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Journal of Medicine and Life Feb 2024Numerous studies have established a link between gene variants within the inflammasome complex and the incidence of periodontitis and cardiovascular illness across...
Numerous studies have established a link between gene variants within the inflammasome complex and the incidence of periodontitis and cardiovascular illness across various ethnic groups. This study investigated the association between gene polymorphism and susceptibility to periodontal disease and coronary heart disease (CHD) and their correlation with clinical periodontal indices. A total of 120 participants were enrolled, categorized into four groups: 30 healthy controls (C), 30 patients with generalized periodontitis (P), 30 patients with atherosclerotic CHD but clinically healthy periodontium (AS-C), and 30 patients with both atherosclerotic CHD and generalized periodontitis (AS-P). We recorded demographic data, collected blood samples, and measured periodontal indices, including plaque index, clinical attachment loss, bleeding on probing, and pocket depth. The genomic variant of the gene was analyzed using a conventional polymerase reaction. A significant prevalence of T and G allele mutations and a higher distribution of CT and TT genotypes in C/T (rs8056505) and the AG genotype in A/G (rs372507365) were observed in groups P, AS-P, and AS-C. These single nucleotide polymorphisms (SNPs) were also positively correlated with the severity of clinical periodontitis indices. Our findings suggest that the increased frequency of T and G alleles and the distribution of CT, TT, and AG genotypes in SNPs are significantly associated with an elevated risk for periodontal disease and CHD. These SNPs may participate in the pathogenesis of these conditions. The study reinforces the potential role of these genetic markers as risk factors for both diseases in the Iraqi population.
Topics: Adult; Female; Humans; Male; Middle Aged; Alleles; CARD Signaling Adaptor Proteins; Case-Control Studies; Coronary Disease; Genetic Predisposition to Disease; Genotype; Periodontal Diseases; Periodontitis; Polymorphism, Single Nucleotide
PubMed: 38813354
DOI: 10.25122/jml-2023-0263 -
Cell Reports. Medicine Feb 2024Prenatal dexamethasone exposure (PDE) can lead to increased susceptibility to various diseases in adult offspring, but its effect on gut microbiota composition and the...
Prenatal dexamethasone exposure (PDE) can lead to increased susceptibility to various diseases in adult offspring, but its effect on gut microbiota composition and the relationship with disease susceptibility remains unclear. In this study, we find sex-differential changes in the gut microbiota of 6-month-old infants with prenatal dexamethasone therapy (PDT) that persisted in female infants up to 2.5 years of age with altered bile acid metabolism. PDE female offspring rats show abnormal colonization and composition of gut microbiota and increased susceptibility to cholestatic liver injury. The aberrant gut microbiota colonization in the PDE offspring can be attributed to the inhibited Muc2 expression caused by decreased CDX2 expression before and after birth. Integrating animal and cell experiments, we further confirm that dexamethasone could inhibit Muc2 expression by activating GR/HDAC11 signaling and regulating CDX2 epigenetic modification. This study interprets abnormal gut microbiota and disease susceptibility in PDT offspring from intrauterine intestinal dysplasia.
Topics: Humans; Pregnancy; Rats; Animals; Female; Infant; Dexamethasone; Gastrointestinal Microbiome; Rats, Wistar; Disease Susceptibility; Prenatal Exposure Delayed Effects; Epigenesis, Genetic
PubMed: 38301654
DOI: 10.1016/j.xcrm.2024.101398 -
BMC Medicine Dec 2023Major psychiatric disorders such as schizophrenia (SCZ) and bipolar disorder (BPD) are complex genetic mental illnesses. Their non-Mendelian features, such as those...
BACKGROUND
Major psychiatric disorders such as schizophrenia (SCZ) and bipolar disorder (BPD) are complex genetic mental illnesses. Their non-Mendelian features, such as those observed in monozygotic twins discordant for SCZ or BPD, are likely complicated by environmental modifiers of genetic effects. 5-Hydroxymethylcytosine (5hmC) is an important epigenetic mark in gene regulation, and whether it is linked to genetic variants that contribute to non-Mendelian features remains largely unexplored.
METHODS
We combined the 5hmC-selective chemical labeling method (5hmC-seq) and whole-genome sequencing (WGS) analysis of peripheral blood DNA obtained from monozygotic (MZ) twins discordant for SCZ or BPD to identify allelic imbalances in hydroxymethylome maps, and examined association of allele-specific hydroxymethylation (AShM) transition with disease susceptibility based on Bayes factors (BF) derived from the Bayesian generalized additive linear mixed model. We then performed multi-omics integrative analysis to determine the molecular pathogenic basis of those AShM sites. We finally employed luciferase reporter, CRISPR/Cas9 technology, electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), PCR, FM4-64 imaging analysis, and RNA sequencing to validate the function of interested AShM sites in the human neuroblastoma SK-N-SH cells and human embryonic kidney 293T (HEK293T) cells.
RESULTS
We identified thousands of genetic variants associated with AShM imbalances that exhibited phenotypic variation-associated AShM changes at regulatory loci. These AShM marks showed plausible associations with SCZ or BPD based on their effects on interactions among transcription factors (TFs), DNA methylation levels, or other epigenomic marks and thus contributed to dysregulated gene expression, which ultimately increased disease susceptibility. We then validated that competitive binding of POU3F2 on the alternative allele at the AShM site rs4558409 (G/T) in PLLP-enhanced PLLP expression, while the hydroxymethylated alternative allele, which alleviated the POU3F2 binding activity at the rs4558409 site, might be associated with the downregulated PLLP expression observed in BPD or SCZ. Moreover, disruption of rs4558409 promoted neural development and vesicle trafficking.
CONCLUSION
Our study provides a powerful strategy for prioritizing regulatory risk variants and contributes to our understanding of the interplay between genetic and epigenetic factors in mediating SCZ or BPD susceptibility.
Topics: Humans; Bayes Theorem; Alleles; Twins, Monozygotic; HEK293 Cells; DNA Methylation; Schizophrenia; Genetic Predisposition to Disease; Epigenesis, Genetic
PubMed: 38082312
DOI: 10.1186/s12916-023-03177-y -
Current Treatment Options in Oncology May 2024Cardio-oncology is an emerging interdisciplinary field dedicated to the early detection and treatment of adverse cardiovascular events associated with anticancer... (Review)
Review
Cardio-oncology is an emerging interdisciplinary field dedicated to the early detection and treatment of adverse cardiovascular events associated with anticancer treatment, and current clinical management of anticancer-treatment-related cardiovascular toxicity (CTR-CVT) remains limited by a lack of detailed phenotypic data. However, the promise of diagnosing CTR-CVT using deep phenotyping has emerged with the development of precision medicine, particularly the use of omics-based methodologies to discover sensitive biomarkers of the disease. In the future, combining information produced by a variety of omics methodologies could expand the clinical practice of cardio-oncology. In this review, we demonstrate how omics approaches can improve our comprehension of CTR-CVT deep phenotyping, discuss the positive and negative aspects of available omics approaches for CTR-CVT diagnosis, and outline how to integrate multiple sets of omics data into individualized monitoring and treatment. This will offer a reliable technical route for lowering cardiovascular morbidity and mortality in cancer patients and survivors.
Topics: Humans; Precision Medicine; Neoplasms; Genomics; Cardiovascular Diseases; Cardiotoxicity; Antineoplastic Agents; Biomarkers; Metabolomics; Proteomics; Medical Oncology; Disease Management; Disease Susceptibility; Cardio-Oncology
PubMed: 38676836
DOI: 10.1007/s11864-024-01203-6 -
Journal of Virology Jul 2023Powassan virus (POWV) is an emerging tick-borne flavivirus that causes neuroinvasive diseases, including encephalitis, meningitis, and paralysis. Similar to other...
Powassan virus (POWV) is an emerging tick-borne flavivirus that causes neuroinvasive diseases, including encephalitis, meningitis, and paralysis. Similar to other neuroinvasive flaviviruses, such as West Nile virus (WNV) and Japanese encephalitis virus (JEV), POWV disease presentation is heterogeneous, and the factors influencing disease outcome are not fully understood. We used Collaborative Cross (CC) mice to assess the impact of host genetic factors on POWV pathogenesis. We infected a panel of -null CC lines with POWV and observed a range of susceptibility, indicating that host factors other than the well-characterized flavivirus restriction factor modulate POWV pathogenesis in CC mice. Among the -null CC lines, we identified multiple highly susceptible lines (0% survival), including CC071 and CC015, and two resistant lines, CC045 and CC057 (>75% survival). The susceptibility phenotypes generally were concordant among neuroinvasive flaviviruses, although we did identify one line, CC006, that was specifically resistant to JEV, suggesting that both pan-flavivirus and virus-specific mechanisms contribute to susceptibility phenotypes in CC mice. We found that POWV replication was restricted in bone marrow-derived macrophages from CC045 and CC057 mice, suggesting that resistance could result from cell-intrinsic restriction of viral replication. Although serum viral loads at 2 days postinfection were equivalent between resistant and susceptible CC lines, clearance of POWV from the serum was significantly enhanced in CC045 mice. Furthermore, CC045 mice had significantly lower viral loads in the brain at 7 days postinfection than did CC071 mice, suggesting that reduced central nervous system (CNS) infection contributes to the resistant phenotype of CC045 mice. Neuroinvasive flaviviruses, such as WNV, JEV, and POWV, are transmitted to humans by mosquitoes or ticks and can cause neurologic diseases, such as encephalitis, meningitis, and paralysis, and they can result in death or long-term sequelae. Although potentially severe, neuroinvasive disease is a rare outcome of flavivirus infection. The factors that determine whether someone develops severe disease after a flavivirus infection are not fully understood, but host genetic differences in polymorphic antiviral response genes likely contribute to the outcome of infection. We evaluated a panel of genetically diverse mice and identified lines with distinct outcomes following infection with POWV. We found that resistance to POWV pathogenesis corresponded to reduced viral replication in macrophages, more rapid clearance of virus in peripheral tissues, and reduced viral infection in the brain. These susceptible and resistant mouse lines will provide a system for investigating the pathogenic mechanisms of POWV and identifying polymorphic host genes that contribute to resistance.
Topics: Humans; Mice; Animals; Flavivirus; Collaborative Cross Mice; Flavivirus Infections; West Nile virus; Encephalitis Viruses, Tick-Borne; Encephalitis Virus, Japanese; Encephalitis; Disease Susceptibility; Paralysis; 2',5'-Oligoadenylate Synthetase
PubMed: 37310228
DOI: 10.1128/jvi.00715-23 -
Scientific Reports Feb 2024Infectious diseases challenge health and welfare of humans and animals. Unlike for humans, breeding of genetically resistant animals is a sustainable solution,...
Infectious diseases challenge health and welfare of humans and animals. Unlike for humans, breeding of genetically resistant animals is a sustainable solution, also providing unique research opportunities. Chances to survive a disease are improved by disease resistance, but depend also on chances to get infected and infect others. Considerable knowledge exists on chances of susceptible and resistant animals to survive a disease, yet, almost none on their infectivity and if and how resistance and infectivity correlate. Common carp (Cyprinus carpio) is widely produced in aquaculture, suffering significantly from a disease caused by cyprinid herpes virus type 3 (CyHV-3). Here, the infectivity of disease-resistant and susceptible fish types was tested by playing roles of shedders (infecting) and cohabitants (infected) in all four type-role combinations. Resistant shedders restricted spleen viral load and survived more than susceptible ones. However, mortality of susceptible cohabitants infected by resistant shedders was lower than that of resistant cohabitants infected by susceptible shedders. Virus levels in water were lower in tanks with resistant shedders leading to lower spleen viral loads in cohabitants. Thus, we empirically demonstrated that disease resistant fish survive better and infect less, with implications to epidemiology in general and to the benefit of aquaculture production.
Topics: Animals; Humans; Herpesviridae Infections; Disease Resistance; Carps; Herpesviridae; Disease Susceptibility; Fish Diseases
PubMed: 38409362
DOI: 10.1038/s41598-024-55133-2 -
Neurobiology of Disease Aug 2023Alzheimer's disease (AD) is a common neurodegenerative disease in aging individuals. Alternative splicing is reported to be relevant to AD development while their roles...
Alzheimer's disease (AD) is a common neurodegenerative disease in aging individuals. Alternative splicing is reported to be relevant to AD development while their roles in etiology of AD remain largely elusive. We performed a comprehensive splicing transcriptome-wide association study (spTWAS) using intronic excision expression genetic prediction models of 12 brain tissues developed through three modelling strategies, to identify candidate susceptibility splicing introns for AD risk. A total of 111,326 (46,828 proxy) cases and 677,663 controls of European ancestry were studied. We identified 343 associations of 233 splicing introns (143 genes) with AD risk after Bonferroni correction (0.05/136,884 = 3.65 × 10). Fine-mapping analyses supported 155 likely causal associations corresponding to 83 splicing introns of 55 genes. Eighteen causal splicing introns of 15 novel genes (EIF2D, WDR33, SAP130, BYSL, EPHB6, MRPL43, VEGFB, PPP1R13B, TLN2, CLUHP3, LRRC37A4P, CRHR1, LINC02210, ZNF45-AS1, and XPNPEP3) were identified for the first time to be related to AD susceptibility. Our study identified novel genes and splicing introns associated with AD risk, which can improve our understanding of the etiology of AD.
Topics: Humans; Alzheimer Disease; Transcriptome; Neurodegenerative Diseases; Genetic Predisposition to Disease; RNA Splicing; Polymorphism, Single Nucleotide; Repressor Proteins; Kruppel-Like Transcription Factors; Cell Adhesion Molecules
PubMed: 37354922
DOI: 10.1016/j.nbd.2023.106209 -
Frontiers in Public Health 2023Observational studies have revealed that socioeconomic status is associated with neurological disorders and aging. However, the potential causal effect between the two...
Exploring the bidirectional causal link between household income status and genetic susceptibility to neurological diseases: findings from a Mendelian randomization study.
OBJECTIVES
Observational studies have revealed that socioeconomic status is associated with neurological disorders and aging. However, the potential causal effect between the two remains unclear. We therefore aimed to investigate the causal relationship between household income status and genetic susceptibility to neurological diseases using a bidirectional Mendelian randomization (MR) study.
METHODS
An MR study was conducted on a large-sample cohort of the European population pulled from a publicly available genome-wide association study dataset, using a random-effects inverse-variance weighting model as the main standard. MR-Egger regression, weighted median, and maximum likelihood estimation were also performed concurrently as supplements. A sensitivity analysis, consisting of a heterogeneity test and horizontal pleiotropy test, was performed using Cochran's Q, MR-Egger intercept, and MR-PRESSO tests to ensure the reliability of the conclusion.
RESULTS
The results suggested that higher household income tended to lower the risk of genetic susceptibility to Alzheimer's disease (odds ratio [OR]: 0.740, 95% confidence interval [CI] = 0.559-0.980, -value = 0.036) and ischemic stroke (OR: 0.801, 95% CI = 0.662-0.968, -value = 0.022). By contrast, higher household income tended to increase the risk of genetic susceptibility to Parkinson's disease (OR: 2.605, 95% CI = 1.413-4.802, -value = 0.002). No associations were evident for intracranial hemorrhage (OR: 1.002, 95% CI = 0.607-1.653, -value = 0.993), cerebral aneurysm (OR: 0.597, 95% CI = 0.243-1.465, -value = 0.260), subarachnoid hemorrhage (OR: 1.474, 95% CI = 0.699-3.110, -value = 0.308), or epilepsy (OR: 1.029, 95% CI = 0.662-1.600, -value = 0.899). The reverse MR study suggested no reverse causal relationship between neurological disorders and household income status. A sensitivity analysis verified the reliability of the results.
CONCLUSION
Our results revealed that the populations with a superior household income exhibit an increased predisposition of genetic susceptibility to Parkinson's Disease, while demonstrating a potential decreased genetic susceptibility to ischemic stroke and Alzheimer's disease.
Topics: Humans; Genetic Predisposition to Disease; Parkinson Disease; Alzheimer Disease; Genome-Wide Association Study; Mendelian Randomization Analysis; Reproducibility of Results; Nervous System Diseases; Ischemic Stroke
PubMed: 37564429
DOI: 10.3389/fpubh.2023.1202747 -
International Journal of Molecular... Aug 2023Understanding the factors creating genetic susceptibility in psoriasis may provide a basis for improving targeted treatment strategies. In this review, we discuss the... (Review)
Review
Understanding the factors creating genetic susceptibility in psoriasis may provide a basis for improving targeted treatment strategies. In this review, we discuss the genes linked to the pathogenesis of psoriasis and their relationship to the available treatment options. To identify the relevant genetic markers and treatments, we searched PubMed, Google Scholar, MEDLINE, and Web of Science with keywords, including , , , and . The articles in English from database inception to 1/1/23 were included. Case reports and series were excluded. Gene variant forms commonly implicated in the pathogenesis of psoriasis include those encoding for interleukins, interferons, and other mediators involved in inflammatory pathways, such as JAK/STAT, and NF-κB. Several of the treatments for psoriasis (for example IL23 and TYK2 inhibitors) target the products of genes linked to psoriasis. Multiple genes are linked to the pathogenesis of psoriasis. This understanding may provide an avenue for the development of new psoriasis treatment strategies and for more effective, safer treatment outcomes.
Topics: Humans; Genetic Predisposition to Disease; Psoriasis; Interleukins
PubMed: 37569685
DOI: 10.3390/ijms241512310 -
International Journal of Molecular... Nov 2023The eye is a complex sensory organ that enables visual perception of the world. The dysfunction of any of these tissues can impair vision. Conduction studies on... (Review)
Review
The eye is a complex sensory organ that enables visual perception of the world. The dysfunction of any of these tissues can impair vision. Conduction studies on laboratory animals are essential to ensure the safety of therapeutic products directly applied or injected into the eye to treat ocular diseases before eventually proceeding to clinical trials. Among these tissues, the cornea has unique homeostatic and regenerative mechanisms for maintaining transparency and refraction of external light, which are essential for vision. However, being the outermost tissue of the eye and directly exposed to the external environment, the cornea is particularly susceptible to injury and diseases. This review highlights the evidence for selecting appropriate animals to better understand and treat corneal diseases, which rank as the fifth leading cause of blindness worldwide. The development of reliable and human-relevant animal models is, therefore, a valuable research tool for understanding and translating fundamental mechanistic findings, as well as for assessing therapeutic potential in humans. First, this review emphasizes the unique characteristics of animal models used in ocular research. Subsequently, it discusses current animal models associated with human corneal pathologies, their utility in understanding ocular disease mechanisms, and their role as translational models for patients.
Topics: Animals; Humans; Cornea; Corneal Diseases; Models, Animal; Blindness; Disease Susceptibility
PubMed: 38068983
DOI: 10.3390/ijms242316661