Polycystic ovarian syndrome (PCOS) is a common endocrine disorder and the leading cause of anovulatory infertility in women of reproductive age. Changes in the pulsatility of hypothalamic gonadotropin-releasing hormone (GnRH) have been linked to the pathophysiology of PCOS. Kisspeptin, a neuropeptide encoded by the KISS1 gene, plays a crucial role in regulating GnRH secretion and has emerged as a potential factor contributing to reproductive dysfunction associated with PCOS. This review aims to evaluate the association between KISS1 gene polymorphisms and hormone profiles in women with PCOS across different populations. A comprehensive literature search was conducted to identify original studies examining KISS1 gene variants and kisspeptin levels in patients with PCOS. Eligible articles were selected based on predefined inclusion criteria.The analysis identified several KISS1 polymorphisms—most notably rs4889 C>G, rs372790354 G>A, rs12998 G>A, and rs587777844—associated with PCOS susceptibility, hormonal dysregulation (including elevated luteinizing hormone, testosterone, and altered LH/FSH ratios), and metabolic markers. Among these, rs4889 was the most frequently studied variant, reported across multiple populations, including Saudi Arabia, Iraq, Sri Lanka, and China. Population-specific differences were noted in the distribution and significance of individual SNPs, suggesting possible ethnic variation in genetic risk. Kisspeptin levels were also variably associated with reproductive hormones such as Anti-Müllerian Hormone and estradiol, but less consistently with metabolic markers like insulin and HOMA-IR. KISS1 gene polymorphisms, particularly rs4889, may contribute to the complex, multifactorial etiology of PCOS through their regulatory effects on reproductive hormones. Further large-scale, phenotype-stratified, and functionally validated studies are warranted to confirm these associations and explore their clinical utility in the diagnosis and management of PCOS.
Abstract Background Breast cancer susceptibility is shaped by regulatory variation that may act in a subtype-dependent manner, yet miRNA polymorphisms, particularly those in the out-seed region that can modulate non-canonical target pairing, remain underexplored in Vietnamese populations. Methods A pathway-informed case–control study was conducted with 50 breast cancer patients and 50 non-cancer controls to evaluate 23 single-nucleotide polymorphisms located in miRNA out-seed regions. These SNPs were predicted in-silico to target key genes within the WNT/β-catenin and NOTCH signaling networks. SNPs were genotyped using a custom-targeted panel NGS approach. Associations with breast cancer risk were assessed using logistic regression with codominant, dominant, recessive, over-dominant, and log-additive models, reporting both unadjusted and age-adjusted odds ratios, along with 95% confidence intervals. Results Three SNPs showed nominal associations with breast cancer or breast cancer subtypes: rs10061133 (hsa-miR-449b-5p; predicted target DLL1), rs404337 (hsa-miR-8084; predicted target NOTCH1), and rs2986407 (hsa-miR-1343-5p; predicted target CSNK1A1). In the overall analysis, rs10061133 was associated with breast cancer risk before age adjustment (dominant model OR = 2.47, p = 0.026; over-dominant model OR = 2.25, p = 0.044), although this effect was attenuated after age adjustment. In exploratory subtype analyses, rs10061133 remained significant after age adjustment in HER2-positive, Ki-67-positive, and HR+HER2 + cases. rs404337 showed over-dominant associations in ER-negative, PR-negative, and HER2-positive subgroups, whereas rs2986407 was associated with PR-negative breast cancer only after age adjustment. Conclusions These findings suggest that miRNA out-seed variants, rs10061133, rs404337, and rs2986407, predicted to regulate WNT/NOTCH pathway nodes may contribute to breast cancer susceptibility in a subtype-dependent manner. However, replication in a larger population and functional validation of allele-specific miRNA–target interactions are warranted.
Abstract Background Maternal clinical characteristics studies and the potential outcome of pregnancy depict a strong influence on newborn telomere genetics and the immune system. This study aims to evaluate the association between maternal clinical and anthropometric factors with newborn telomere length (TL) and immune senescence. Materials and methods This cross-sectional study recruited 204 mother–newborn dyads from Ziauddin Hospitals after taking the informed consent. Blood was collected following delivery from mothers and the cord while it was still attached. Demographic, anthropometric and clinical data were recorded on structured questionnaires from mothers or medical records. The relative TL was quantified by QPCR and immune senescence markers (CD57, KLRG1) by flow cytometry. For statistical analysis, a p-value < 0.05 was considered significant. Results The maternal clinical characteristics showed significant associations with newborn TL. Newborn TL varied across BMI groups, with longer TL (2.67 + 1.46) ( p = 0.048), observed in the 25-29.9 group, and the expression of CD67 and KLRG1 (8.31 ± 4.57) was found to be highest in obese mothers ( p = 0.002). Increasing maternal hemoglobin (Hb) levels were associated with newborn TL, showing longer TL (2.53 ± 1.70) ( p = 0.041) in mothers with Hb > 12 g/dl and single parity (2.50 ± 2.75) ( p = 0.025). Newborn gender was also found to influence TL length, girls had significantly longer TL (2.45 ± 1.46) but decreased CD57, KLRG1 (6.76 ± 4.45) difference was statistically significant ( p = 0.017). Conclusions Maternal BMI, hemoglobin levels, and parity reflect a dynamic interaction that significantly influences newborn telomere length and immune senescence. Male newborns exhibited higher immune senescence marker expression, indicating sex-specific differences during early biological aging.
Immune checkpoint (ICP) and epithelial-mesenchymal transition (EMT) pathways are key biological processes implicated in the progression of esophageal squamous cell carcinoma (ESCC). However, their transcriptional interplay and interactions with the tumor immune microenvironment remain incompletely characterized. Transcriptomic, somatic mutation, and clinical data from TCGA-ESCC (n = 95) were analyzed using a predefined hypothesis-driven gene panel comprising five ICP genes (PDCD1, CD274, CTLA-4, HAVCR2, LAG-3) and two EMT markers (TWIST1, MMP13). Immune cell infiltration was estimated using multiple computational deconvolution algorithms. Tumor mutational burden (TMB), ESTIMATE, and TIDE scores were assessed as exploratory immune-related metrics. Findings were validated in an independent microarray cohort (GSE53624). ICP and EMT genes formed distinct yet partially overlapping expression modules. HAVCR2 demonstrated the strongest and most consistent association with EMT-related signatures across datasets. Elevated expression of most ICP genes and MMP13 was associated with poorer overall survival, whereas TWIST1 exhibited dataset-dependent prognostic behavior. ICP-high tumors were characterized by features of an immunologically active yet regulatory-enriched microenvironment, while EMT-related genes were linked to fibroblast- and stroma-dominant profiles. Advanced-stage tumors displayed concurrent immune activation and immune evasion signals. TMB was low overall and tended to decreased across stages, with no significant prognostic association. These findings delineate context-dependent transcriptional interactions between ICP and EMT pathways in ESCC and highlight the complexity of the tumor immune microenvironment beyond single-parameter biomarkers such as TMB. All associations are exploratory and hypothesis-generating, requiring mechanistic and prospective validation prior to translational application.
Abstract Background Isolated Methylmalonic acidaemia (MMA) is a rare inherited metabolic disorder. Nutritional intervention for MMA patients includes dietary restriction of proteins along with medical food and dietary supplements. Decreased bone mineral density (BMD) is a widely accepted complication of protein restricted diet and accumulation of acids and toxic metabolites. Aim of the study To assess bone health in patients with isolated MMA and investigate the contributing factors. Patients and methods The study included all patients biochemically confirmed with isolated MMA above the age of 5 years. Clinical, dietary, and biochemical data were systematically collected. Patient compliance was assessed using author-derived score. Bone mineral density (BMD) was evaluated using dual-energy X-ray absorptiometry (DXA). Bone formation was assessed using serum osteocalcin level, while bone resorption was evaluated using carboxy-terminal telopeptide of collagen type 1 (S-CTX) in addition to selected other bone health laboratory parameters. Results The study included 24 patients. A history of fractures was present in 5 patients (20.83%). Decreased total body BMD was found in 14 patients (54.5 %) with a mean Z score of -1.31 ± 1.38 SD. Decreased spine BMD was present in 21 patients (79.16%) with a mean Z score of -1.9 ± 1.1 SD. This decrease was significantly related to non-compliance, chronic acidosis, disease severity, and low serum copper. There was no significant relation between BMD and creatinine, calcium, vitamin D, zinc, selenium, osteocalcin, or S-CTX levels. Conclusion Isolated MMA patients have defective bone formation and increased bone resorption manifested by decreased BMD and related to poor compliance, chronic acidosis, disease severity and copper deficiency.
Abstract Diabesotension refers to the pathophysiological association between diabetes mellitus, obesity, and hypertension. Despite their frequent coexistence, the underlying molecular mechanisms driving this triad remain poorly understood, and current therapeutic strategies typically address each condition in isolation rather than targeting their shared pathophysiological pathways. To identify potential hallmark genes underlying diabesotension, we mined gene associations with the triad from the NCBI database. Our analysis revealed that AKT1 and NF-κB1 are implicated in four major hallmarks of diabesotension, such as insulin resistance, inflammation, neurohormonal regulation, and oxidative stress. Collectively, these findings highlight the PI3K/Akt and NF-κB pathways as potential molecular drivers in the pathogenesis of diabesotension. This commentary will provide a comprehensive discussion of these findings within the broader context of current knowledge on the role of PI3K/Akt and NF-κB signaling in diabesotension.
Abstract Background Diabetes mellitus is still a major global health concern, and current treatments mostly target glycemic control rather than the underlying loss of β-cells that produce insulin. Type 2 diabetes is characterized by insulin resistance and β-cell depletion, whereas type 1 diabetes is caused by autoimmune-mediated β-cell death. Exogenous insulin, oral medications, and lifestyle changes are examples of conventional treatments that reduce hyperglycemia without restoring endogenous β-cell function. Although stem cell-based treatments and islet transplantation have promise, their use is constrained by safety issues, immunological rejection, and donor availability. In this regard, CRISPR-Cas9 gene-editing technology has become a revolutionary instrument that can precisely reprogramme, regenerate, and shield βcells. Main body Main Body CRISPR-Cas9 enables targeted genetic alterations that promote β-cell growth, reprogram pancreatic cells into insulin-secreting cells, and shield regenerated β-cells from immune attack According to preclinical research, α-cells can be transformed into β-like cells and βcell replication can be accelerated by interfering with negative cell cycle regulators. In autoimmune conditions, immune-evasive tactics like upregulating protective molecules may guarantee the long-term survival of regenerated cells. Insulin production has been restored with controllable safety profiles thanks to early therapeutic uses, such as ex vivo alteration of patient-derived progenitors. CRISPR addresses the underlying cause of diabetes by facilitating long-lasting β-cell regeneration, setting it apart from traditional medications and transplantation. Off-target editing, immunological reactions to Cas proteins, transport obstacles, exorbitant expenses, and ethical issues are still problems. But developments in AIguided design, high-fidelity nucleases, and nanoparticle delivery are gradually improving safety and effectiveness, advancing CRISPR-based treatments into clinical application. Conclusion The management of diabetes has met an emerging early translational promise changing the horizons of treatment from symptomatic treatment to disease modification thanks to CRISPR-Cas9-mediated β-cell regeneration. Early evidence points to the possibility of therapeutic therapies that restore endogenous insulin production and lessen treatment dependence for the remainder of one’s life, despite the fact that there are still many obstacles to overcome. Transforming this promising technology into a broadly accessible treatment will require sustained innovation, thorough safety assessment, and fair access measures.
Abstract Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary cerebral small-vessel disease, typically with adult-onset. It is most often caused by NOTCH3 mutations that involve cysteine residues. Cases of CADASIL type 1 with cysteine-sparing mutations presenting with seizures are rarely reported. Case presentation A 66-year-old Chinese Han woman was admitted for two episodes of focal to bilateral tonic-clonic seizures, as documented by interictal video electroencephalogram (VEEG). Brain magnetic resonance imaging (MRI) showed severe white matter hyperintensity (WMH) sparing the temporal lobes and lacunar infarcts in the basal ganglia. She had a 31-year history of cognitive impairment, a 26-year history of headaches, and a six-month history of gait disturbance. Whole exome sequencing (WES) identified a heterozygous NOTCH3 c.1715 C > T (p. Pro572Leu) mutation on exon 11, which, despite being a variant of uncertain significance (VUS) in ClinVar, is suggested to be pathogenic by in silico tools and family co-segregation, supporting the diagnosis of CADASIL type 1. Her affected son carried the same mutation, while her two daughters did not. The proband improved with valproate, aspirin, atorvastatin, and donepezil. Conclusions This report is the first to comprehensively describe a CADASIL type 1 patient with cysteine-sparing Pro572Leu mutation presenting with focal to bilateral tonic-clonic seizures.
Abstract Background Osteoprotegerin (OPG) is a protein that prevents excessive bone resorption by binding to its receptor, and its genetic variations may contribute to the development of cardiovascular disorders. Methods Eighty-two beta-thalassemia major patients of Sorour medical center of Mashhad, Iran who were older than 11 years old enrolled for the study. Two dimensional and M-mode echocardiography analysis were done in all patients. Sequencing for OPG rs2073617 (950T > C), rs2073618 (1181G > C)] polymorphisms was done using the Sanger method. Serum OPG levels estimated by ELISA. Results Mean age of patients was 23.62 ± 6.92 years. LVH and diastolic dysfunction were present in 34 (41.5%) and 36 (43.9%) patients, respectively. Thalassemia patients carrying the OPG rs2073617 and rs2073618 polymorphisms exhibited an increased risk of left ventricular hypertrophy (LVH) and diastolic dysfunction, as reflected by higher odds ratios. Specifically, for rs2073617, the CC genotype was associated with a markedly elevated risk (OR: 4.51). Moreover, serum OPG levels were significantly higher in patients with LVH and diastolic dysfunction, with odds ratios of 1.64 and 1.58, respectively (P < 0.001), highlighting a strong association between elevated OPG and cardiac abnormalities in these patients. Conclusion OPG rs2073617, rs2073618 SNPs may predispose LVH and diastolic dysfunction in thalassemia patients. Patients with LVH and diastolic dysfunction showed increased levels of serum OPG.
Abstract Background Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by metabolic and reproductive disturbances. Genetic factors contribute to its pathogenesis, with polymorphisms in various genes being implicated. This study investigates the association of the rs16901946 A/G polymorphism within the PRNCR1 gene with PCOS among women in Zahedan city. Methods A case-control study was conducted involving 150 confirmed PCOS patients and 150 healthy controls from Zahedan. Genomic DNA was extracted from peripheral blood samples, and genotyping for the rs16901946 A/G polymorphism was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Statistical analyses were conducted to compare allele frequencies and genotype distributions between the two groups, adjusting for potential confounders. Results The results indicate that individuals with PCOS have significantly higher mean levels of BMI, WC, FBS, TC, and TG, whereas HDL levels are notably lower, with all differences having p-values < 0.001. However, age and LDL levels did not show significant differences between the groups. Additionally, analysis of the PRNCR1 gene polymorphism revealed significant associations with PCOS risk. Specifically, the heterozygous codominant model (p = 0.039), indicating a 2.10-fold increased risk. The homozygous codominant model had a stronger association with an OR of 5.29 (p = 0.027). In the dominant model the OR was 2.49 (p = 0.009), and in the recessive model, the OR was 4.81 (p = 0.042). Finally, the allelic model yielded an OR of 2.61 (p = 0.002). Conclusion The findings of this study suggest a significant association between the rs16901946 A/G polymorphism in the PRNCR1 gene and the susceptibility to PCOS in the Zahedan population. These results underscore the importance of genetic factors in the etiology of PCOS and may provide insights for future research and personalized treatment approaches.
Abstract Background Hypodontia, the congenital absence of one or more teeth, is influenced by genetic factors, including variations in the Axis inhibition protein 2 (AXIN2) gene. The rs7224837 A/G in AXIN2 has been implicated in tooth development, but its precise role remains unclear. This study aimed to investigate the association between rs7224837 A/G and hypodontia in a case-control design. Methods and Materials A total of 96 participants (41 hypodontia cases and 55 healthy controls) were genotyped for rs7224837 A/G using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Allelic and genotypic frequencies were compared between groups using chi-square tests. Results Multivariable analysis with Bonferroni correction (P < 0.01) revealed that the G allele of AXIN2 rs7224837 was significantly associated with reduced risk of hypodontia under allelic (OR = 0.25; 95% CI: 0.11–0.58; P = 0.001) and dominant models (OR = 0.25; 95% CI: 0.08–0.59; P = 0.008), suggesting a protective role for this variant. Conclusion This study demonstrates that the G allele of rs7224837 A/G may play a protective role against hypodontia, supporting the involvement of genetic variations in tooth agenesis.
Abstract Background Chronic kidney disease (CKD) is influenced by genetic and environmental factors. ACE I/D and CYP11B2 polymorphism have been associated with kidney disease, though their impact varies across studies. This study aimed to investigate the association of the ACE I/D and CYP11B2 -344T/C polymorphisms with susceptibility to CKD. Methods This case-control study included 200 CKD patients and 180 control subjects. Genotyping for ACE I/D and CYP11B2 polymorphism was performed by the Polymerase Chain Reaction and RFLP method, and allele and genotype frequencies were analysed using the chi-square test. In silico analysis was conducted using the AliBaba2.1 tool to assess the effect of ACE I/D and CYP11B2 polymorphism on transcription factor binding to DNA target sequences. Results No significant association was observed between the ACE DD genotype and CKD after adjustment for comorbidities, diet, and addiction [adjusted odds ratio (AOR) = 0.915, 95% confidence interval (CI) = 0.372–2.251, p = 0.847]. The CYP11B2 -344T/C CT genotype [AOR = 0.329, 95% CI = 0.148–0.732, p = 0.006] and dominant model (CT + CC) [AOR = 0.425, 95% CI = 0.211–0.854, p = 0.016] showed a significant association with CKD. Furthermore, ACE I/D but not CYP11B2 -344T/C polymorphism was significantly associated with variation in serum urea, creatinine, phosphorus, and eGFR levels in CKD patients (p < 0.05). In silico analysis predicted potential loss of transcription factor binding sites in the D allele of ACE I/D and the C allele of CYP11B2-344T/C. Conclusions The findings suggest that the CYP11B2 -344T/C but not the ACE I/D polymorphisms may modulate susceptibility to CKD. The in silico analysis predicted allele-specific transcription factor binding alterations, implying regulatory functional relevance, warranting functional validation.
Abstract Background Hepatocellular carcinoma (HCC) remains one of the most lethal malignancies worldwide, with survival improvements lagging behind other solid tumors. Its molecular heterogeneity and complex signaling architecture continue to limit the success of targeted therapies. To address this challenge, we applied an integrated transcriptomic and systems biology framework to identify key oncogenic drivers, characterize their functional roles, and evaluate their potential as druggable therapeutic targets. Methods Gene expression data from the GEO dataset GSE101685 were processed using R/Bioconductor pipelines with MAS5.0 normalization. Differentially expressed genes (DEGs) were identified using the limma package with adjusted p < 0.05 and |log₂FC|≥ 1.5. Protein–protein interaction (PPI) networks were reconstructed via STRING and analyzed in Cytoscape to identify hub genes using multiple centrality metrics. Network clustering was performed with the Louvain algorithm. Functional annotation and pathway enrichment were conducted using Enrichr. Clinical significance was assessed through GEPIA and Human Protein Atlas survival data. Druggability of top hub genes was examined using DGIdb, Pharos, and PockDrug. Results We identified 5562 DEGs, including 748 upregulated genes. Centrality analysis revealed 106 hub genes, with AURKA, AURKB, TOP2A, PLK1, CDC6, CCNA2, CDC20, CCNB1, CDK1, BUB1, CDC45, and KIF23 emerging as top candidates. These genes were strongly enriched in pathways involved in cell cycle regulation, p53 signaling, DNA replication, and cellular senescence. Survival analyses demonstrated consistently poorer outcomes among patients with high expression of these genes. Druggability assessment highlighted several promising targets, and computational predictions suggested previously underexplored druggable pockets for CDC6, CDC20, and CDC45. Conclusion Our integrated systems analysis identifies a focused panel of druggable hub genes that may serve as promising therapeutic targets in HCC, providing a foundation for future experimental validation and rational drug design.
Abstract Background/aim Given that phosphorylation/dephosphorylation of many important proteins at tyrosine residues play a vital role in various cellular functions, it can be inferred that protein tyrosine phosphatase enzymes, including the protein tyrosine phosphatase non-receptor type 13 (PTPN13), are involved in numerous critical cellular processes. PTPN13 influences several signaling pathways and biological activities, suggesting a potential role in carcinogenesis. This study aimed to select the most relevant PTPN13 polymorphism using “polymorphism selection index” (PSI) and investigate its association with gastric (GC) and colorectal (CRC) cancer risk. Methods Missense polymorphisms with minor allele frequency ≥ 0.01 were retrieved and PSI was calculated for each. We conducted two case-control studies in an Iranian population (197 CRC/215 controls; 150 GC/230 controls). Genotyping was carried out by PCR-RFLP. Associations with cancer risk were assessed using odds ratios (ORs) and 95% confidence intervals (CIs). Results Among seven missense polymorphisms, rs989902 (T > G, Y2081D) had the highest PSI and was selected. Consequently, we focused on investigating the association between this polymorphism and the risk of CRC and GC. The GG genotype was found to increase the risk of both cancers (for CRC: OR = 2.36, 95% CI = 1.18–4.69, p = 0.014; for GC: OR = 2.14, 95% CI = 1.06–4.31, p = 0.033). Conclusion This study demonstrates that the rs989902 is significantly associated with the risk of CRC and GC in an additive manner. Furthermore, the cancer risk elevated with an increasing number of combined risk factors, including the rs989902-GG genotype, smoking, and family history of cancer, highlighting the importance of this genetic variant in the etiology of these malignancies.
Abstract Parkinson’s disease (PD) is a complex neurodegenerative disorder with a substantial genetic component. Over the past decade, genome-wide association studies (GWAS) have identified numerous loci associated with PD risk; however, interpretation of these findings and their broader applicability remain challenging. In this systematic review, we synthesize results from 35 GWAS published between 2015 and 2025, encompassing diverse study designs and ancestries. Recurrent risk loci, including SNCA, LRRK2, MAPT, and GBA1, were consistently replicated across multiple studies, while several ancestry-specific associations were reported, particularly in East Asian and African ancestry cohorts. Nevertheless, representation of African, South Asian, and Latino populations remains limited, constraining the global generalizability of current findings. We also discuss methodological extensions beyond single-variant GWAS, including rare variant analyses, polygenic risk scores, and machine learning–based approaches, which have been applied to complement traditional analyses but remain primarily research tools due to limited validation and interpretability. Together, this review outlines the current genetic landscape of PD and identifies key methodological and population-based gaps that must be addressed to support robust and equitable translation of GWAS discoveries.
Abstract Background Ghosal hematodiaphyseal dysplasia (GHDD) is a rare hypoplastic anemia characterized increased bone density in the long bones with predominant diaphyseal involvement and a regenerative corticosteroid-sensitive anemia due to bone marrow fibrosis. It follows an autosomal recessive inheritance pattern and is caused by mutations in the TBXAS1 gene. Case presentation: Reporting a case of 18-month-old male with severe anemia, and thrombocytopenia, without any skeletal deformities ultimately diagnosed with GHDD. Bone marrow biopsy revealed reticulin fibrosis, and whole exome sequencing identified biallelic mutations in TBXAS1. The patient was successfully treated with oral prednisolone, leading to improved hemoglobin, platelet counts and overall general wellbeing. Conclusion: Refractory anemia with bone marrow fibrosis should prompt pediatricians to investigate for inherited bony dysplasia. Early molecular diagnosis and treatment significantly improve outcomes in GHDD. This case uniquely demonstrates the diagnosis of GHDD at a pre-radiographic stage, highlighting the critical role of early molecular testing before the development of characteristic skeletal changes.
Abstract The intersection of genetics and epigenetics offers a profound framework for understanding complex behavioral phenotypes, including major depressive disorder (MDD), schizophrenia, addiction, and post-traumatic stress disorder (PTSD). While the global scientific community has mapped significant epigenetic markers associated with behavior, population-specific data remains crucial due to genetic heterogeneity. The Iranian population presents a unique genetic landscape characterized by high rates of consanguinity and distinct allelic frequencies in neuroregulatory genes such as BDNF, COMT, and 5-HTTLPR. This review synthesizes the interaction between this specific genetic background and epigenetic modifications triggered by environmental stressors such as war-related trauma providing a deeper understanding of the onset and heritability of these disorders. We highlight the potential role of homozygosity in amplifying epigenetic susceptibility and discuss the necessity for local “epigenome-wide association studies” (EWAS) to develop precision medicine (Nat Rev Genet 24(11):712–725, 2023, Methods Mol Biol 2745:187–212, 2024).
Abstract Background Methicillin-resistant Staphylococcus aureus (MRSA) is a significant clinical problem, the principal resistance determinant of which is the mecA gene. This paper uses extensive bioinformatics resources to determine Methicillin resistance gene A (mecA) on the various levels such as sequence analysis, phylogenetic reconstruction, prediction of protein structure and molecular docking. Methods We identified and used National Center for Biotechnology Information, GenBank, Clustal Omega, MEGA X, SWISS-MODEL, and AutoDock Vina to retrieve and analyze twenty-five mecA sequences in various strains of MRSA. Results Findings showed a high level of sequence conservation (97.2–99.8% identity) to the presence of absolutely conserved catalytic residues (Ser403, Lys406, Thr600). Phylogenetic studies confirmed that mecA was spread by horizontal gene transfer using Staphylococcal Cassette Chromosome mec (SCCmec) traveling elements. PBP2a was shown to have a constricted active site that was identified through three-dimensional modeling, which causes low beta-lactam affinity. Phenotypic resistance was described by the use of molecular docking indicating a weak binding of methicillin to PBP2a (-4.2 kcal/mol) in comparison to the native Penicillin-binding protein 2 (PBP2) (-7.5 kcal/mol). The functional analysis has determined that there are three domains and new motifs of PBP2a. Comparative analysis of SCCmec showed the presence of fourteen types (I-XIV) having different sizes and resistance genes. Conclusions These results offer a molecular understanding of resistance to methicillin and can be used as a guide to develop novel anti-MRSA drugs with potential therapeutic targets.
Abstract Background Poor ovarian response (POR) is a major clinical challenge in assisted reproductive technologies (ART), characterized by suboptimal response to ovarian stimulation. While age and environmental factors contribute to POR, genetic determinants, especially within regulatory regions of key reproductive genes, remain underexplored. Objective This study aimed to investigate the association between single-nucleotide polymorphisms (SNPs) in the 3′-untranslated regions (3′-UTRs) of GATA4 and WT1 genes and POR, and to assess their spatial and demographic distribution using advanced computational and spatial genetics methods. Methods A total of 100 Iranian women undergoing IVF (50 POR and 50 controls) were genotyped for selected SNPs in GATA4 and WT1. Logistic regression, Factor Analysis of Mixed Data (FAMD), redundancy analysis (RDA), canonical correspondence analysis (CCA), and spatial principal component analysis (sPCA) were used to explore associations between SNPs, demographic factors, and geographic variables. Global linkage disequilibrium (LD)-based SNP data from diverse populations were also analyzed to assess population differentiation and geographic structuring. All analyses were performed after bootstrapping to ensure robust results. Results SNP8 (rs3203358) in the 3′-UTR of GATA4 showed a significant association with POR, with individuals carrying the CG genotype having a substantially elevated risk (OR = 37.4, p = 0.0018). FAMD highlighted the number of oocytes, age, and weight as key demographic differentiators. RDA, CCA, and sPCA revealed significant spatial structuring of POR-associated SNPs across Iranian regions (p = 0.001), and similar patterns were observed in global populations for SNPs linked to GATA4 and WT1. Several SNPs showed strong linkage to latitude and longitude, supporting both global and local genetic differentiation. An isolation-by-distance pattern (p = 0.01) was detected, while Moran’s I was non-significant (p = 0.95), indicating limited fine-scale autocorrelation. Given the modest sample size and exploratory nature of the analysis, findings were interpreted cautiously. Conclusions This study identifies SNP8 as a potential genetic marker for poor ovarian response and shows that its distribution varies across geographic and demographic contexts. By integrating spatial analyses with genetic and clinical data, we demonstrate that regional heterogeneity may contribute to differences in ovarian response. These findings support the value of incorporating spatially informed genetic assessments into fertility planning to improve the precision of risk prediction and personalize ovarian stimulation strategies.
