Search Results (165)

Background/Objectives: The genes encoding HSPA1A, HSPA1B, and HSPA1L, located in the MHC class III region at 6p21.3–22.1, a region implicated in susceptibility to schizophrenia, are critical regulators of neurodevelopmental processes and contribute to synaptic neuroprotection. This study investigated whether the HSPA1A, HSPA1B, and HSPA1L genes are associated with schizophrenia. Methods: We sequenced the coding regions of HSPA1A, HSPA1B, and HSPA1L from 100 patients with schizophrenia to identify genetic variants. Further, we conducted a genetic association analysis of three SNPs (rs9469057, rs142416335, and rs2075800) in the HSPA1L gene in 519 patients with schizophrenia and 1492 healthy controls from the Taiwan Biobank. We analyzed the function of the HSPA1L protein via immunoblotting. Results: We identified 17 coding variants, including 8 missense and 9 synonymous mutations, in 100 patients with schizophrenia. Three variants (HSPA1L^p.Ala8Pro, HSPA1L^p.Ala8Thr, and HSPA1L^p.Glu602Lys) in the HSPA1L gene did not exhibit any significant differences in allele or genotype frequencies between patients and control subjects. Notably, one ultra-rare missense mutation, HSPA1L^p.Val262Met, was not documented in the control sample in Taiwan BioBank. Immunoblotting revealed HSPA1L^p.Val262Met mutant with decreased protein expression in SH-SY5Y cells compared with the wild type. Conclusions: While common variants in the HSPA1A, HSPA1B, and HSPA1L genes do not seem to be significant genetic risk factors for schizophrenia in this cohort, the ultra-rare mutation, HSPA1L^p.Val262Met, significantly reduces protein expression. These preliminary findings suggest that a potential loss-of-function or reduced expression of the HSPA1L gene may be a predisposing factor contributing to schizophrenia vulnerability in certain individuals. However, the finding should be replicated in other independent samples. The in vitro and in vivo impacts of the associated mutation at the HSPA1L gene on the pathophysiology of schizophrenia are worthy of future investigation. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by progressive memory impairment and cognitive decline. The APOE4 allele represents one of the most prominent genetic risk factors. In this study, we investigated the impact of APOE4 on the cholinergic neuronal development and on the neuronal inflammatory response to TNF-α stimulation. To address this, human induced pluripotent stem cells (hiPSCs) carrying a homozygous APOE4 genotype and an isogenic APOE3 control were differentiated into cholinergic-like induced neurons (iNs) by LHX8 overexpression. APOE4 was associated with accelerated early neuronal differentiation, as reflected by earlier downregulation of the progenitor marker Nestin. However, delayed expression of synaptophysin indicated impaired synaptic maturation. Functionally, APOE3 iNs exhibited a robust but temporally regulated response to TNF-α, whereas APOE4 iNs were characterized by a delayed yet sustained induction of inflammatory signaling. Moreover, APOE4 iNs displayed an enhanced stress-associated transcriptional response at early differentiation stages. Collectively, these findings suggest that APOE4 influences both neuronal development and the timing and persistence of inflammatory responses, potentially predisposing cholinergic neurons to later dysfunction in AD. Full article

Epidemiological and biological evidence indicate a close connection between Alzheimer’s disease (AD) and type-2 diabetes mellitus. Glucose transporter 1 (GLUT1), encoded by the SLC2A1 gene, has a major role in glucose metabolism, the dysregulation of which has been implicated in both diseases. We conducted a case-control association study in a sample of 439 non-diabetic patients with late-onset AD and 304 cognitively healthy, non-diabetic elderly controls to determine the potential risk for developing AD associated with SLC2A1 rs841847 polymorphism. The rs841847 C/C genotype occurrence was higher in the AD group (AD: 60.4%, controls: 50.7%), while the minor T allele-containing genotypes were more frequent among controls (AD: 39.6%, controls: 49.3%). A multivariate logistic regression model adjusted for age, sex, and apolipoprotein E (APOE) ε4 status (ε4 allele carriers versus non-carriers) demonstrated that carriers of the T allele had a significantly reduced risk for AD compared to C/C homozygotes (OR = 0.672; 95% CI: 0.493–0.916; p = 0.012). Although the rs841847 polymorphism has been linked to type-2 diabetes mellitus, the present study investigated this gene variant in AD for the first time. Our findings indicate a moderate protective effect for the rs841847 T allele on the susceptibility to AD. We demonstrated the rs841847 polymorphism as a candidate single nucleotide polymorphism for further examination as a predisposing genetic factor for AD. Full article

In this study, we combined computational predictions with experimental validation as a hybrid strategy to explore whether the E protein of tick-borne encephalitis virus (TBEV) possesses autoimmune potential. Using in silico homology searches, we identified two viral epitopes (evglekl and vtgtqgt) within the TBEV E protein that share sequence identity with fragments of the human proteins DNAH7 and CSMD2. Antibodies against these epitopes were detected in the plasma of a subset of patients after natural TBEV infection. Notably, no such antibodies were found in recipients of the Tick-E-Vac vaccine, indicating that the current vaccine does not induce cross-reactive humoral responses to these epitopes. Further computational analysis predicted that these epitopes could be presented by HLA class II molecules (alleles DRB1*09:01 and DRB1*07:01), which are known to be associated with autoimmune pathologies. Molecular dynamics simulations confirmed stable binding of the peptides within the HLA grooves, with favorable binding energies. These findings suggest a possible involvement of T-helper cells in the autoreactive process. Natural TBEV infection can give rise to antibodies against epitopes homologous to human proteins, particularly in genetically predisposed hosts. While such homology alone does not predict the onset of autoimmune disease, it represents a risk factor. Full article

Background and Clinical Significance: Alpha-1 antitrypsin deficiency (AATD) is an autosomal codominant disorder caused by pathogenic variants in the SERPINA1 gene, resulting in reduced circulating alpha-1 antitrypsin (AAT) or production of dysfunctional protein. AAT is the principal inhibitor of neutrophil elastase, and its deficiency leads to unchecked proteolytic activity, progressive destruction of lung parenchyma, and increased susceptibility to infections. Severe deficiency, particularly in individuals homozygous for the Z allele (PI*ZZ), predisposes to early-onset panacinar emphysema, chronic airflow obstruction, and liver disease. Despite its clinical relevance, AATD remains markedly underdiagnosed and is frequently misclassified as smoking-related chronic obstructive pulmonary disease (COPD), delaying access to disease-modifying therapy, genetic counselling, and preventive strategies. Early recognition is therefore essential to improve outcomes. Case Presentation: We report the case of a 68-year-old ex-smoker with a long-standing diagnosis of “COPD” who presented with acute-on-chronic type 2 respiratory failure and community-acquired pneumonia. Spirometry revealed severe airflow obstruction, and high-resolution computed tomography demonstrated extensive basilar panlobular emphysema, raising suspicion for AATD. Serum AAT concentration was critically low at 26.8 mg·dL⁻¹, and isoelectric focusing confirmed a PI*ZZ phenotype. Next-generation sequencing identified homozygosity for the SERPINA1 c.1096G>A (Z) variant, with no additional pathogenic alleles. Cascade family screening revealed multiple heterozygous PI*MZ relatives. Before augmentation therapy could be initiated, the patient developed severe Legionella pneumophila pneumonia with secondary bacterial superinfection, progressing to refractory septic shock and death. Conclusions: This case illustrates how AATD can masquerade as smoking-related COPD for years, leading to missed opportunities for timely intervention. It underscores the importance of testing all adults with COPD or refractory asthma at least once, regardless of age or smoking history. Early diagnosis enables initiation of augmentation therapy, targeted vaccination, lifestyle modification, and genetic counselling, ultimately improving prognosis and reducing preventable morbidity and mortality. Full article

Background: Familial prostate cancer (PCa) accounts for nearly 20% of all PCa cases and is associated with increased genetic susceptibility and earlier disease onset. However, early detection and risk stratification in genetically predisposed individuals remain challenging. Circulating cell-free DNA (cfDNA) provides a minimally invasive source of tumor-derived genomic and epigenomic information. Integrating multi-omic cfDNA analyses may enhance the discovery of biomarkers relevant to familial PCa biology. Methods: We conducted a pilot feasibility study employing whole-genome, strand-specific sequencing of cfDNA from eight patients with familial PCa. A unified analytical pipeline was used to jointly profile genomic alterations and epigenomic features. Variant calling, methylation mapping, and allele-specific methylation (ASM) analysis were performed to identify somatic mutations, characterize epigenetic dysregulation, and explore potential interactions between genetic and epigenetic mechanisms. Results: Sequencing revealed 18,878 genetic variants, including 2276 potentially pathogenic alterations. We identified 26 recurrent high-impact mutations, such as stop-gain and start-loss variants, in genes including MUC4, MCM9, and SKA3. Epigenomic profiling demonstrated widespread gene-specific hypermethylation, consistent with transcriptional repression in these loci. ASM events were detected in TTC22, TEX51, WDR89, LAIR2, and SKA3, suggesting coordinated interactions between somatic variation and epigenetic regulation in familial PCa. Conclusions: This proof-of-concept study highlights the feasibility and potential of integrating whole-genome and epigenome profiling of cfDNA to decode the molecular architecture of familial prostate cancer. By jointly capturing genomic alterations and epigenetic signatures, including allele-specific methylation, this multi-omic liquid biopsy approach supports a high-resolution exploration of biologically relevant molecular features. Moreover, this integrated profiling strategy provides a minimally invasive and clinically scalable tool that may substantially improve risk assessment. These findings offer a promising foundation for future validation studies in larger cohorts, with the aim of advancing multi-omic cfDNA analysis as a next-generation technology in the field of precision oncologic epigenetics. Full article

Background/Objectives: Thoracic aortic aneurysms have long been associated with germline mutations such as FBN1, TGFBR2, and COL3A1, which predispose to Marfan, Loeys–Dietz, and Ehlers–Danlos syndromes, respectively. However, recent research has identified a correlation between the JAK2 V617F somatic mutation and thoracic aortic aneurysm formation. This review aims to synthesize the current evidence on the relationship between JAK2 V617F and TAA development. Methods: A literature review was conducted using PubMed reviewed articles up to June 2025. Search terms included “thoracic aortic aneurysm”, “somatic mutations” and “JAK2 V617F”. Relevant clinical datasets and population-based cohort studies were identified and evaluated. Results: The available studies demonstrated a consistent association between JAK2 V617F and thoracic aortic aneurysm formation, with JAK2 V617F variant allele frequency (VAF) being a valuable biomarker of aneurysm risk. The mutation is accompanied by the onset of increased cytokine production, pro-inflammatory leukocytes, and elevated expression levels of MMPs—all of which drive elastin degradation and are classically associated with thoracic aortic aneurysm development. Conclusions: Compelling emerging evidence supports an association between the JAK2 V617F somatic mutation and the formation of thoracic aortic aneurysms, with VAF acting as a valuable biomarker for aneurysm risk. However, no studies have evaluated whether increasing VAF influences aneurysm growth rate, highlighting the need for future clinical research. Full article

Background: The etiopathogenesis of juvenile systemic lupus erythematosus (JSLE), a complex and complicated illness, is unknown. Genetic, environmental, and dysregulated immune system responses are all thought to contribute to the disease’s etiology. Important immunological molecules that regulate different immune cells and are associated with autoimmune disorders are TNFSF4 and IKZF1. Thus, our purpose was to discover if TNFSF4 and IKZF1 mutations left the Egyptian population genetically predisposed to SLE. Methods: Using real-time polymerase chain reaction (RT-PCR), polymorphism analysis of the TNFSF4 rs1234315 C/T and IKZF1 rs11980379 C/T genes was performed on extracted DNA from JSLE patients and healthy controls. Results: TNFSF4 frequencies (rs1234315 T allele, CT, TT genotypes, dominant and recessive models) were substantially associated with a higher incidence of JSLE (p < 0.05) compared to healthy controls. Conversely, IKZF1 frequencies (rs11980379 T allele, TC, TT genotypes, and dominant model) significantly correlated with a lower incidence of JSLE. Furthermore, the TC + CC rs11980379 genotype was identified as significantly associated with lower kidney biopsy grades and a lower incidence of lupus nephritis. Conclusions: Our findings suggest that TNFSF4 and IKZF1 polymorphisms affect vulnerability to juvenile SLE. Full article

Background: COPD is a multifactorial chronic lung disease driven by an abnormal inflammatory reaction. It is well recognized that genetic factors play a role in susceptibility to COPD. Hence, polymorphism in pro-inflammatory cytokines, including interleukin-1 (IL-1), may confer a risk for the development of COPD. Methods: We genotyped 163 patients with COPD and 174 control individuals using a TaqMan genotyping assay for IL1B -511 C>T SNP and a PCR-RFLP-based method for IL1B +3953 C>T SNP and VNTR polymorphism in IL1RN in order to elucidate their possible role as candidate risk factors of COPD in a Bulgarian population. Results: The genotypes containing at least one variant T allele of IL1B -511 C>T SNP demonstrated a 2.1-fold higher risk for COPD after adjustment for age, sex, and smoking status (p = 0.011). The genotype with at least one T allele of IL1B +3953 C>T appeared to be protective, with a 2.21-fold lower risk for COPD after adjustment for sex, age, and smoking status (p = 0.007). The IL1B T_C haplotype showed a 1.70-fold higher risk of COPD (p = 0.018) in comparison to the C_T haplotype. Carriers of the VNTR IL1RN 1*3 genotype develop COPD earlier compared to 1*1 (p = 0.099). Patients with the 2*2 genotype had slightly higher FEV1/FVC (%) in comparison to 1*2 carriers (p = 0.09). Conclusions: To our knowledge, this study is the first to provide exploratory evidence on the T_C haplotype of IL1B -511 C>T; +3953 C>T that may be a predisposing factor for COPD in Bulgarian population. We suggest that the VNTR polymorphism of the IL1RN gene does not affect the risk for COPD but may lead to early disease development. Full article

Background: The common fat mass and obesity-associated (FTO) gene variant rs9939609 has been linked to elevated risk of obesity and Type 2 diabetes mellitus (T2DM). Eating and sleeping windows gained clinical interest as factors in weight maintenance and have been linked to T2DM risk. Objective: To study the association and interaction between the common FTO rs9939609 variant and eating and sleeping windows to affect T2DM risk in a large community cohort. Methods: This cross-sectional study included 12,254 adult participants. Genetic, anthropometric, and lifestyle behaviors data including eating and fasting windows were analyzed. Logistic and linear regression models, as well as chi-square tests, were applied under additive, dominant, and recessive genetic models (adjusted for age, sex, and BMI). Results: Significant associations between FTO rs9939609 x eating and sleeping window interactions were demonstrated in relation to T2DM risk. Longer eating windows and later last meal timing were associated with an increased risk for T2DM under the additive model (OR = 1.029, 95% CI = 1.002–1.055, and OR = 1.066, 95% CI = 1.012–1.122, respectively), while longer fasting windows were found to be protective under additive model (OR = 0.972, 95% CI = 0.947–0.998). Later bedtime onset was associated with an increased risk for T2DM under additive model (OR = 1.101, 95% CI = 1.005–1.220). Hours of night sleep significantly interacted with FTO rs9939609 under additive genetic model. FTO rs9939609 risk allele carriers with prolonged sleeping windows (OR = 1.137, 95% CI = 1.039–1.354) and poorer sleeping quality (OR = 1.185, 95% CI = 1.038–1.354) had increased risk of T2DM. Conclusions: Eating and fasting windows, late last meal timing, hours of night sleep, late bedtime onset, and poorer sleep quality are significantly associated with T2DM risk among FTO rs9939609 risk carriers and may reflect metabolic vulnerability associated with FTO risk alleles. These findings highlight potential behavioral modification to attenuate genetic risk and provide evidence for actionable prevention strategies in genetically predisposed populations. Full article

The sodium iodide symporter (NIS) is a key protein in thyroid function responsible for iodine uptake, and it may be involved in the pathogenesis of autoimmune thyroiditis. However, it is also expressed in the salivary glands, the primary target of autoreactive cells in Sjögren’s syndrome (SS). Given the common link between the two diseases, we computationally investigated whether the epitopes of NIS can trigger an immune response leading to SS in Hashimoto’s thyroiditis (HT) patients genetically predisposed to both diseases. The TepiTool 2016, ABCpred 2006, and DiscoTope 2.0 servers were used to predict T-cell and B-cell epitopes by inputting the FASTA sequences and 3D structures of NIS, thyroid peroxidase (TPO) and Ro60 Y RNA-binding protein (Ro60), which served as reference antigens for HT and SS, respectively. T-cell epitopes were selected based on their binding to a panel of human leukocyte antigen (HLA) alleles associated with both SS and HT. We identified a total of 376 linear T-cell epitopes, 64 linear B-cell epitopes and 68 conformational B-cell epitopes of NIS. Compared to TPO, NIS T-cell epitopes showed significantly lower affinity for HLA alleles (p < 0.0001), while no significant difference was found compared to Ro60. While linear B-cell epitopes of NIS, TPO, and Ro60 showed similar binding affinity, conformational epitopes of NIS were predicted to have higher immunogenicity than Ro60 (p = 0.04), while no significant difference was found compared to TPO. These pivotal findings, discovered by the methods of computer modeling, suggest that NIS can potentially activate T cells and B cells in patients with genetic predisposition to SS and HT and need to be confirmed by further laboratory studies. Full article

Background and Clinical Significance: Mastocytosis and mast cell activation syndrome (MCAS) include conditions in which patients manifest signs, symptoms, and laboratory findings consistent with mast cell activation and can only be diagnosed in the presence of specific criteria. Mutations of ZRSR2, a gene involved in RNA splicing, are not closely associated with mast cell disorders, but rather with myelodysplastic syndromes development. Case Presentation: We report a case of a 37-year-old man who was referred to our institution for anaphylaxis after a bee sting and elevated serum tryptase levels (17.8 ng/mL in the first sample and 19.2 ng/mL in the second sample). Complete blood count was unremarkable. Bone marrow biopsy showed signs of dysplasia and some CD25+ mast cells. ASO-qPCR and targeted myeloid NGS analysis did not detect the KIT p.D816V mutation, but rather showed the presence of a pathogenetic variant of the ZRSR2 gene (p.S447_R448del) with a variant allele frequency of 7.4%. Mastocytosis could not be diagnosed based on the established diagnostic criteria. The patient’s symptoms were not recurrent and tryptase release was not event-related; therefore, a diagnosis of MCAS could not be made either. Taken together, these findings led to the diagnosis of clonal hematopoiesis of indeterminate potential (CHIP). A watch and wait strategy consisting of clinical evaluations, blood tests, and cardiovascular risk assessment was initiated. Conclusions: This case report highlights the importance of combining clinical and laboratory findings, hematopathology, and molecular analyses to establish the most probable diagnosis in challenging cases. It also underscores the possible relevance of identifying predisposing conditions, such as CHIP, in order to guide counseling and follow-up strategy. Full article

Among mouse models of neurological disease, Theiler’s murine encephalomyelitis virus (TMEV) provides a unique platform by using a naturally occurring viral trigger, paralleling the role of infections like Epstein–Barr virus in multiple sclerosis (MS). Just as not all individuals with predisposing viral infections develop the same neurological disease, not all mouse strains develop the same diseases following TMEV infection, so susceptibility is dictated by genetic background. For example, certain sets of alleles, called haplotypes, of the major histocompatibility complex (MHC) region have been associated with susceptibility to TMEV-induced demyelination (TVID) and MS. However, our previous work revealed that these MHC susceptibility haplotypes are not the sole contributors to TMEV-induced diseases in all mice. We infected mice from the genetically diverse Collaborative Cross (CC), a resource designed to reflect human population-level genetic variation. All 15 CC strains tested exhibited some form of neurological phenotype or CNS lesion following TMEV infection. However, chronic radiculoneuropathy characterized by axonal degeneration with myelin loss was observed in the CNS of only two strains, CC002 and CC023, which had markedly different immune responses and clinical profiles throughout the course of infection. Moreover, the pathology seen in CC002 and CC023 was not the same as what is typically seen in TVID. We used previous results from RNA sequencing of the hippocampus and spinal cord to test our hypothesis that myelin loss in these strains resulted from the convergent biological effects of multiple genetic risk variants, many previously unassociated with TMEV-induced diseases. These findings identify novel genetic targets and demonstrate the utility of genetically diverse models for uncovering complex neuroimmune interactions. Full article

The role of the genetic component in the development of schizophrenia and the formation of its clinical heterogeneity has been proven. To conduct a pilot associative analysis between positive and negative schizophrenia symptoms and polymorphic variants of the Transcription Factor 4 (TCF4) gene. The study included 373 patients with schizophrenia of Caucasian ethnicity, who underwent a comprehensive clinical examination, and a control group consisted of 194 mentally and somatically healthy individuals. Genotyping of three polymorphic variants of the TCF4 gene was carried out in the studied samples (rs2958182, rs8766, and rs9636107). Statistical analysis of the results was performed using Statistica for Windows V.12.0. Association analysis in SNPs was conducted using the chi-square criterion and Bonferroni correction. Groups of schizophrenia patients and healthy individuals were compared for selected TCF4 gene polymorphisms. No statistically significant differences in genotype and allele frequencies were found. The AA genotype and the A allele of the rs2958182 polymorphic variant, as well as the A allele of the rs9636107 polymorphic variant, had an effect predisposing to the predominance of negative symptoms. The TT genotype and the T allele of the rs2958182 polymorphic variant, as well as the G allele of the rs9636107 polymorphic variant, were statistically significantly more common among patients with leading positive symptoms. As a result of the study, associations of the polymorphic variant TCF4 rs2958182 and TCF4 rs9636107 with the leading symptoms of schizophrenia were discovered for the first time in Caucasian populations of the Siberian region. The obtained data confirm the contribution of the genetic component to the formation of clinical heterogeneity of schizophrenia and open up prospects for further search for genetic markers in order to prevent an unfavorable outcome of the disease. Full article

Purpose: Genetic polymorphisms within specific genes play a role in both the genetic predisposition to Major Depressive Disorder (MDD) and the variation observed in responses to antidepressant treatments. Pharmacogenetics examines how these polymorphisms affect medication response. This review highlights significant disparities in the pharmacogenetic influences on antidepressant response, with a focus on ethnic and sex-based differences. Methods: This review synthesizes findings from a comprehensive literature search conducted between 2000 and 2025. It utilized databases such as PubMed, Scopus, and Web of Science, using search terms including “pharmacogenetics”, “antidepressants”, “Major Depressive Disorder”, “CYP450”, “neuroplasticity”, and “genetic variations”. This review integrates pharmacogenetics with neurotransmitters and their transporters, neuroplasticity, growth factors, and the cytochrome P450 family, providing promising insights for personalized MDD treatment strategies. We analyzed and synthesized findings from over 50 relevant studies, focusing on those with a clear emphasis on genetic associations with antidepressant efficacy and adverse effects. Results: Pharmacogenetic analysis facilitates personalized antidepressant prescriptions by identifying key genetic variants that influence treatment outcomes. Specifically, variations in CYP2D6 and CYP2C19 can significantly impact drug metabolism and tolerability. A high percentage of patients with non-normal metabolizer phenotypes are predisposed to adverse drug reactions or ineffective responses. Furthermore, this review identifies significant ethnic and sex-based disparities in treatment response. For example, the L allele of the 5-HTTLPR polymorphism confers a higher likelihood of response and remission following SSRI treatment in white people compared to Asians. Additionally, in women, specific 5-HTTLPR polymorphisms have a more pronounced influence on mood and MDD pathophysiology, with a significant reduction in mood in response to tryptophan depletion. Conclusions: Integrating pharmacogenetic insights, encompassing genetic factors, neurotransmitter pathways, neuroplasticity, and the influence of ethnicity and sex, is crucial for developing personalized antidepressant treatment strategies. This will ultimately optimize patient recovery and minimize adverse effects. Full article