BMC Medical Genomics最新文献

Endogenous retroelements (EREs) comprise a significant portion of the human genome and there is a growing appreciation for their roles in eukaryotic physiology. In lymphomas, EREs may contribute to proto-oncogene expression and their RNA expression can be useful to better define lymphoma sub-classifications. Several emerging cancer therapies suggest that targeting ERE expression may even be beneficial to patient outcome. In this study, we investigated how enitociclib, a CDK9 inhibitor, impacted ERE expression over time. Using in vitro models of T and B lymphocytes, we found that CDK9 inhibition upregulates transcriptional abundances of ERE RNAs in a cell type- and temporal- specific manner. Leveraging this data with data collected from a retrospective cohort of patients with lymphomas receiving enitociclib, we found that ERE activity was initially downregulated, followed by a substantial upregulation in expression before a return to baseline expression levels within forty-eight hours. These results showed that ERE activity is differentially sensitive to CDK9 inhibition and highlights the complexity of interactions between the P-TEFb complex and nascent ERE RNAs.

Ankylosing spondylitis (AS) is a common immune inflammatory disease. PANoptosis, as a novel programmed cell death pathway, its mechanism of action in ankylosing spondylitis remains unclear. Therefore, this study aims to clarify the role of a novel programmed cell death pattern - PANoptosis - in the pathogenesis of ankylosing spondylitis (AS), and to screen and verify key genes (APRGS), providing new ideas for the diagnosis and treatment of AS. Based on multiple gene expression datasets (GSE25101, GSE73754, GSE11886, GSE134290) of AS patients and known gene libraries related to panoptosis, by integrating differential expression genes analysis (DEGs), weighted gene co-expression network analysis (WGCNA), protein-protein interaction network (PPI), and three machine learning algorithms (RF, LASSO-logistic regression, SVM), six core APRGs were identified: AIM2, TNF, IFNG, CASP8, ADAR, ALKBH5. These genes are significantly enriched in signaling pathways such as NOD-like receptors, TNF and p53, and exhibit excellent diagnostic efficacy for as (ROC analysis). Immune infiltration analysis revealed that as patients had characteristics such as an increase in activated NK cells and CD4+ t cells. In vivo validation was carried out by establishing a rat model of as induced by complete freesier adjuvant (CFA). HE staining showed that obvious inflammatory infiltration and abnormal ossification occurred in the sacroiliac joint of the model rats, and the levels of serum pro-inflammatory factors (TNF-α, IL-6) increased, and anti-inflammatory factors (IL-10, IL-4) significantly decreased. Molecular testing confirmed that the expression of RIPK1 protein was upregulated. The mRNA and protein expressions of AIM2, TNF, IFNG, CASP8 and ALKBH5 in core APRGs were significantly increased, while the expression of ADAR was decreased. Our research has clarified that PANoptosis drives chronic inflammation and bone destruction in as through the synergistic action of six key genes: AIM2, TNF, IFNG, CASP8, ADAR, and ALKBH5, involving NOD-like receptors, TNF, and p53 pathways. These genes are potential diagnostic markers and therapeutic targets for as, providing an important basis for the development of targeted intervention strategies.

Background: Sepsis is a syndrome caused by the host's inflammatory response to an infection with an unknown mechanism. This study aimed to identify differentially expressed genes (DEGs) potentially involved in the development and recovery of tracheal injury from septic shock.

Methods: Nine New Zealand white rabbits were randomized to control (CON), septic shock model (SS), and septic shock norepinephrine treatment (SSNE) groups (each group n = 3). The SS and SSNE groups were injected with lipopolysaccharide to induce septic shock. The SSNE group was administered Ringer lactate with norepinephrine to maintain normal blood pressure. All animals underwent cuffed endotracheal intubation for 2 h. The injured tracheal segment was harvested. RNA sequencing was performed to identify the DEGs, followed by bioinformatics analysis, and pathological staining (both HE and Masson) was performed for pathological evaluation. Bioinformatics analysis included principal component analysis (PCA), gene set enrichment analysis (GSEA), and protein-protein interaction (PPI) network construction. Key findings were validated by qRT-PCR and immunohistochemistry.

Results: We obtained 124 upregulated and 28 downregulated DEGs in SS vs. CON groups, along with 60 upregulated and 178 downregulated DEGs in SSNE vs. SS groups. The pathological score showed that trachea tissue in the SS group had the highest score. The protein-protein interaction (PPI) prediction identified APOB and CD36 as the hub genes. The molecular experiments further confirmed that at mRNA and protein levels, APOB was significantly upregulated, while CD36 was significantly downregulated. Subsequent qRT-PCR and immunohistochemical analyses confirmed that APOB expression was significantly upregulated while CD36 was downregulated in the septic shock group, a trend partially reversed by norepinephrine treatment.

Conclusions: Our study results suggest that APOB and CD36 may be involved in the pathogenesis of tracheal injury recovery in septic shock patients treated with NE.

Clinical trial number: Not applicable.

Background: Sequencing reanalysis can benefit from the inclusion of new information about the patient and from the literature. We studied approaches needed to make reanalysis part of routine follow-up by clinical geneticists.

Methods: Reanalysis used the SimulConsult diagnostic decision support software, which generates a pertinence metric for gene zygosities determined from the variant table and the patient's findings. Twenty patients had routine exome sequencing at St. George's Hospital (London, UK). Twenty were admitted to the Undiagnosed Diseases Network at Vanderbilt University Medical Center (VUMC) and had all remained undiagnosed despite previous evaluations and sequencing.

Results: For St. George's cases, reanalysis picked 7 of the 7 initial diagnoses plus 2 diagnoses found later, and suggested another diagnosis with a gene absent from the variant table. For VUMC, reanalysis picked 5 of 8 diagnoses that were in the variant tables, and suggested a non-coding variant absent from the variant table.

Conclusion: Rapid reanalysis by clinicians could increase the yield of genetic diagnosis with minimal effort and no new lab expenses. For the routine cases at St. George's, diagnostic yield increased from 7 to 10 (43%). Capabilities that could further increase yield include joint variant calling, robust phenotyping, clinical correlation after sequencing, and adding CNV data to variant tables.

Background and aim: PNPLA3 rs738409 reduces the triglyceride hydrolase activity. This systematic review and meta-analysis aimed to assess the association between PNPLA3 rs738409 polymorphism and the risk of liver cirrhosis across various etiologies.

Methods: Potential articles were selected from PubMed, Embase, Cochrane Library, and Web of Science databases, guided by well-defined inclusion and exclusion criteria. The quality of each article was rigorously evaluated using the Newcastle-Ottawa Scale (NOS). Association between PNPLA3 rs738409 and liver cirrhosis was expressed in terms of odds ratios (ORs) accompanied by 95% confidence intervals (CIs).

Results: This meta-analysis encompassed 21 studies (22 tests, comprising 79102 controls and 4006 cases). The aggregate findings revealed a notable positive correlation between the rs738409 and the risk of liver cirrhosis across all genetic models: G vs. C (OR = 1.75, 95% CI = 1.64-1.86), GC vs. CC (OR = 1.77, 95% CI = 1.61-1.94), GG vs. CC (OR = 2.69, 95% CI = 2.34-3.08), GG vs. CG + CC (OR = 2.02, 95% CI = 1.79-2.28), and GG + CG vs. CC (OR = 1.99, 95% CI = 1.82-2.17). There was a pronounced heterogeneity observed across all genetic models, and might be induced by race and control groups. Subgroup analyses showed significant association respectively in Caucasian and Asian, as well as healthy controls, ALD and other liver diseases control types.

Conclusion: PNPLA3 rs738409 polymorphism has been robustly linked to an increased risk of etiology-specific liver cirrhosis.

Background: Consanguineous marriage (≥ second cousins) is prevalent in Yemen (40-50%) and linked to increased genetic disorders. This study assesses its prevalence and health impacts in Radfan districts.

Methodology: A 2024 cross-sectional study of 1065 randomly selected households. Data were collected via validated questionnaires supplemented by medical records where available. Analyses included consanguinity rates, inbreeding coefficients (F), sociocultural factors, and clinically validated genetic disorders. Statistical analysis employed χ² tests, multivariable logistic regression (adjusted ORs), and Cohen's d for effect sizes.

Results: The consanguinity rate was 57.46%, significantly higher in rural (37.09%) than urban areas (20.38%). Wives with a university education had a 71.9% lower likelihood of consanguineous marriage (adjusted OR = 0.28; 95% CI: 0.18-0.44). Consanguineous couples had significantly higher odds of adverse outcomes compared to non-consanguineous couples, including abortion (adjusted OR = 1.8; 95% CI: 1.4-2.3), child mortality (adjusted OR = 2.1; 95% CI: 1.6-2.8), blood disorders (adjusted OR = 3.5; 95% CI: 1.7-7.4), and disabilities (adjusted OR = 2.6; 95% CI: 1.4-4.8). Blood disorders were predominantly hemoglobinopathies (87%). The mean inbreeding coefficient was F = 0.0625 (first-cousin equivalent).

Conclusions: The high prevalence of consanguineous marriages is a significant, modifiable risk factor for the increased burden of genetic disorders in the population. Addressing this urgent public health challenge requires a multi-faceted strategy: implementing mandatory premarital screening for hemoglobinopathies, launching community-based genetic literacy programs, and establishing economic incentives to encourage non-consanguineous unions.

Background: Chromosomal structural variations (CSVs) that comprise multiple gene mutations are important determinants for multiple diseases. However, the relationship between CSVs, rheumatoid arthritis (RA), and lung cancer is not well understood.

Materials and methods: In this study, we analyzed CSV associations and differences between RA and RA with lung cancer (RA LC) using genome sequencing, with RA-associated interstitial lung disease (RA ILD) as a disease control. First, we analyzed the CSVs of each individual. Then, we identified common CSVs within each disease group and finally analyzed specific CSVs between different diseases. Gene Ontology/KEGG terms, canonical pathways, and feature gene sets were used for the functional annotation and analysis of CSV-related pathways.

Results: Cell size regulation and axon guidance were mutated in all disease groups. Protein deubiquitination was mutated in RA LC, while the negative regulation of extractable stroma and protein catabolism was mutated in RA ILD. Characterization of clinical data also revealed correlations with these specific pathways.

Conclusion: This study identifies common and specific CSVs and associated pathways for RA, LC, and ILD, uncovering key genetic factors that provide new insights into their diagnosis and treatment.