Frontiers in Genetics最新文献

Objective: To investigate the association of specific genetic polymorphisms (rs2371597 in STON2, rs11720822 in PDIA5, rs387907358 in WNT1, and rs77542162 in ABCA6) in a Saudi cohort of keratoconus (KC) patients compared to controls.

Methods: A retrospective case-control genetic association study was conducted. The study included 99 KC patients and 193 healthy controls. Genotyping was performed using real-time PCR with TaqMan assays. Associations between genetic polymorphisms and KC were assessed using various genetic models and binary logistic regression analysis.

Results: None of the tested polymorphisms showed an overall association with KC risk. Specifically, the rs2371597 polymorphism in STON2 did not demonstrate a significant association with KC risk across different genetic models. However, a gender-specific effect of rs2371597 was noted: in men, the C/G genotype was associated with a higher risk of KC, particularly in the dominant model, while no significant association was observed in women. Age and sex were identified as significant predictors of KC risk, but rs2371597 did not significantly affect KC risk in regression analysis.

Conclusion: Preliminary evidence suggests a gender-specific effect of the rs2371597 polymorphism in STON2, with an increased KC risk associated with C/G-C/C genotypes in men which was age-dependent. This result highlights the importance of considering population-specific genetic factors and the potential gender-specific effects on KC susceptibility. However, these findings need further validation with larger age- and sex-matched samples of diverse populations.

Taurine and indicine gray cattle represent relevant livestock resources in many countries of the world. A gray coat color and pigmented skin, which are common in most of the gray cattle breeds, have been demonstrated to confer better adaptation to solar radiation and thermal stresses. In a previous study adopting the F_ST-outlier approach with BayeScan v2.0, we identified differentially selected genomic regions in a set of gray cattle breeds, including the Podolica Italiana, and contrasted these findings with four non-gray cattle breeds. More supported signals were detected on bovine chromosomes (BTAs) 2, 4, 14, and 26 that encompassed more than fifty genes known to be directly or indirectly related to one or more steps in pigment biology. In the present study, we aimed to validate the previously observed signals using the same methodological approach on three new Podolica Italiana sample sets (N = 30 animals each). These animals were selected from the ANABIC genetic station during performance tests as being representative of the Podolica Italiana population at three different timeframes separated by approximately 10 years each. We typed these samples to the loci of 23,027 quality-controlled single-nucleotide polymorphisms. We also analyzed the dataset using the haplotype-based approach available in hapFLK v1.4 software. Both the F_ST-outlier and hapFLK approaches validated the abovementioned signals on BTAs 2, 4, 14, and 26. Moreover, both methods detected additional supported regions on BTAs 7 and 18 that included a total of 42 genes, of which most were already known from literature to be implicated in pigmentation traits.

Background: Ulcerative colitis has a serious impact on the quality of life of patients and is more likely to progress to colon cancer. Therefore, early diagnosis and timely intervention are of considerable importance.

Methods: Gene expression data of active ulcerative colitis were downloaded from the Gene Expression Omnibus (GEO) database, and genes with significant differential expression were identified. Biochemical markers with diagnostic significance were selected through machine learning methods. The expression differences of the selected markers between colon adenocarcinoma (COAD) and healthy control groups in The Cancer Genome Atlas (TCGA) database were analyzed to evaluate their diagnostic value. In addition, the correlation between the selected markers and clinical indicators, as well as their predictive efficacy for the survival of COAD patients, was explored.

Results: Through machine learning and LASSO regression analysis, UGT2A3 was finally determined as a diagnostic marker for ulcerative colitis. It demonstrated high diagnostic accuracy in both the training set and the external validation set. Furthermore, UGT2A3 was significantly downregulated in COAD tissues compared to normal control tissues. The ROC curve suggested that UGT2A3 could serve as a diagnostic marker for COAD with excellent performance, achieving an AUC of 0.969. Immune infiltration analysis indicated a significant negative correlation between the expression of UGT2A3 and neutrophils. Correlation analysis suggested a link between UGT2A3 and the pathological classification of colon cancer. Survival analysis showed that UGT2A3 is negatively correlated with OS, PPS, and RFS in colon cancer.

Conclusion: The author identified UGT2A3 as a diagnostic marker for ulcerative colitis through bioinformatics methods, and verified its significant downregulation in colon cancer, as well as its predictive role in the survival of COAD patients. These findings suggest that UGT2A3 may serve not only as a diagnostic marker for ulcerative colitis and colon cancer but also as a potential prognostic indicator for colon cancer.

Manul (Otocolobus manul) is the only representative of the genus Otocolobus, which makes up the Leopard Cat lineage along with the genus Prionailurus. Their habitat is characterized by harsh environmental conditions. Although their populations are probably more stable than previously thought, it is still the case that their population size is declining. Conservation programs exist to protect manuls, but those based on captive breeding are often unsuccessful due to their increased susceptibility to diseases. The manul is therefore a suitable model species for evolutionary and diversity studies as well as for studying mechanisms of adaptation to harsh environment and mechanisms of susceptibility to diseases. Recently, the genome of the O. manul based on nanopore long-range sequencing has been published. Aiming to better understand inter- and intraspecific variation of the species, we obtained information on genome sequences of four other manuls, based on whole genome resequencing via the Illumina platform. On average, we detected a total of 3,636,571 polymorphic variants. Information on different types of structural variants and on the extent of SNP homozygosity, not available from the reference genome, was retrieved. The average whole-genome heterozygosity was almost identical to that found in the O. manul reference genome. In this context, we performed a more detailed analysis of the candidate gene EPAS1 potentially related to adaptation to the hypoxic environment. This analysis revealed both inter- and intraspecific variation, confirmed the presence of a previously described non-synonymous substitution in exon 15 unique to manuls and identified three additional unique non-synonymous substitutions located in so far not analyzed EPAS1 exonic sequences. The analysis of lncRNA located in the intron 7 of EPAS1 revealed interspecific variability and monomorphic nature of the sequence among analyzed manuls. The data obtained will allow more detailed analyses of the manul genome, focusing on genes and pathways involved in their adaptation to the environment and in susceptibility to diseases. This information can be helpful for optimizing conservation programs for this understudied species.

Drought is a persistent and serious threat to crop yield and quality. The identification and functional characterization of drought tolerance-related genes is thus vital for efforts to support the genetic improvement of drought-tolerant crops. Barley is highly adaptable and renowned for its robust stress resistance, making it an ideal subject for efforts to explore genes related to drought tolerance. In this study, two barley materials with different drought tolerance were subjected to soil drought treatment, including a variety with strong drought tolerance (Hindmarsh) and a genotype with weaker drought tolerance (XZ5). Transcriptomic sequencing data from the aboveground parts of these plants led to the identification of 1,206 differentially expressed genes associated with drought tolerance. These genes were upregulated in Hindmarsh following drought stress exposure but downregulated or unchanged in XZ5 under these same conditions, or were unchanged in Hindmarsh but downregulated in XZ5. Pathway enrichment analyses suggested that these genes are most closely associated with defense responses, signal recognition, photosynthesis, and the biosynthesis of various secondary metabolites. Using protein-protein interaction networks, the ankyrin repeat domain-containing protein 17-like isoform X2 was predicted to impact other drought tolerance-related protein targets in Hindmarsh. In MapMan metabolic pathway analyses, genes found to be associated with the maintenance of drought tolerance in Hindmarsh under adverse conditions were predicted to include genes involved in the abscisic acid, cytokinin, and gibberellin phytohormone signaling pathways, genes associated with redox homeostasis related to ascorbate and glutathione S-transferase, transporters including ABC and AAAP, transcription factors such as AP2/ERF and bHLH, the heat shock proteins HSP60 and HSP70, and the sucrose non-fermenting-1-related protein kinase. Heterologous HvSnRK2 (one of the identified genes, which encodes the sucrose non-fermenting-1-related protein kinase) gene expression in yeast conferred significant drought tolerance, highlighting the functional importance of this gene as one linked with drought tolerance. This study revealed the drought tolerance mechanism of Hindmarsh by comparing transcriptomes while also providing a set of candidate genes for genetic efforts to improve drought tolerance in this and other crop species.

Objective: This study evaluated the real-world efficacy and safety of combining PARP inhibitors with novel hormonal therapy (NHT) as a first-line treatment in Chinese patients with metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene mutations.

Methods: We enrolled 41 mCRPC patients who received at least 1 month of combined treatment with PARP inhibitors and NHT. Patients were divided into two groups: Cohort A (mutations in BRCA1, BRCA2, or ATM genes) and Cohort B (mutations in other HRR genes). The primary endpoint was imaging-based progression-free survival (PFS), with secondary endpoints including objective response rate (ORR), disease control rate (DCR), overall survival (OS), PSA50 response, and adverse events (AEs). To ensure accurate research results and control confounding factors, we will employ multivariate Cox proportional hazards models to evaluate key variables affecting mCRPC patient survival outcomes.

Results: This study enrolled 41 patients, 22 in Cohort A and 19 in Cohort B. The median PFS for all patients was 21.8 months, and the median OS had yet to be reached. The overall ORR was 48.8%, and the DCR was 61.0%. Specifically, the median PFS for Cohort A was 21.8 months compared to 14.5 months for Cohort B. The median OS had yet to be reached for either cohort. Regarding efficacy, 81.8% of patients in Cohort A and 73.7% in Cohort B achieved a PSA50 response. Imaging assessments showed ORRs of 54.6% for Cohort A and 42.1% for Cohort B, with DCRs of 72.7% and 47.4%, respectively. 85.4% of patients experienced grade 1 or 2 adverse events, and 51.2% encountered grade 3 or 4. In the multivariate Cox regression analysis focusing on PFS, the Gleason score was identified as a significant predictor (HR = 5.8, 95% CI: 1.65-20.2, p = 0.006).

Conclusion: Combined first-line treatment with PARP inhibitors and NHT is effective and well-tolerated in mCRPC patients with HRR gene mutations, particularly those with BRCA1, BRCA2, or ATM mutations. These findings underscore the potential of this therapeutic combination in managing mCRPC in the Chinese population, suggesting a favorable outcome for those with specific genetic backgrounds.

Myotonia congenita, both in a dominant (Thomsen disease) and recessive form (Becker disease), is caused by molecular defects in CLCN1 that encodes the major skeletal muscle chloride channel, ClC-1. This channel is important for the normal repolarization of muscle action potentials and consequent relaxation of the muscle, and its dysfunction leads to impaired muscle relaxation after voluntary or evoked contraction and muscle stiffness. More than 300 CLCN1 pathogenic variants have been found in association with congenital myotonia, inherited as recessive or dominant traits (with complete or incomplete penetrance). In this study, we describe the case of a 44-year-old woman complaining of "leg stiffness" since the age of 20 years and presenting with transient muscle weakness, especially after sitting for several minutes, with grip myotonia and feet myotonia, cold-sensitive and warm-up. The strength was normal, but muscle hypertrophy in the lower limbs was evident. EMG myotonia was detected in all explored muscles. The patient's father had precocious cataract correction but did not show myotonic discharges at EMG. Examination of the patient's sons (aged 18 years and 12 years) was unremarkable. The patient started treatment with mexiletine, with improvement in grip myotonia and limb stiffness, but it was soon interrupted due to gastrointestinal disturbances. Direct sequencing of CLCN1 identified the previously described heterozygous intronic variant c.1471 + 1G > A, which resulted in the skipping of exon 13 in the CLCN1 muscle transcript. In addition, the rare heterozygous synonymous nucleotide change c.762C > T p.Cys254Cys was identified and predicted to alter physiological splicing. The detection of multiple splicing abnormalities leading to premature termination codons supported the in silico prediction. We developed a Western blot assay to assess the ClC-1 protein in muscle biopsy, and we observed that ClC-1 levels were consistently reduced in the patient's muscle, supporting the pathogenic behavior of the variants disclosed. Overall, we report a novel case of Becker myotonia and highlight the importance of multiple levels of analysis to achieve a firm molecular diagnosis.

Background: Numerous observational studies have shown a potential association between metabolic dysfunction-associated steatotic liver disease (MASLD) and gastroesophageal reflux disease (GERD). However, causality is unclear. This study utilized genome-wide association study (GWAS) genetic data to explore the causal relationship between MASLD and GERD in European and East Asian populations.

Methods: This study utilized a bidirectional, two-sample Mendelian randomization (MR) approach. All disease data were obtained from the GWAS database, and single nucleotide polymorphisms strongly associated with exposure were selected as instrumental variables. The inverse variance weighted (IVW) method is primarily utilized to evaluate the causal relationship between exposure and outcome. Finally, sensitivity analyses were performed to ensure the robustness of the results.

Results: The IVW estimates indicated that non-alcoholic fatty liver disease (NAFLD) (odds ratio (OR) = 1.054, 95% confidence interval (CI), 0.966-1.150, p = 0.236) and percent liver fat (OR = 0.977, 95% CI, 0.937-1.018, p = 0.258) in European population were not linked to a higher risk of GERD. However, GERD in European population was associated with an increased risk of NAFLD (OR = 1.485, 95% CI, 1.274-1.729, p < 0.001) and percent liver fat (OR = 1.244, 95% CI, 1.171-1.321, p < 0.001). In addition, the IVW analysis in East Asian population showed that alanine aminotransferase (ALT) was associated with an increased risk of GERD (OR = 2.305, 95% CI, 1.241-4.281, p = 0.008), whereas aspartate aminotransferase (AST) had no causal effects on GERD risk (OR = 0.973, 95% CI, 0.541-1.749, p = 0.926). Furthermore, the associations between GERD and ALT (OR = 1.007, 95% CI, 0.998-1.015, p = 0.123) or AST (OR = 1.004, 95% CI, 0.997-1.012, p = 0.246) were not significant. After removing outliers, a significant correlation between GERD and ALT was observed (OR = 1.009, 95% CI, 1.001-1.016, p = 0.020).

Conclusion: There was reverse causality between MASLD and GERD in European population, while there was bidirectional causality between a proxie for MASLD (ALT) and GERD in East Asian population. This study can provide novel insights into cross-ethnic genetic research on MASLD and GERD.

Background: Cutaneous melanoma, characterized by the malignant proliferation of melanocytes, exhibits high invasiveness and metastatic potential. Thus, identifying novel prognostic biomarkers and therapeutic targets is essential.

Methods: We utilized single-cell RNA sequencing data (GSE215120) from the Gene Expression Omnibus (GEO) database, preprocessing it with the Seurat package. Dimensionality reduction and clustering were executed through Principal Component Analysis (PCA) and Uniform Manifold Approximation and Projection (UMAP). Cell types were annotated based on known marker genes, and the AUCell algorithm assessed the enrichment of deubiquitination-related genes. Cells were categorized into DUB_high and DUB_low groups based on AUCell scores, followed by differential expression analysis. Importantly, we constructed a robust prognostic model utilizing various genes, which was evaluated in the TCGA cohort and an external validation cohort.

Results: Our prognostic model, developed using Random Survival Forest (RSF) and Ridge Regression methods, demonstrated excellent predictive performance, evidenced by high C-index and AUC values across multiple cohorts. Furthermore, analyses of immune cell infiltration and tumor microenvironment scores revealed significant differences in immune cell distribution and microenvironment characteristics between high-risk and low-risk groups. Functional experiments indicated that TBC1D16 significantly impacts the migration and proliferation of melanoma cells.

Conclusion: This study highlights the critical role of deubiquitination in melanoma and presents a novel prognostic model that effectively stratifies patient risk. The model's strong predictive ability enhances clinical decision-making and provides a framework for future studies on the therapeutic potential of deubiquitination mechanisms in melanoma progression. Further validation and exploration of this model's applicability in clinical settings are warranted.

Recessively inherited limb-girdle muscular dystrophy type 1, caused by mutations in the calpain 3 gene, is the most common limb-girdle muscular dystrophy worldwide. Recently, cases of autosomal dominant calpainopathy have been described. A man was referred to our neurological outpatient clinic at the age of 54 for persistent hyperCKemia (>1000 U/l) associated with muscle fatigue and myalgia. Clinical examination revealed mild proximal weakness in the lower limbs. His brother exhibited a moderate increase in serum creatine kinase levels (up to 2000 U/l) without other signs of myopathy. Their father experienced slowly progressive lower limb weakness after the age of 50. The calpain 3 variant c.1478G>A (p.Arg493Gln) in the heterozygous state was identified in both brothers. In silico modeling studies predict that this substitution may disrupt protein folding. This represents the first description of the heterozygous p.Arg493Gln calpain 3 variant as a potential cause of mild calpainopathy.