generating nomogram charts and ROC curves for evaluating diagnostic efficacy. Immune cells were estimated by ssGSEA, and then combine ARCGs with immune cells and clinical indicators based on Pearson correlation analysis. Unsupervised cluster analysis was used to construct molecular clusters based on ARCGs and to assess functional characteristics between clusters. The DSigDB database was employed to explore the potential targeted drugs of ARCGs, and the molecular docking was carried out through Autodock Vina. Finally, single-cell data (GSE159677) of arterial intima was used to further explore the expression of aging signature genes in different cell subpopulations.</p><p><strong>Results: </strong>We identified 8 ARCGs associated with CAD, in which HIF1A and FGFR3 were up while NOX4, TCF7L2, HK3, CDK18, TFAP4, and ITPK1 were down in CAD patients. Based on this, CAD patients can be divided into two molecular clusters, among which cluster A mainly involves functional pathways such as ECM receptor interaction and focal adhesion; cluster B mainly involves functional pathways such as amimo sugar and nucleotide sugar metabolism and pyrimidine metabolism. In addition, the molecular docking results showed that retinoic acid and resveratrol had good binding affinity with targets genes. Further single-cell analysis results showed that NOX4, TCF7L2, ITPK1, and HIF1A were specifically expressed in different types of cells in atherosclerotic tissues.</p><p><strong>Conclusion: </strong>Our study identified several ARCGs that may be involved in the pathogenesis and progression of CAD. Further, retinoic acid and resveratrol were potential candidate molecule drugs for inhibiting these targets.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"66"},"PeriodicalIF":2.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11984209/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Spectrum of genetic alterations in patients with peroxisome biogenesis defects in the Iranian population: a case series study. 伊朗人群中过氧化物酶体生物发生缺陷患者的遗传改变谱:一个病例系列研究。
IF 2.1 4区 医学
BMC Medical Genomics Pub Date : 2025-04-09 DOI: 10.1186/s12920-025-02126-3
Sheyda Khalilian, Mohadeseh Fathi, Sanaz Jamshidi, Rasoul Madannejad, Arezou Sayad, Soudeh Ghafouri-Fard, Mohammad Miryounesi
{"title":"Spectrum of genetic alterations in patients with peroxisome biogenesis defects in the Iranian population: a case series study.","authors":"Sheyda Khalilian, Mohadeseh Fathi, Sanaz Jamshidi, Rasoul Madannejad, Arezou Sayad, Soudeh Ghafouri-Fard, Mohammad Miryounesi","doi":"10.1186/s12920-025-02126-3","DOIUrl":"https://doi.org/10.1186/s12920-025-02126-3","url":null,"abstract":"<p><p>Peroxisomal disorders are a group of hereditary metabolic disorders that happen when peroxisomes are defective. Around 80% of individuals affected by peroxisomal disorders are classified within the spectrum of Zellweger syndromes with autosomal recessive inheritance pattern that results from mutations in one of the 13 PEX genes. Clinical exome sequencing plays a vital role in the diagnosis where the symptoms are atypical. In the current study, we used this technique to find the underlying genetic cause in 14 Iranian patients with peroxisomal disorders. PEX1 variants were detected in five patients. PEX2, PEX5, PEX6 and PEX7 variants were detected in three, one, one, and two cases, respectively. Finally, ACOX1 variants were identified in two cases. All cases except two cases were homozygote for the suspected variants in Zellweger syndrome-related genes. Two cases were compound heterozygote for variants in the PEX1 gene. In total, two novel variants were identified, including c.313 C > T (p.Gln105*) and c.961 A > T (p.Ile321Phe) in the PEX1 and ACOX1 genes, respectively. The present research expands the range of genetic variations observed in Iranian individuals diagnosed with various forms of Zellweger spectrum disorders.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"67"},"PeriodicalIF":2.1,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11984031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Putative function and prognostic molecular marker of mast cells in colorectal cancer. 肥大细胞在结直肠癌中的推测功能及预后分子标志物。
IF 2.1 4区 医学
BMC Medical Genomics Pub Date : 2025-04-08 DOI: 10.1186/s12920-025-02117-4
Jiani Guo, Jie Chen, Yiting Wang, Xiaoming Bai, Haimei Feng, Siqi Sheng, Hongyu Wang, Ke Xu, Mengxi Huang, Zengjie Lei, Xiaoyuan Chu
{"title":"Putative function and prognostic molecular marker of mast cells in colorectal cancer.","authors":"Jiani Guo, Jie Chen, Yiting Wang, Xiaoming Bai, Haimei Feng, Siqi Sheng, Hongyu Wang, Ke Xu, Mengxi Huang, Zengjie Lei, Xiaoyuan Chu","doi":"10.1186/s12920-025-02117-4","DOIUrl":"https://doi.org/10.1186/s12920-025-02117-4","url":null,"abstract":"<p><strong>Background: </strong>The increased demand for markers for colorectal cancer (CRC) highlights the importance of investigating immune cells involved in CRC progression. This study aims to dissect the mast cells in CRC, characterize the role of mast cells in CRC development, coordinate molecular communication between mast cells and malignant cells, and construct and validate a prognostic classification model based on mast cell markers.</p><p><strong>Methods: </strong>Single-cell transcriptome data of CRC patients were extracted from GSE146771 for cell classification and annotation. The malignant cells were identified by copykat and the communication between mast cells and malignant cells was analyzed by CellChat. Least absolute shrinkage and selection operator (LASSO) regression analysis and Cox regression analysis of mast cell markers were performed in the TCGA-COAD cohort to construct a prognostic classification model. qRT-PCR was performed to detect the mRNA expression of the molecules in the classification model in P815 and MC-9 cells. The co-culture experiment of MC38 and P815 cells were performed in 12-well transwell dish. Wound healing assay and Transwell assay were performed to detect cell migration and invasion.</p><p><strong>Results: </strong>10,186 high-quality cells in GSE146771 were annotated to 9 cell types. Six markers in mast cells (HDC, GATA2, ASAH1, BTBD19, TIMP1, FAM110A) were selected to construct a classification model. The high-risk score defined showed high infiltration of immunosuppressive cells, including endothelial cells, CAFs, Tregs and high angiogenesis and epithelial-mesenchymal transition (EMT) activities. In the model, HDC were abnormally low expressed in P815 cells, while BTBD19, FAM110A, GATA2, ASAH1 and TIMP1 showed excessive expression in P815 cells. Knockdown of GATA2 in the co-culture system of P815 and MC38 cells blocked cell migration and invasion.</p><p><strong>Conclusion: </strong>This study identified the cell types within CRC, elaborated the cellular functions of mast cells in CRC development and their molecular communication to coordinate malignant cells, and highlighted the molecular components and biological features that constitute promising prognostic classification model.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"65"},"PeriodicalIF":2.1,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11983841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143973659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Exome-wide association study reveals 7 functional variants associated with ex-vivo drug response in acute myeloid leukemia patients. 外显子组关联研究揭示7个与急性髓系白血病患者体外药物反应相关的功能变异。
IF 2.1 4区 医学
BMC Medical Genomics Pub Date : 2025-04-04 DOI: 10.1186/s12920-025-02130-7
Anil K Giri, Jake Lin, Konstantinos Kyriakidis, Garima Tripathi, Henrikki Almusa
{"title":"Exome-wide association study reveals 7 functional variants associated with ex-vivo drug response in acute myeloid leukemia patients.","authors":"Anil K Giri, Jake Lin, Konstantinos Kyriakidis, Garima Tripathi, Henrikki Almusa","doi":"10.1186/s12920-025-02130-7","DOIUrl":"10.1186/s12920-025-02130-7","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML) is an aggressive blood cancer characterized by poor survival outcomes. Further, due to the extreme molecular heterogeneity of the disease, drug treatment response varies from patient to patient. The variability of drug response can cause unnecessary treatment in more than half of the patients with no or partial therapy responses leading to severe side effects, monetary as well as time loss. Understanding the genetic risk factors underlying the drug response in AML can help with improved prediction of treatment responses and identification of biomarkers in addition to mechanistic insights to monitor treatment response. Here, we report the results of the first Exome-Wide Association Study (EWAS) of ex-vivo drug response performed to date with 175 AML cases and 47 drugs. We used information from 55,423 germline exonic SNPs to perform the analysis. We identified exome-wide significant (p < 9.02 × 10<sup>- 7</sup>) associations for rs113985677 in CCIN with tamoxifen response, rs115400838 in TRMT5 with idelalisib response, rs11878277 in HDGFL2 with entinostat, and rs2229092 in LTA associated with vorinostat response. Further, using multivariate genome-wide association analysis, we identified the association of rs11556165 in ATRAID, and rs11236938 in TSKU with the combined response of all 47 drugs and 29 nonchemotherapy drugs at the genome-wide significance level (p < 5 × 10<sup>- 8</sup>). Additionally, a significant association of rs35704242 in NIBAN1 was associated with the combined response for nonchemotherapy medicines (p = 2.51 × 10<sup>- 8</sup>), and BI.2536, gefitinib, and belinostat were identified as the central traits. Our study represents the first EWAS to date on ex-vivo drug response in AML and reports 7 new associated loci that help to understand the anticancer drug response in AML patients.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"64"},"PeriodicalIF":2.1,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11969768/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
FOSB is a key factor in the genetic link between inflammatory bowel disease and acute myocardial infarction: multiple bioinformatics analyses and validation. FOSB是炎症性肠病和急性心肌梗死之间遗传联系的关键因素:多种生物信息学分析和验证。
IF 2.1 4区 医学
BMC Medical Genomics Pub Date : 2025-04-03 DOI: 10.1186/s12920-025-02129-0
Qingan Fu, Tianzhou Shen, Weihan Qiu, Yanhui Liao, Miao Yu, Yue Zhou
{"title":"FOSB is a key factor in the genetic link between inflammatory bowel disease and acute myocardial infarction: multiple bioinformatics analyses and validation.","authors":"Qingan Fu, Tianzhou Shen, Weihan Qiu, Yanhui Liao, Miao Yu, Yue Zhou","doi":"10.1186/s12920-025-02129-0","DOIUrl":"10.1186/s12920-025-02129-0","url":null,"abstract":"<p><strong>Background: </strong>Inflammatory Bowel Disease (IBD), which includes Crohn's disease and ulcerative colitis, is associated with an increased risk of Acute Myocardial Infarction (AMI). The genetic mechanisms underlying this link are not well understood.</p><p><strong>Methods: </strong>We downloaded IBD and AMI-related microarray datasets from the NCBI Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified and analyzed using enrichment analysis and Weighted Gene Co-expression Network Analysis (WGCNA). Machine learning techniques, including LASSO, random forest, and Boruta, were employed to screen for hub genes. These genes were validated through qRT-PCR and Western blotting. Single-cell sequencing was used to confirm findings. Additionally, potential therapeutic targets were identified using the Connectivity Map (CMap) database.</p><p><strong>Results: </strong>Five key hub genes-THBD, FOSB, ADGPR3, IL1R2, and PLAUR-were identified as significantly involved in both IBD and AMI pathogenesis. A diagnostic model for AMI constructed using these hub genes demonstrated high predictive accuracy. Single-cell sequencing analysis and several potential drugs targeting these hub genes were identified, offering new therapeutic avenues.</p><p><strong>Conclusion: </strong>This study highlights the crucial role of FOSB and other hub genes in the comorbidity of IBD and AMI. The findings provide novel insights for early diagnosis and potential therapeutic strategies, emphasizing the importance of further investigation into these genetic links.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"63"},"PeriodicalIF":2.1,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11969767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Methylation patterns of the nasal epigenome of hospitalized SARS-CoV-2 positive patients reveal insights into molecular mechanisms of COVID-19. 住院SARS-CoV-2阳性患者鼻表观基因组甲基化模式揭示COVID-19分子机制
IF 2.1 4区 医学
BMC Medical Genomics Pub Date : 2025-04-01 DOI: 10.1186/s12920-025-02125-4
Benjamin L Spector, Boryana Koseva, Rebecca McLennan, Dithi Banerjee, Kamani Lankachandra, Todd Bradley, Rangaraj Selvarangan, Elin Grundberg
{"title":"Methylation patterns of the nasal epigenome of hospitalized SARS-CoV-2 positive patients reveal insights into molecular mechanisms of COVID-19.","authors":"Benjamin L Spector, Boryana Koseva, Rebecca McLennan, Dithi Banerjee, Kamani Lankachandra, Todd Bradley, Rangaraj Selvarangan, Elin Grundberg","doi":"10.1186/s12920-025-02125-4","DOIUrl":"10.1186/s12920-025-02125-4","url":null,"abstract":"<p><strong>Background: </strong>Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has varied presentations from asymptomatic to death. Efforts to identify factors responsible for differential COVID-19 severity include but are not limited to genome wide association studies (GWAS) and transcriptomic analysis. More recently, variability in host epigenomic profiles have garnered attention, providing links to disease severity. However, whole epigenome analysis of the respiratory tract, the target tissue of SARS-CoV-2, remains ill-defined.</p><p><strong>Results: </strong>We interrogated the nasal methylome to identify pathophysiologic drivers in COVID-19 severity through whole genome bisulfite sequencing (WGBS) of nasal samples from COVID-19 positive individuals with severe and mild presentation of disease. We noted differential DNA methylation in intergenic regions and low methylated regions (LMRs), demonstrating the importance of distal regulatory elements in gene regulation in COVID-19 illness. Additionally, we demonstrated differential methylation of pathways implicated in immune cell recruitment and function, and the inflammatory response. We found significant hypermethylation of the FUT4 promoter implicating impaired neutrophil adhesion in severe disease. We also identified hypermethylation of ELF5 binding sites suggesting downregulation of ELF5 targets in the nasal cavity as a factor in COVID-19 phenotypic variability.</p><p><strong>Conclusions: </strong>This study demonstrated DNA methylation as a marker of the immune response to SARS-CoV-2 infection, with enhancer-like elements playing significant roles. It is difficult to discern whether this differential methylation is a predisposing factor to severe COVID-19, or if methylation differences occur in response to disease severity. These differences in the nasal methylome may contribute to disease severity, or conversely, the nasal immune system may respond to severe infection through differential immune cell recruitment and immune function, and through differential regulation of the inflammatory response.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"62"},"PeriodicalIF":2.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11963311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Causal association between non-steroidal anti-inflammatory drugs use and the risk of benign prostatic hyperplasia: a univariable and multivariable Mendelian randomization study. 非甾体抗炎药使用与良性前列腺增生风险之间的因果关系:单变量和多变量孟德尔随机化研究
IF 2.1 4区 医学
BMC Medical Genomics Pub Date : 2025-03-31 DOI: 10.1186/s12920-025-02128-1
Zi-He Peng, Ming-Rui Li, Min-Xin He, Jing Liu, Jia-Hao Dou, Ya-Wen Wang, Yao Dong, Chong Yan, Zi-Hao Li, Tie Chong, Zhao-Lun Li
{"title":"Causal association between non-steroidal anti-inflammatory drugs use and the risk of benign prostatic hyperplasia: a univariable and multivariable Mendelian randomization study.","authors":"Zi-He Peng, Ming-Rui Li, Min-Xin He, Jing Liu, Jia-Hao Dou, Ya-Wen Wang, Yao Dong, Chong Yan, Zi-Hao Li, Tie Chong, Zhao-Lun Li","doi":"10.1186/s12920-025-02128-1","DOIUrl":"10.1186/s12920-025-02128-1","url":null,"abstract":"<p><strong>Background: </strong>The results of earlier observational research on the relationships between the usage of non-steroidal anti-inflammatory medicines (NSAIDs) and the risk of benign prostatic hyperplasia (BPH) have been inconsistent.</p><p><strong>Methods: </strong>To assess these associations, we performed both univariable and multivariable Mendelian randomization (MR) studies. Instrumental variables (IVs) associated with exposures at the significance level (p < 5 × 10<sup>-6</sup>) were selected from a comprehensive meta-analysis conducted by the United Kingdom Biobank (UKB). Summary data for BPH were obtained from the FinnGen consortium, which comprised 30,066 cases and 119,297 controls. Sensitivity analyses were performed to evaluate heterogeneity and pleiotropy.</p><p><strong>Results: </strong>We found evidence by univariable MR (UVMR) that genetically predicted NSAIDs use increased the risk of BPH (odds ratio [OR] per unit increase in log odds NSAIDs use: 1.164, 95% confidence interval [CI]: 1.041-1.302, p = 0.008). After controlling for inflammation in multivariable MR (MVMR), the link persisted (OR: 1.165, 95% CI: 1.049-1.293, p = 0.004). There were no indications of potential heterogeneity and pleiotropy in UVMR and MVMR analyses.</p><p><strong>Conclusion: </strong>The results of the MR estimates suggest that genetically predicted NSAIDs use may elevate the risk of BPH. This outcome prompts the imperative for deeper exploration into potential underlying mechanisms.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"60"},"PeriodicalIF":2.1,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11956187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Whole-genome sequencing, as a powerful diagnostic tool in hearing loss, reveals novel variants in PTPRQ missed by whole-exome sequencing. 全基因组测序作为听力损失的有力诊断工具,揭示了全外显子组测序遗漏的PTPRQ新变异。
IF 2.1 4区 医学
BMC Medical Genomics Pub Date : 2025-03-31 DOI: 10.1186/s12920-025-02122-7
Daniel Bengl, Asuman Koparir, Wahyu Eka Prastyo, Christian Remmele, Marcus Dittrich, Sophie Flandin, Waafa Shehata-Dieler, Clemens Grimm, Thomas Haaf, Michaela A H Hofrichter
{"title":"Whole-genome sequencing, as a powerful diagnostic tool in hearing loss, reveals novel variants in PTPRQ missed by whole-exome sequencing.","authors":"Daniel Bengl, Asuman Koparir, Wahyu Eka Prastyo, Christian Remmele, Marcus Dittrich, Sophie Flandin, Waafa Shehata-Dieler, Clemens Grimm, Thomas Haaf, Michaela A H Hofrichter","doi":"10.1186/s12920-025-02122-7","DOIUrl":"10.1186/s12920-025-02122-7","url":null,"abstract":"<p><strong>Background/objectives: </strong>Hearing loss (HL) is one of the most common congenital disorders, affecting 1-2 in 1,000 newborns. Modern genetic diagnostics using large gene panels and/or whole exome analysis (WES) can identify disease-causing mutations in 25-50 % of patients, with higher solve rates in individuals with earlier onset.</p><p><strong>Results: </strong>Here, we used whole-genome sequencing (WGS) to reanalyze 14 index patients/families who remained without genetic diagnosis by WES. We were able to identify the genetic cause of HL in 6 families ( <math><mo>∼</mo></math> 43 %). Two families were diagnosed with DFNB84A caused by compound heterozygous recessive mutations in PTPRQ. Three of the four underlying variants, including a structural variant, a deep intronic variant, and a splice variant, escaped detection by WES. Minigene assays confirmed the pathogenicity of the intronic and the splice variants. In addition, we used protein 3D structure prediction and rigid ligand docking to study the pathogenicity of variants that escape nonsense-mediated decay.</p><p><strong>Conclusion: </strong>In our study, we present four novel variants in PTPRQ, three of which were detected only by WGS. To our knowledge, we report here the first pathogenic deep intronic PTPRQ variant causing HL. Our results suggest that the mutational spectrum of PTPRQ is not well covered by standard WES and that PTPRQ-associated hearing loss may be more frequent than previously thought. WGS provides an additional layer of information in the diagnostics of HL.</p>","PeriodicalId":8915,"journal":{"name":"BMC Medical Genomics","volume":"18 1","pages":"59"},"PeriodicalIF":2.1,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11956499/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
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