Genetic Profile Research Articles

Unraveling the Genetics of Shared Clinical and Serological Manifestations in Patients With Systemic Inflammatory Autoimmune Diseases.

Systemic inflammatory autoimmune diseases (SIADs) such as systemic lupus erythematosus (SLE), primary Sjögren disease (pSS), and idiopathic inflammatory myopathies (myositis) are complex conditions characterized by shared circulating autoantibodies and clinical manifestations, including skin rashes, among others. This study was aimed at elucidating the genetics underlying these common features. We performed targeted DNA sequencing of coding and regulatory regions from approximately 1,900 immune-related genes in a large cohort of 2,292 well-characterized Scandinavian patients with SIADs with SLE, pSS, and myositis as well as 1,252 controls. A gene-based functionally weighted genetic score for aggregate testing of all genetic variants, including rare variants, was complemented by in silico functional analyses and in vitro reporter experiments. Case-control association analysis detected known and potentially novel genetic loci in agreement with previous genetic and transcriptomics findings linked to the SIAD autoimmune background. Intriguingly, case-case comparisons between patient subgroups with and without specific autoantibodies revealed that the subgroups defined by antinuclear antibodies and anti-double-stranded DNA antibodies have unique genetic profiles reflecting their heterogeneity. When focusing on clinical features, we overall showed that dual-specificity phosphatase 1 (DUSP1) protective genetic variants lead to increased gene expression and potentially to anti-inflammatory effects on the SIAD-associated skin phenotype. This is consistent with recent genetic findings on eczema and with the previously reported down-regulation of the MAPK signaling-related gene DUSP1 in other skin disorders. Together, this suggests common molecular mechanisms potentially underlying overlapping clinical manifestations shared among different disorders and informs clinical heterogeneity, which could be translated to improve disease diagnostic and treatment, also in more generalized disease frameworks.

Abstract A023: Patient-Derived Organoid Cultures for Personalized Therapies and Targeted Drug Screening Applications

Abstract Patient-derived organoids (PDOs) have emerged as a powerful tool for modeling human cancers due to their ability to closely mirror in vivo architecture and preserve the genetic landscape of tumors. They offer a crucial platform for studying disease progression and treatment responses. In this study, we present a comprehensive characterization of a unique collection of PDO cultures derived from pancreatic ductal adenocarcinoma (PDAC), a particularly aggressive malignancy often diagnosed in advanced stages with limited treatment options and poor prognosis. Our investigation explores morphological and genetic profiling of 10 PDAC PDOs, specifically identifying distinct drug-response patterns. The morphological characteristics of these PDO cultures were investigated by microscopy, while the mutational status was acquired by panel sequencing. Subsequently, PDOs were treated with a panel of 10 inhibitors, either individually or in combination. The response to these treatments was assessed through live-cell imaging (Incucyte®) to capture and quantify changes in organoid morphology and endpoint measurements of cellular viability using a CellTiter-Glo® assay. Our detailed in vitro drug sensitivity testing revealed a remarkable diversity in the responses of the PDAC PDOs to different chemotherapeutic agents, including those currently under clinical trials. Of notable significance is the depth of understanding we have achieved, allowing us to establish potential correlations between PDO morphology, genetic mutations, and drug reactions. This finding provides a key insight into the complex interplay of these factors and their impact on treatment outcomes, offering valuable insights into understanding individual tumor subtypes' sensitivity or resistance to treatments. The PDOs exhibited a spectrum of cancer-associated mutations, including KRAS, TP53, SMAD4, CDKN2A, and ARID1A, reflecting the heterogeneity observed in PDAC patients. Morphologically, the organoids displayed various growth patterns, ranging from cystic and regular structures to filled or unfilled, granular, dark, and light membrane structures. Drug treatments underscored the diverse and unique drug-response profiles within the PDOs, with some demonstrating sensitivity to multiple treatments. In contrast, others exhibited resistance, highlighting the intricate nature of drug responses within this model. Overall, our findings emphasize the ability of PDAC organoids to faithfully capture the complexity and heterogeneity of the disease, making them promising platforms for guiding personalized oncology approaches. The diverse drug response profiles observed in PDOs advocate leveraging this model to develop precision medicine strategies tailored to patients' characteristics, ultimately paving the way for more effective and personalized treatment regimens in the fight against PDAC. Citation Format: Constanza Tapia Contreras, Günter Schneider, Denise Müller, Kimia Mirzakhani, Karly Conrads, Silke Kaulfuß, Tim Beißbarth, Gabriela Salinas, Nils Beyer, Sophia Reinländer, Ulrix Sax, Elisabeth Heßmann, Volker Ellenrieder, Philipp Ströbel, Michael Ghadimi. Patient-Derived Organoid Cultures for Personalized Therapies and Targeted Drug Screening Applications [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A023.

Spinocerebellar ataxia type 7: A case report

Introduction: Spinocerebellar ataxia type 7 is part of a rare group of neurodegenerative diseases, characterized by lesions in the brainstem, cerebellum, spinal cord, and retina, manifesting as motor disturbances associated with signs of pyramidal involvement and amaurosis. The dysfunction is caused by autosomal dominant genetic alterations, with disease severity and the age of symptom onset being directly linked to the patient’s genetic expression. Case Report: We present the case of a 24-year-old woman, previously healthy, who denied smoking, drinking alcohol, or taking any other drugs. She reported that approximately nine months, she had experienced a decline in dexterity for tasks requiring fine motor skills. She also exhibited impaired gait, frequent falls, and difficulties in performing basic activities of daily living (ADLs). On neurological examination, she presented with an ataxic and staggering gait, tremor during movement, dysmetria, dysdiadochokinesia, movement decomposition, dysarthria (scanning speech), dysphagia, dystasia, dysbasia, and nystagmus, all of which are indicative of cerebellar impairment. A genetic panel revealed the presence of 44 cytosine-adenine-guanine nucleotide repeat expansions on allele 2 of the ATXN7 gene, confirming the diagnosis of spinocerebellar ataxia type 7. Conclusion: In this case report, the diagnosis of spinocerebellar ataxia was established through a comprehensive assessment of the patient’s clinical history, neurological examination, imaging studies, and genetic profiling, all of which are essential for reaching a definitive diagnosis. The prognosis for this disease varies due to ongoing research into its pathophysiology. Furthermore, discussions within the scientific community regarding potential cures for this condition continue

Transcriptomic analysis unveils alterations in the genetic expression profile of tree peony (Paeonia suffruticosa Andrews) infected by Alternaria alternata

BackgroundBlack spot disease in tree peony caused by the fungal necrotroph A. alternata, is a primary limiting factor in the production of the tree peony. The intricate molecular mechanisms underlying the tree peony resistance to A. alternata have not been thoroughly investigated.ResultsThe present study utilized high-throughput RNA sequencing (RNA-seq) technology to conduct global expression profiling, revealing an intricate network of genes implicated in the interaction between tree peony and A. alternata. RNA-Seq libraries were constructed from leaf samples and high-throughput sequenced using the BGISEQ-500 sequencing platform. Six distinct libraries were characterized. M1, M2 and M3 were derived from leaves that had undergone mock inoculation, while I1, I2 and I3 originated from leaves that had been inoculated with the pathogen. A range of 10.22–11.80 gigabases (Gb) of clean bases were generated, comprising 68,131,232 − 78,633,602 clean bases and 56,677 − 68,996 Unigenes. A grand total of 99,721 Unigenes were acquired, boasting a mean length of 1,266 base pairs. All these 99,721 Unigenes were annotated in various databases, including NR (Non-Redundant, 61.99%), NT (Nucleotide, 45.50%), SwissProt (46.32%), KEGG (Kyoto Encyclopedia of Genes and Genomes, 49.33%), KOG (clusters of euKaryotic Orthologous Groups, 50.18%), Pfam (Protein family, 47.16%), and GO (Gene Ontology, 34.86%). In total, 66,641 (66.83%) Unigenes had matches in at least one database. By conducting a comparative transcriptome analysis of the mock- and A. alternata-infected sample libraries, we found differentially expressed genes (DEGs) that are related to phytohormone signalling, pathogen recognition, active oxygen generation, and circadian rhythm regulation. Furthermore, multiple different kinds of transcription factors were identified. The expression levels of 10 selected genes were validated employing qRT-PCR (quantitative real-time PCR) to confirm RNA-Seq data.ConclusionsA multitude of transcriptome sequences have been generated, thus offering a valuable genetic repository for further scholarly exploration on the immune mechanisms underlying the tree peony infected by A. alternata. While the expression of most DEGs increased, a few DEGs showed decreased expression.

Clinicopathological and genetic analysis of interstitial disease-like pulmonary intravascular large B cell lymphoma

Objective: To investigate the clinicopathological features and genetic mutation status of pulmonary intravascular large B cell lymphoma. Methods: The clinicopathological data of eight patients diagnosed with pulmonary intravascular large B cell lymphoma, from April 2018 to May 2023, were retrospectively analyzed. The genetic profile of six patients was detected via next-generation sequencing (NGS) and followed up. Results: All patients included one male and seven females, with a median age of 64 years (ranging from 45 to 66 years). Respiratory symptoms were the most common (7 cases), B symptoms in two cases, hemophagocytic syndrome in two cases. Multiple diffuse ground-glass opacities in both lungs were observed based on the high-resolution chest CT scan. Six cases of mild to moderate ventilation or diffusion dysfunction were observed based on the pulmonary function tests. Moreover, two cases of hypoxemia and two cases with type Ⅰ respiratory failure were recorded. The serum lactate dehydrogenase level increased (7/8), β2-MG level increased (2/8), neuron-specific enolase level increased (7/8), total number of peripheral blood lymphocytes decreased (7/8), and clinical stages were all stage Ⅳ. The neoplastic lymphoid cells were lodged in the lumina of venules and capillaries of the alveolar septum; the tumor cells were large, with prominent nucleoli and frequent mitotic figures. The malignant cells were detected in the extravascular surrounding lung tissue in all cases. The tumor cells expressed mature B cell-associated antigens CD20 and CD79a, and the vascular endothelial markers CD31 and CD34 showed that the tumor cells were filled in the blood vessels, infiltrated blood vessel walls, and perivascular areas. One case was germinal center-type, seven cases were non-germinal center-type, two cases were double-expressing lymphoma, and all cases were EBER-negative. Furthermore, the top five genes with mutation frequencies detected by NGS were MYD88 (5/6), PIM1 (5/6), CD79B (4/6), TCF3 (4/6), and TP53 (3/6). Of the eight cases, seven patients received R-CHOP-based chemotherapy, six cases had complete remission after chemotherapy, one case died, and one case was lost to follow-up. Conclusions: Pulmonary vascular large B cell lymphoma is rare, which shares similar patterns with interstitial lung disease on imaging. Transbronchial lung biopsy is an effective method to confirm the diagnosis. Immunochemotherapy with BTK inhibitors can provide a survival advantage for patients in the future based on molecular typing.

Advancing Cancer Care in Colombia: Results of the First In Situ Implementation of Comprehensive Genomic Profiling.

Comprehensive genomic profiling (CGP) identifies genetic alterations and patterns that are crucial for therapy selection and precise treatment development. In Colombia, limited access to CGP tests underscores the necessity of documenting the prevalence of treatable genetic alterations. This study aimed to describe the somatic genetic profile of specific cancer types in Colombian patients and assess its impact on treatment selection. A retrospective cohort study was conducted at Clínica Colsanitas S.A. from March 2023 to June 2024. Sequencing was performed on the NextSeq2000 platform with the TruSight Oncology 500 (TSO500) assay, which simultaneously evaluates 523 genes for DNA analysis and 55 for RNA; additionally, analyses were performed with the SOPHiA DDM software. The tumor mutational burden (TMB), microsatellite instability (MSI), and programmed cell death ligand 1 (PDL1) were assessed. Among 111 patients, 103 were evaluated, with gastrointestinal (27.93%), respiratory (13.51%), and central nervous system cancers (10.81%) being the most prevalent. TP53 (37%), KMT2C (28%), and KRAS (21%) were frequent mutations. Actionable findings were detected in 76.7% of cases, notably in digestive (20 patients) and lung cancers (8 patients). MSI was stable at 82.52% and high at 2.91%, whilst TMB was predominantly low (91.26%). The test has facilitated access to targeted therapies, improving clinical outcomes in Colombian patients. This profiling test is expected to increase opportunities for personalized medicine in Colombia.

Clinical and genetic profile of Chinese patients with indolent natural killer-cell lymphoproliferative disorder of the gastrointestinal tract

Indolent natural killer cell lymphoproliferative disorder of the gastrointestinal tract (iNKLPD-GI) is an uncommon, recently recognized lymphoid proliferation of mature NK cells primarily manifesting in the GI tract. Unlike NK/T lymphoma, iNKLPD-GI exhibits a rather indolent clinical course, underscoring the need for cautious management to prevent unnecessary interventions. However, clinical and molecular features of this entity have not been thoroughly understood. This study aimed to add more information to the current knowledge of this disease. Seven patients with iNKLPD-GI were included in our study. Clinical data included initial symptoms, endoscopic manifestations, pathological features, and therapies. Besides, next-generation sequencing was arranged to explore the underlying genetic mechanism of this disease. In our study, iNKLPD-GI in the urinary bladder was first identified. Edema of extremities (3, 42.8 %) was the most prevalent onset symptom which was reported for the first time. Pathological and immunohistological features were found to display the phenotype of NK cells. Unlike extranodal NK/T cell lymphoma, Epstein-Barr virus-encoded small RNA (EBER) were negative in all patients. Moreover, we found that two patients harbored JAK3 mutation. Apart from JAK3 K563_C565del previously reported in the literature, we discovered new JAK3 mutation sites. Other mutations including BRAF, KRAS, and SH2B3 were also identified. In conclusion, iNKLPD-GI was an indolent atypical NK-cell proliferation with diverse clinical characteristics. “Watch and wait” therapy was preferable to intense chemotherapy. Recurrent JAK3 mutation may be the underlying mechanism responsible for the neoplastic nature of the disease and may serve as a potential target for patients with severe symptoms.

Vitamin D in Primary Sjogren's Syndrome (pSS) and the Identification of Novel Single-Nucleotide Polymorphisms Involved in the Development of pSS-Associated Diseases.

Sjögren's syndrome (SS) is a chronic autoimmune disorder characterised by lymphocytic infiltration of the exocrine glands, which leads to dryness of the eyes and mouth; systemic manifestations such as arthritis, vasculitis, and interstitial lung disease; and increased risks of lymphoma and cardiovascular diseases. SS predominantly affects women, with a strong genetic component linked to sex chromosomes. Genome-wide association studies (GWASs) have identified numerous single-nucleotide polymorphisms (SNPs) associated with primary SS (pSS), revealing insights into its pathogenesis. The adaptive and innate immune systems are crucial to SS's development, with viral infections implicated as environmental triggers that exacerbate autoimmune responses in genetically susceptible individuals. Moreover, recent research has highlighted the role of vitamin D in modulating immune responses in pSS patients, suggesting its potential therapeutic implications. In this review, we focus on the recently identified SNPs in genes like OAS1, NUDT15, LINC00243, TNXB, and THBS1, which have been associated with increased risks of developing more severe symptoms and other diseases such as fatigue, lymphoma, neuromyelitis optica spectrum disorder (NMOSD), dry eye syndrome (DES), and adverse drug reactions. Future studies should focus on larger, multi-ethnic cohorts with standardised protocols to validate findings and identify new associations. Integrating genetic testing into clinical practise holds promise for improving SS management and treatment strategies, enabling personalised interventions based on comprehensive genetic profiles. By focusing on specific SNPs, vitamin D, and their implications, future research can lead to more effective and personalised approaches for managing pSS and its complications.

Identification of a "Blue Zone" in the Netherlands: A Genetic, Personal, Sociocultural, and Environmental Profile.

"Blue Zones" (BZs) are regions with exceptionally high numbers of longevous inhabitants. Several factors have been suggested to promote longevity in BZs, but the evidence generally does not meet scientific quality criteria. We aimed to characterize a municipality as a "relative BZ," satisfying 3 criteria: compared to other municipalities, more exceptionally longevous inhabitants, a higher life expectancy, and a more stable population. The population-based Longitudinal Aging Study Amsterdam has been ongoing since 1992 in 11 municipalities across the Netherlands with 3- or 4-yearly measurement waves. Using all available waves, we included 39 genetic, personal, sociocultural, and environmental characteristics. One municipality satisfied the 3 BZ criteria. In comparison with participants in other municipalities in the same province and other provinces in the Netherlands, BZ-participants more often had a polygenic risk score linked to longevity, smoked less, consumed less alcohol and more fruit, biked more minutes, did more often paid work, practiced singing more often, attached higher importance to religion, and lived in a more walkable and livable environment. In contrast, BZ-participants had a slower walking speed, more depressive symptoms, felt less purpose in life, had a larger waist circumference, walked and did sports less often, consumed less vegetables, and exchanged less instrumental support. Other indicators of their physical and mental health and social connectedness did not substantially differ from non-BZ-participants. Rather than clues to healthy aging, our findings suggest factors conducive to longevity regardless of impaired health.

Stochasticity in Dietary Restriction-Mediated Lifespan Outcomes in Drosophila.

Dietary restriction (DR) is widely considered to be one of the most potent approaches to extend healthy lifespan across various species, yet it has become increasingly apparent that DR-mediated longevity is influenced by biological and non-biological factors. We propose that current priorities in the field should include understanding the relative contributions of these factors to elucidate the mechanisms underlying the beneficial effects of DR. Our work conducted in two laboratories, represents an attempt to unify DR protocols in Drosophila and to investigate the stochastic effects of DR. Across 64 pairs of survival data (DR/ad libitum, or AL), we find that DR does not universally extend lifespan. Specifically, we observed that DR conferred a significant lifespan extension in only 26.7% (17/64) of pairs. Our pooled data show that the overall lifespan difference between DR and AL groups is statistically significant, but the median lifespan increase under DR (7.1%) is small. The effects of DR were overshadowed by stochastic factors and genotype. Future research efforts directed toward gaining a comprehensive understanding of DR-dependent mechanisms should focus on unraveling the interactions between genetic and environmental factors. This is essential for developing personalized healthspan-extending interventions and optimizing dietary recommendations for individual genetic profiles.

Genetic variants associated with response to anti-CGRP monoclonal antibody therapy in a chronic migraine Han Chinese population

BackgroundAnti-calcitonin gene-related peptide (CGRP) monoclonal antibodies have emerged as promising therapeutic options for the treatment of chronic migraine. However, treatment response varies considerably among individuals, suggesting a potential role for genetic factors. This study aimed to identify genetic variants affecting the efficacy of anti-CGRP monoclonal antibody therapy in chronic migraine among the Han Chinese population in Taiwan to enhance treatment precision and to understand the genetic architecture of migraine.MethodsWe conducted a quantitative trait locus (QTL) association study in patients with chronic migraines from a tertiary medical center in Taiwan using the Taiwan Precision Medicine Array Chip. The patients received fremanezumab or galcanezumab for at least 12 weeks. Treatment efficacy was assessed based on the improvement rate in monthly migraine days. Genetic variants were identified, and their associations with treatment efficacy were examined through quantitative trait loci analysis, linkage disequilibrium studies, and functional annotations using the Gene Ontology database.ResultsSix single nucleotide polymorphisms (SNPs) relative variants were significantly associated with anti-CGRP therapy response (p < 1 × 10− 7): rs116870564, rs75244870, rs56216870, rs12938101, rs74655790, and rs149540851. These variants are located in or near genes, including LRRC4C, ATAD2B, and OXR1, which are involved in neuronal development, DNA-dependent ATPase activity, and oxidation-reduction processes, respectively. The rs116870564 variant in LRRC4C showed the strongest association (β = -0.551, p = 6.65 × 10− 9). The functional impact of these variants is attributed to their regulatory effects on gene expression, which are influenced by intron splicing regulation, transcription factors, and changes in chromatin structure.ConclusionThe identification of key genetic markers associated with response to anti-CGRP therapy emphasizes the importance of genetic variability in treatment efficacy. This could lead to more personalized chronic migraine management strategies and tailored therapeutic approaches based on individual genetic profiles. Further research in larger, diverse populations is warranted to validate these findings and refine our understanding of the role of CGRP in chronic migraine pathophysiology.Trial registrationNot applicable.

Angiosarcoma of the breast gland: molecular genetic profile, diagnosis and treatment

Angiosarcoma of the breast gland: molecular genetic profile, diagnosis and treatment

Advancements and Challenges in Personalized Therapy for BRAF-Mutant Melanoma: A Comprehensive Review.

Over the past several decades, advancements in the treatment of BRAF-mutant melanoma have led to the development of BRAF inhibitors, BRAF/MEK inhibitor combinations, anti-PD-1 therapy, and anti-CTLA4 therapy. Although these therapies have shown substantial efficacy in clinical trials, their sustained effectiveness is often challenged by the tumor microenvironment, which is a highly heterogeneous and complex milieu of immunosuppressive cells that affect tumor progression. The era of personalized medicine holds substantial promise for the tailoring of treatments to individual genetic profiles. However, tumor heterogeneity and immune evasion mechanisms contribute to the resistance to immunotherapy. Despite these challenges, tumor-infiltrating lymphocyte (TIL) therapy, as exemplified by lifileucel, has demonstrated notable efficacy against BRAF V600-mutant melanoma. Additionally, early response biomarkers, such as COX-2 and MMP2, along with FDG-PET imaging, offer the potential to improve personalized immunotherapy by predicting patient responses and determining the optimal treatment duration. Future efforts should focus on reducing the T-cell harvesting periods and costs associated with TIL therapy to enhance efficiency and accessibility.

Virulence Genes Prevalence and Enterobacterial Repetitive Intergenic Consensus‐PCR Profiles of Goose‐Derived Campylobacter jejuni Isolates

ABSTRACTCampylobacter jejuni is a causative agent of gastroenteritis in humans worldwide, and wild and domestic poultry carry of this bacterium in their gastrointestinal tract. Molecular studies to determine the pathogenicity, origin, and epidemiological relationships among C. jejuni isolates from poultry such as chicken, turkey, and goose consumed as human food are important for public health and infection control. This study aimed to investigate the prevalence of virulence genes and Enterobacterial Repetitive Intergenic Consensus (ERIC‐PCR) based genotyping of C. jejuni isolates obtained from goose cloacal swab samples. For this purpose, PCR analysis of flaA, racR, dnaJ, pldA, cadF, cdtC, ciaB, cdtB, cdtA, virB11, and wlaN virulence genes and ERIC‐PCR analysis of 50 C. jejuni isolates were performed. The emerged genetic profiles and antimicrobial resistance genes regarding the isolates were interpreted with the existing multi‐drug resistance (MDR) findings. Virulence gene positivity was detected as 88%, 84%, 82%, 82%, 80%, 80%, 72%, 30%, and 18% for flaA, racR, dnaJ, pldA, cadF, cdtC, ciaB, cdtB, and cdtA, respectively. VirB11 and wlaN genes were not detected among the C. jejuni isolates. Virulence genes‐based genotyping revealed that the C. jejuni isolates exhibited 22 profiles (A–V). As a result of ERIC‐PCR analysis, the C. jejuni isolates showed heterogeneous distribution, exhibiting 14 different ERIC‐PCR profiles (Cluster I [Cl‐I]–Cluster XIV [Cl‐XIV]). The MDR positivity was detected in 7 (14%) of the C. jejuni isolates. Tetracycline and ciprofloxacin were the antibiotics most frequently included in the MDR profiles. There was no clear correlation between ERIC‐PCR profiles, virulence gene profiles, and MDR profiles. However, isolates with triple‐MDR resistant to ampicillin, tetracycline, and ciprofloxacin showed significant heterogeneity in both ERIC‐PCR profile and virulence gene‐based genetic profile, all of which were positive for ciaB and flaA genes. These results indicate that carriage of the C. jejuni isolates with high gene prevalence and MDR profiles by geese may pose a risk for Campylobacter infections in humans.

Genomic portraits of methicillin-resistant staphylococci (MRS) from food fish unveiled the genes associated with staphylococcal food poisoning (SFP), virulence and antimicrobial resistance

BackgroundCharacteristics of non-clinical strains of methicillin-resistant Staphylococcus aureus (MRSA) especially from fishery environment are poorly understood. This research, in addition to comprehensive characterisation, sought to delineate the genetic relatedness between the MRSA strains originating from clinical as well as non-clinical settings. Out of 39 methicillin-resistant staphylococcal isolates from 197 fish samples, 6 (Three each of methicillin-resistant S. haemolyticus (MRSH) and MRSA) with distinct resistance profiles were selected for whole-genome sequencing. Using respective bioinformatics tools, MRSA genomes were comprehensively characterized for resistome, virulomes, molecular epidemiology and phylogenetic analysis. Simultaneously, MRSH genomes were specifically examined to characterize antimicrobial resistance genes (ARGs), owing to the fact that MRSH is often recognized as a reservoir for resistance determinants.ResultsThree MRSA clones identified in this study include ST672-IVd/t13599 (sequence type-SCCmec type/spa type), ST88-V/t2526, and ST672-IVa/t1309. Though, the isolates were phenotypically vancomycin-sensitive, five of the six genomes carried vancomycin resistance genes including the VanT (VanG cluster) or VanY (VanM cluster). Among the three MRSA, only one harbored the gene encoding Panton-Valentine Leukocidin (PVL) toxin, while staphylococcal enterotoxin (SEs) genes such as sea and seb, associated with staphylococcal food poisoning were identified in two other MRSA. Genomes of MRSH carried a composite of type V staphylococcal cassette chromosome mec (SCCmec) elements (5C2 & 5). This finding may be explained by the inversion and recombination events that may facilitate the integration of type V elements to the SCC elements of S. aureus with a methicillin-susceptible phenotype. Phylogenetically, MRSA from a non-clinical setting displayed a considerable relatedness to that from clinical settings.ConclusionThis study highlights the genetic diversity and resistance profiles of MRSA and MRSH, with non-clinical MRSA showing notable relatedness to clinical strains. Future research should explore resistance gene transfer mechanisms and environmental reservoirs to better manage MRSA spread.

Genomic insights into mRNA COVID-19 vaccines efficacy: Linking genetic polymorphisms to waning immunity

ABSTRACT Genetic polymorphisms have been linked to the differential waning of vaccine-induced immunity against COVID-19 following vaccination. Despite this, evidence on the mechanisms behind this waning and its implications for vaccination policy remains limited. We hypothesize that specific gene variants may modulate the development of vaccine-initiated immunity, leading to impaired immune function. This study investigates genetic determinants influencing the sustainability of immunity post-mRNA vaccination through a genome-wide association study (GWAS). Utilizing a hospital-based, test negative case-control design, we enrolled 1,119 participants from the Taiwan Precision Medicine Initiative (TPMI) cohort, all of whom completed a full mRNA COVID-19 vaccination regimen and underwent PCR testing during the Omicron outbreak. Participants were classified into breakthrough and protected groups based on PCR results. Genetic samples were analyzed using SNP arrays with rigorous quality control. Cox regression identified significant single nucleotide polymorphisms (SNPs) associated with breakthrough infections, affecting 743 genes involved in processes such as antigenic protein translation, B cell activation, and T cell function. Key genes identified include CD247, TRPV1, MYH9, CCL16, and RPTOR, which are vital for immune responses. Polygenic risk score (PRS) analysis revealed that individuals with higher PRS are at greater risk of breakthrough infections post-vaccination, demonstrating a high predictability (AUC = 0.787) in validating population. This finding confirms the significant influence of genetic variations on the durability of immune responses and vaccine effectiveness. This study highlights the importance of considering genetic polymorphisms in evaluating vaccine-induced immunity and proposes potential personalized vaccination strategies by tailoring regimens to individual genetic profiles.

Genetics and Epigenetic in Mental Health

Genetics and epigenetics play critical roles in mental health, offering insights into the complex interplay between biological predisposition and environmental influences in the development and progression of mental disorders. Genetic studies have identified numerous risk loci associated with conditions such as schizophrenia, bipolar disorder, and depression, highlighting the polygenic nature of these illnesses. However, the presence of genetic risk factors alone does not fully account for the variability in disease onset, severity, or response to treatment. This gap is increasingly understood through the lens of epigenetics, which involves heritable changes in gene expression that do not alter the DNA sequence itself but are influenced by environmental factors, such as stress, diet, and exposure to toxins. Epigenetic mechanisms, including DNA methylation, histone modification, and non-coding RNAs, can modulate gene activity in response to external stimuli, leading to long-lasting effects on brain function and behavior. These processes are particularly important during critical periods of brain development, where epigenetic modifications can shape neural circuits involved in emotion regulation, cognition, and stress response. Emerging research suggests that the interaction between genetic predisposition and epigenetic changes contributes to the heterogeneity observed in mental health disorders, explaining why individuals with similar genetic risks can have different outcomes. Understanding these intricate genetic and epigenetic networks is essential for developing personalized therapeutic strategies, which could revolutionize the prevention, diagnosis, and treatment of mental health conditions. Advances in this field hold the promise of identifying biomarkers for early intervention and creating targeted interventions that consider an individual’s unique genetic and epigenetic profile, ultimately improving mental health outcomes on a global scale.

Genetic and Epigenetic Interactions Involved in Senescence of Stem Cells.

Cellular senescence is a permanent condition of cell cycle arrest caused by a progressive shortening of telomeres defined as replicative senescence. Stem cells may also undergo an accelerated senescence response known as premature senescence, distinct from telomere shortening, as a response to different stress agents. Various treatment protocols have been developed based on epigenetic changes in cells throughout senescence, using different drugs and antioxidants, senolytic vaccines, or the reprogramming of somatic senescent cells using Yamanaka factors. Even with all the recent advancements, it is still unknown how different epigenetic modifications interact with genetic profiles and how other factors such as microbiota physiological conditions, psychological states, and diet influence the interaction between genetic and epigenetic pathways. The aim of this review is to highlight the new epigenetic modifications that are involved in stem cell senescence. Here, we review recent senescence-related epigenetic alterations such as DNA methylation, chromatin remodeling, histone modification, RNA modification, and non-coding RNA regulation outlining new possible targets for the therapy of aging-related diseases. The advantages and disadvantages of the animal models used in the study of cellular senescence are also briefly presented.

Clinical and genetic features of Fanconi anemia associated with a variant of FANCA gene: Case report and literature review.

Fanconi anemia (FA) is a hereditary disease caused by mutations in the genes involved in the DNA damage repair pathway. The FANCA gene is the most commonly pathogenic gene, accounting for more than 60% of all causative genes. The clinical case is a 3-year-old boy showed mild anemia and scattered bleeding spots the size of a needle tip all over his body. Compound heterozygous mutation was identified in the FANCA gene in the FA case: c.1A > T from the father in exon 1; the deletion of chr16: 89857810-89858476 (exon13-14 del) from the mother; finally, the patient was diagnosed as Fanconi anemia. After diagnosis, the child received chemotherapy (Ara-C + Flu + Cy + ATG). Then, the hematopoietic stem cell transplantation and unrelated umbilical cord blood transfusion were performed. The child is recovering well and is in regular follow-up. The discovery of new mutations in the FANCA gene enriches the genetic profile of FA and helps clinicians to further understand this disease and guide genetic counseling and prenatal diagnosis. Whole-exome sequencing is a powerful tool for diagnosing FA.

Uncovering novel regulatory variants in carbohydrate metabolism: a comprehensive multi-omics study of glycemic traits in the Indian population.

Clinical biomarkers such as fasting glucose, HbA1c, and fasting insulin, which gauge glycemic status in the body, are highly influenced by diet. Indians are genetically predisposed to type 2 diabetes and their carbohydrate-centric diet further elevates the disease risk. Despite the combined influence of genetic and environmental risk factors, Indians have been inadequately explored in the studies of glycemic traits. Addressing this gap, we investigate the genetic architecture of glycemic traits at genome-wide level in 4927 Indians (without diabetes). Our analysis revealed numerous variants of sub-genome-wide significance, and their credibility was thoroughly assessed by integrating data from various levels. This identified key effector genes, ZNF470, DPP6, GXYLT2, PITPNM3, BEND7, and LORICRIN-PGLYRP3. While these genes were weakly linked with carbohydrate intake or glycemia earlier in other populations, our findings demonstrated a much stronger association in the Indian population. Associated genetic variants within these genes served as expression quantitative trait loci (eQTLs) in various gut tissues essential for digestion. Additionally, majority of these gut eQTLs functioned as methylation quantitative trait loci (meth-QTLs) observed in peripheral blood samples from 223 Indians, elucidating the underlying mechanism of their regulation of target gene expression. Specific co-localized eQTLs-meth-QTLs altered the binding affinity of transcription factors targeting crucial genes involved in glucose metabolism. Our study identifies previously unreported genetic variants that strongly influence the diet-glycemia relationship. These findings set the stage for future research into personalized lifestyle interventions integrating genetic insights with tailored dietary strategies to mitigate disease risk based on individual genetic profiles.