Genetics research最新文献

Arthritis is a genetic disorder characterized by bones and joint degradation assisted by severe pain and inflammation. It is evident by the studies that 0 candidate genes variations play vital role in its development and progression. Therefore, we investigated the genetic variation of TLR-8, TNF, and ESR-1α genes in the Pakistani population. A case-control study comprising 300 RA, 316 OA, and 412 control subjects was conducted. PCR-RFLP and direct sequencing methods were used for determining genetic variations. Analysis was performed by using PLINK and MEGA 6.0 software. Allelic and genetic frequencies of polymorphisms identified on rs3764879 (TLR-8), rs3764880 (TLR-8), rs5744080 (TLR-8), rs1800629 (TNF), rs2228480 (ESR-1α), and rs1451501590 (ESR-1α) were significantly varied among RA, OA, and controls. Novel functional mutations SCV000844945 and SCV000844946 on TLR-8 as well as a non-functional SCV000804801 and functional variation SCV000804802 on ESR-1α were also identified and reported for the first time in the studied population. Multiple site analyses indicated that polymorphisms on TLR-8 and ESR-1α genes were significant risk factors in disease onset to the next generation. In conclusion, TLR-08 and ESR-1α were significant in the onset of arthritis whereas the TNF was not found as a significant risk factor in the onset of RA and OA.

Wilms tumor (WT) is the most common genitourinary renal tumor that typically occurs in children under 15 and is thought to be linked to somatic and germline mutations. However, the specific functional role of competing endogenous RNAs (ceRNAs) and their potential implications in WT remain unclear. In this study, we developed an lncRNA-mediated (long noncoding RNA-mediated) ceRNA network via the R packages for WT with expression data obtained from the tumor alterations relevant for genomics-driven therapy (TARGET) database. Unsupervised hierarchical clustering analysis revealed that the WT specimens could be clearly distinguished from healthy specimens with respect to the expression of disordered RNAs. A total of 1,607 differentially expressed (DE) lncRNAs, 116 DE microRNAs (DEmiRNAs), and 3,262 DE messenger RNAs (DEmRNAs) were identified as WT-specific RNAs, and a lncRNA-miRNA-mRNA ceRNA network with 159 DElncRNAs, 18 DEmiRNAs, 131 DEmRNAs, and 792 interactions was constructed. According to the clinical survival data, 12 DElncRNAs, 5 DEmRNAs, and 2 DEmiRNAs were selected from the ceRNA network that could significantly impact the overall survival of WT patients (P < 0.05). Functional enrichment analysis showed that the biological processes and pathways of DEmRNAs, such as cell cycle and virus infection, may be associated with WT. The present study constructed a dysregulated lncRNA-mediated ceRNA network in WT and discovered that lncRNA-mediated ceRNAs may serve as important regulators in WT development and progression. Survival-associated RNAs may serve as new potential biomarkers, suggesting that the constructed ceRNA network in WT might be important for determining optimal therapeutic strategies.

Methylmalonic acidemia (MMA) is an autosomal recessive metabolic disorder mainly caused by mutations in the methylmalonyl coenzyme A mutase (MCM) gene (MMUT) and leads to the reduced activity of MCM. In this study, a 3-year-old girl was diagnosed with carnitine deficiency secondary to methylmalonic acidemia by tandem mass spectrometry (MS/MS) and gas chromatography/mass spectrometry (GS/MS). Whole-exome sequencing (WES) was performed on the patient and identified two compound heterozygous mutations in MMUT: c.554C>T (p. S185F) and c.729-730insTT (p. D244Lfs ^∗ 39). Bioinformatics analysis predicted that the rare missense mutation of c.554C>T would be damaging. Moreover, this rare mutation resulted in the reduced levels of MMUT mRNA and MMUT protein. Collectively, our findings provide a greater understanding of the effects of MMUT variants and will facilitate the diagnosis and treatment of patients with MMA.

Introduction: Efavirenz is an antihuman immunodeficiency virus (HIV) drug metabolized by cytochrome P450 2B6 (CYP2B6) enzyme. Cytochrome P450 2B6 is an enzyme that in humans is encoded by the CYP2B6 gene. Polymorphisms of this gene play a crucial role in the metabolism of drugs such as Efavirenz. This study aims to evaluate the frequency of three clinically significant CYP2B6 polymorphisms (CYP2B6 ^∗ 6 (516G > T), CYP2B6 ^∗ 4 (785A > G), and CYP2B6 ^∗ 5 (1459C > T)) in three major Iranian ethnicities.

Methods: One hundred forty-seven participants from three main Iranian ethnicities were included in this study. After DNA extraction, CYP2B6 ^∗ 6 (516G > T), CYP2B6 ^∗ 4 (785A > G), and CYP2B6 ^∗ 5 (1459C > T) were genotyped using tetra-primer amplification refractory mutation system polymerase chain reaction (ARMS-PCR).

Results: The frequency of the mutated allele in the Iranian population for CYP2B6 ^∗ 6 (516G > T) was 41.50 (95% CI: 35.81, 47.36), which was significantly lower than in Kurds (59.62, 95% CI: 45.10, 72.99). Similarly, Kurds had a higher frequency of mutated allele of CYP2B6 ^∗ 5 (1459C > T) (46.15%, 95% CI: 32.23, 60.53) than in Iranians (24.49%, 95% CI: 19.68, 29.82). The frequency of A and G alleles of CYP2B6 ^∗ 4 (785A > G) was 62.59% (95% CI: 56.78, 68.13) and 37.41 (95% CI: 31.87, 43.22), respectively.

Conclusion: Kurds are at higher risk of adverse drug reactions (ADRs) and insufficient anti-HIV response compared to other Iranians.

Object. β-Elemene is an emerging antitumor Chinese medicine, but the exact mechanism of action of β-elemene in colorectal cancer (CRC) remains unclear. This study aimed to explore the mechanism of the lncRNA-miRNA-mRNA network in the process of β-elemene inhibiting CRC. Methods. RNA sequencing was performed on CRC cells from the control group (untreated) and the case group (β-elemene-treated). According to the sequencing data, we screened the differentially expressed (DE) lncRNAs, miRNAs, and mRNAs and then analyzed them by functional enrichment analyses. Through the lncRNA-miRNA-mRNA network, the key miRNAs and mRNAs involved in the process of β-elemene inhibiting CRC were further identified. Results. Totally, 607 upregulated and 599 downregulated DElncRNAs, 12 downregulated and 24 upregulated DEmiRNAs, and 3153 downregulated and 3248 upregulated DEmRNAs were identified. Through the lncRNA-miRNA-mRNA network, 3 miRNAs (miR-7109-3p, miR-4506, and miR-3182), 7 prognostic mRNAs (ALPG, DTX1, HOXD13, RIMS3, SLC16A8, SYT1, and TNNT1), and 2 key mRNAs (RIMS3 and SLC16A8) were determined to participate in the inhibitory mechanism of β-elemene in CRC. Conclusion. This study revealed for the first time that the lncRNA-miRNA-mRNA network is involved in the regulation of β-elemene in CRC, and these identified miRNAs and mRNAs could be new clinical prognostic biomarkers and therapeutic targets for CRC patients.

We aimed to explore the mechanism of the linoleic acid metabolism in metabolic syndrome (MetS). RNA-seq data for 16 samples with or without MetS from the GSE145412 dataset were collected. Gene set variation analysis (GSVA), gene set enrichment analysis (GSEA), and gene differential expression analysis were performed. Expression data of differentially expressed genes (DEGs) involved in the linoleic acid metabolism pathway were mapped to the pathway by using Pathview for visualization. There were 19 and 10 differentially expressed biological processes in the disease group and healthy group, respectively. 9 KEGG pathways were differentially expressed in the disease group. Linoleic acid metabolism was the only differentially expressed pathway in the healthy group. The GSVA enrichment score of the linoleic acid metabolism pathway in the disease group was markedly lower than that in the healthy group. The GSEA result showed that the linoleic acid metabolism pathway was significantly downregulated in the disease group. JMJD7-PLA2G4B, PLA2G1B, PLA2G2D, CYP2C8, and CYP2J2 involved in the pathway were significantly downregulated in the disease group. This study may provide novel insight into MetS from the point of linoleic acid metabolism dysregulation.

Backgrounds: Retinol-binding protein 4 (RBP4) is a monomeric-binding protein belonging to the lipocalin protein family, which has been reported to be dysregulated in several malignancies such as breast cancer and lung cancer. However, the expression and function of RBP4 in glioblastoma (GBM) are completely unknown.

Materials and methods: TCGA datasets were used for analyzing the mRNA level of RBP4 in GBM and its clinical relevance. A retrospective GBM cohort (n = 73) was enrolled from our hospital to test the protein expression profile of RBP4 in GBM tissues as well as its correlation with patients' prognoses. Two human GBM cell lines, LN229 and U251, were collected to conduct overexpression and knockdown experiments targeting RBP4. The tumor-related effects of RBP4 in GBM were finally evaluated by proliferation and invasion assays.

Results: Both the higher mRNA level and protein level of RBP4 in GBM tissues were significantly correlated with poorer patients' overall survival. Multivariate analysis identified RBP4 as a novel independent prognostic predictor in GBM patients. Overexpression of RBP4 resulted in enhanced GBM proliferation capacity, which was consistent with clinical findings on the positive correlation between RBP4 level and tumor size. Meanwhile, overexpressing RBP4 promoted GBM cell migration and invasion, while silencing RBP4 led to the opposite results.

Conclusions: RBP4 overexpression in tumor tissues is correlated with poorer prognosis of GBM patients, which functions by promoting GBM proliferation and invasion, thus, may serve as an invaluable predictive biomarker and therapeutic target.

Objective: The current study aimed to compare the characteristics of chromosome abnormalities detected by conventional G-banding karyotyping, chromosome microarray analysis (CMA), or fluorescence in situ hybridization (FISH)/CNVplex analysis and further explore the application value of combined karyotype analysis and CMA in prenatal diagnosis with a larger sample size.

Methods: From March 2019 to March 2021, 3710 amniocentesis samples were retrospectively collected from women who accepted prenatal diagnosis at 16 to 22 + 6 weeks of pregnancy. The pregnant women underwent karyotype analysis and CMA. In the case of fetal chromosomal mosaicism, FISH or CNVplex analysis was utilized for validation.

Results: In total, 3710 G-banding karyotype results and CMA results from invasive prenatal diagnosis were collected. Of these, 201 (5.41%) fetuses with an abnormal karyotype were observed. The CMA analysis showed that the abnormality rate was 9.14% (340/3710). The detection rate of CMA combined with karyotype analysis was 0.35% higher than that of CMA alone and 4.08% higher than that of karyotyping alone. Additionally, 12 cases had abnormal karyotype analysis, despite normal CMA results. To further detect the chromosome mosaicism, we used FISH analysis to correct the karyotype results of case 1. Correspondingly, a total of 157 cases showed abnormal CMA results but normal karyotype analysis. We also found chromosomal mosaicism in 4 cases using CMA. Moreover, CNVplex and CMA demonstrated that representative case 15 was mosaicism for trisomy 2.

Conclusions: Conventional G-banding karyotyping and CMA have their own advantages and limitations. A combination of karyotype analysis and CMA can increase the detection rate of chromosome abnormalities and make up for the limitation of signal detection.

The clinical significance and potential targets of miR-150-5p have not been elucidated in nasopharyngeal carcinoma (NPC). The pooled analysis based on 539 NPC samples and 75 non-NPC nasopharyngeal samples demonstrated that the expression of miR-150-5p was down-regulated in NPC, with the area under the curve being 0.89 and the standardized mean difference being -0.66. Subsequently, we further screened the differentially expressed genes (DEGs) of 14 datasets, including 312 NPC samples and 70 non-NPC nasopharyngeal samples. After the DEGs were narrowed down with the predicted targets from the miRWalk database, 1316 prospective target genes of miR-150-5p were identified. The enrichment analysis suggested that "pathways in cancer" was the most significant pathway. Finally, six hub genes of "pathways in cancer", including EGFR, TP53, HRAS, CCND1, CDH1, and FGF2, were screened out through the STRING database. In conclusion, the down-regulation of miR-150-5p modulates the tumorigenesis and progression of NPC.

Background: Glioblastoma (GBM) is a highly prevalent brain tumor characterized by high rates of morbidity, recurrence, and mortality. While temozolomide (TMZ) is commonly used as a first-line treatment for this cancer, the emergence of TMZ resistance limits its utility. The long noncoding RNA HOXA-AS2 reportedly drives GBM progression, but whether it can influence therapeutic resistance to TMZ has yet to be established.

Methods: HOXA-AS2 expression was analyzed in TMZ-resistant and sensitive GBM tissue samples and cell lines by qPCR. A siRNA-based approach was used to knock down HOXA-AS2 in GBM cells, after which TMZ resistance was tested. Bioinformatics approaches were used to predict miRNA binding targets of HOXA-AS2, after which a series of luciferase reporter assay and rescue experiments with appropriate miRNA inhibitor/mimic constructs were performed to validate these predictions and to clarify the ability of HOXA-AS2 to regulate chemoresistant activity.

Results: TMZ-resistant GBM patients and cell lines exhibited increased HOXA-AS2 expression that was correlated with worse overall survival. Knocking down HOXA-AS2 increased the sensitivity of resistant GBM cells to TMZ. miR-302a-3p was identified as a HOXA-AS2 target confirmed through luciferase reporter assays and rescue experiments, and IGF1 was further identified as a confirmed miR-302a-3p target. In addition, HOXA-AS2 knockdown resulted in a corresponding drop in IGF1 expression consistent with indirect regulation mediated by miR-302a-3p.

Conclusion: In summary, these results highlight the role of HOXA-AS2 as a driver of TMZ resistance in GBM through its ability to regulate the miR-302a-3p/IGF1 signaling axis, highlighting this pathway as a promising target for the diagnosis, therapeutic sensitization, and/or treatment of affected patients.