BMC Medical Genomics最新文献

Ischemic stroke (IS) represents a harmful neurological disorder with limited treatment options. Ferroptosis accounts for the iron-dependent, nonapoptotic cell death pattern, which shows the feature of fatal lipid ROS accumulation. Nonetheless, ferroptosis-related biomarkers for identifying IS early are currently lacking. The present study focused on investigating the possible ferroptosis-related biomarkers for IS and analyzing their effects on immune infiltration. Altogether five hub differentially expressed ferroptosis-related genes (DEFRGs) were identified from the relevant databases. Additionally, single-cell RNA-sequencing (seq) analysis was conducted for the comprehensive mapping of cell populations based on the IS database. These five hub DEFRGs were analyzed using gene set enrichment analysis, miRNA prediction, and single-cell RNA-seq analysis. A transient middle cerebral artery occlusion mouse model was constructed. We also adopted bioinformatics methods combined with western blot, changes to mitochondria, hematoxylin & eosin staining, Nissl staining, ROS fluorescence staining, immunohistochemistry, and quantitative real-time polymerase chain reaction (qRT-PCR) to show the involvement of ferroptosis in IS progression. The results revealed that nuclear factor erythroid-derived 2-like 2 (Nfe2l2) was the potential candidate biomarker for IS diagnosis, and ferroptosis may be suppressed via the Nfe2l2/HO-1 pathway. Thus, drug targeting Nfe2l2 can shed novel lights on IS treatment.

Background: This study aims to investigate the differences in postoperative prognosis associated with the single nucleotide polymorphism (SNP) rs2228226 (G > C) in gastric adenocarcinoma (GAC) patients.

Methods: This study enrolled 661 patients with locally advanced (pT4a) GAC after surgery. DNA was extracted from their tissues and genotyped for rs2228226 using a MassARRAY Analyzer. Based on the patients' clinical and pathological information, a multifactorial Cox regression analysis was performed to assess the correlation between rs2228226 and the clinical prognosis of pT4a GAC patients. Survival differences among patients who received postoperative chemotherapy were also examined according to rs2228226.

Results: After excluding patients with distant metastasis, loss to follow-up, and those not meeting the inclusion criteria, a total of 463 patients with complete data were included. The rs2228226 genotype distribution was as follows: C/C = 57 (12.3%), G/C = 200 (43.2%), and G/G = 206 (44.5%). Patients with the C/C genotype had significantly shorter disease-free survival (DFS = 12 months) and overall survival (OS = 27 months) compared to those with the G/C or G/G genotype (DFS = 19 months, log-rank P = 0.003; OS = 35 months, log-rank P = 0.002). Further analysis of patients receiving chemotherapy identified the C/C genotype, advanced age, lymph node metastasis, degree of differentiation, and failure to achieve R0 resection as independent risk factors for tumor recurrence and metastasis (P < 0.05). The C/C genotype, lymph node metastasis, and tumor recurrence and metastasis were independent risk factors for mortality (P < 0.05).

Conclusions: In pT4a GAC patients undergoing postoperative chemotherapy, the C/C genotype at rs2228226 is an independent risk factor for tumor recurrence, metastasis, and death. The rs2228226 (G > C) polymorphism may serve as a potential biomarker for predicting prognosis after chemotherapy in GAC.

Background: This study aims to investigate the association between candidate host genetic polymorphisms and COVID-19 susceptibility, severity, hospitalization, hypoxia, and their combined effect, measured by the polygenic risk score (PRS).

Methods: Three hundred and seventy-six Lebanese participants, comprising 151 controls and 225 cases, were included. Clinical data were obtained from questionnaires and medical records. DNA isolated from peripheral blood was genotyped for ACE1 rs1799752, ACE2 rs2074192, TMPRSS2 rs75603675 and OAS1 rs107746771 using TaqMan assays, and for TMPRSS2 rs35074065 using Sanger Sequencing. Candidate genetic variants were analyzed in association with COVID-19 susceptibility, severity, hospitalization and hypoxia, using univariate and multivariate models. PRS constructed from the weighted sum of variants was evaluated in association with COVID-19 outcomes.

Results: In this study, there were no statistically significant differences in the frequencies of candidate variant alleles between cases, controls and within disease outcomes subgroups, after adjustment for confounders. PRS was not associated with COVID-19 susceptibility and hospitalization, it however significantly predicted COVID-19 severity (P = 0.01).

Conclusion: This study highlights the importance of genetic testing for key host genes involved in COVID-19 life cycle and eventually measuring the PRS which proves to be an important tool for prognosis assessment in vulnerable individuals, potentially enhancing patient care.

Background: Non-invasive prenatal testing is widely used for screening common fetal aneuploidy disorders such as trisomy 21, trisomy 18, and trisomy 13. However, its ability to detect rare autosomal trisomies has introduced a new layer of complexity and clinical uncertainty.

Methods: A retrospective analysis was conducted on the prenatal diagnostic results and pregnancy outcomes of cases identified as high-risk for rare autosomal trisomies through non-invasive prenatal testing at the reproductive medicine center, Renmin hospital, Hubei university of medicine, from 2015 to 2023.

Results: 66 cases identified as high-risk for rare autosomeal trisomies, yielding a detection rate of 0.20% (66/33,079). 7 declined amniocentesis, while the others underwent the procedure. Prenatal diagnostic procedures did not confirm the presence of the corresponding rare autosomal trisomy in any of these cases. Among the 66 cases of rare autosomal trisomies (RATs), 5 cases were lost to follow-up, and 1 case underwent termination of pregnancy (TOP) for personal reasons, leaving 60 cases with valid pregnancy outcomes. Of these 60 valid outcomes, 50 (83.33%) resulted in full-term births, while 10 (16.67%) experienced adverse pregnancy outcomes.

Conclusion: Prenatal diagnosis for high-risk rare autosomal trisomies typically reveals a normal karyotype with no detectable chromosomal abnormalities, and most cases can achieve full-term pregnancy outcomes. However, adverse pregnancy outcomes such as preterm birth, fetal demise, placental abnormalities, and intrauterine growth restriction are common and should be given clinical attention and consideration.

Background: The association between educational attainment (EA) and arterial thrombotic disease has been reported, but the causal relationship between EA and venous thromboembolism (VTE) is not clear. We aimed to assess the causal effect of EA on VTE using the two-sample mendelian randomization (MR) method.

Methods: Data mining was conducted on the genome wide association studies (GWAS), with exposure factor EA and outcome factor VTE. Two-sample Mendelian Randomization (TSMR) analysis was conducted, with the results obtained from the random effects inverse variance weighted method (IVW). Use the MR-Egger method for pleiotropy analysis and leave one method for sensitivity analysis to verify the reliability of the data.

Results: Genetically predicted decreased EA was associated with a decreased risk of VTE in both the FinnGen consortium and UK Biobank (FinnGen-VTE: OR = 0.848; 95% CI 0.776-0.927; P = 2.84 × 10^-4; UKB-VTE OR = 0.996; 95% CI 0.994-0.999; P = 0.008) under a multiplicative random-effects IVW model. Results were consistent in all sensitivity analyses and no horizontal pleiotropy was detected.

Conclusions: The MR technique instructed a potential inverse causative relationship between EA and occurrence of VTE. Therefore, patients with low EA should be more vigilant about the occurrence of VTE.

Background: Screening tests, particularly liquid biopsy with circulating miRNAs, hold significant potential for non-invasive cancer detection before symptoms manifest.

Methods: This study aimed to identify biomarkers with high sensitivity and specificity for multiple and specific cancer screening. 972 Serum miRNA profiles were compared across thirteen cancer types and healthy individuals using weighted miRNA co-expression network analysis. To prioritize miRNAs, module membership measure and miRNA trait significance were employed. Subsequently, for specific cancer screening, gastric cancer was focused on, using a similar strategy and a further step of preservation analysis. Machine learning techniques were then applied to evaluate two distinct miRNA panels: one for multi-cancer screening and another for gastric cancer classification.

Results: The first panel (hsa-miR-8073, hsa-miR-614, hsa-miR-548ah-5p, hsa-miR-1258) achieved 96.1% accuracy, 96% specificity, and 98.6% sensitivity in multi-cancer screening. The second panel (hsa-miR-1228-5p, hsa-miR-1343-3p, hsa-miR-6765-5p, hsa-miR-6787-5p) showed promise in detecting gastric cancer with 87% accuracy, 90% specificity, and 89% sensitivity.

Conclusions: Both panels exhibit potential for patient classification in diagnostic and prognostic applications, highlighting the significance of liquid biopsy in advancing cancer screening methodologies.

Dystrophic epidermolysis bullosa is a rare subtype of inherited epidermolysis bullosa, caused by variants in the collagen type VII alpha 1 chain (COL7A1) gene (MIM120120). Both autosomal dominant and recessive inheritance has been reported with variable phenotype. We investigated a Pakistani family with dystrophic epidermolysis bullosa via exome sequencing and identified a pathogenic nonsense variant in COL7A1 NM_000094 c.1573 C > T:p.(Arg525*). The inheritance pattern observed was consistent with a semi-dominant model, where heterozygous parents exhibited a mild phenotype, and homozygous children were more severely affected. For dystrophic epidermolysis bullosa, loss-of-function variants are typically associated with the autosomal recessive form, while missense variants are linked to the autosomal dominant form. A review of the literature suggests a semi-dominance pattern for some missense variants, particularly glycine substitutions, but this concept had not been formally recognized. This study highlights the importance of considering semi-dominant inheritance models for dystrophic epidermolysis bullosa and other Mendelian diseases with an autosomal recessive mode of inheritance, as it can significantly impact diagnosis and genetic counseling.

Background: Gallstones, a common surgical condition globally, affect around 20% of patients. The development of gallstones is linked to abnormal cholesterol and bilirubin metabolism, reduced gallbladder function, insulin resistance, biliary infections, and genetic factors. In addition to these factors, research has shown that mucins play a role in gallstone formation. This study aims to explore the connection between different types of gallstones and mucin gene polymorphisms.

Methods: For this purpose, a total of 121 patients with gallbladder stones PNS and 107 patients with healthy controls PNS were enrolled in this case-control study. One SNPs (rs4072037) of MUC1 gene、 three SNPs (rs2856111、rs41532344、rs41349846) of MUC2 gene、four SNPs (rs712005、rs2246980、rs2258447、rs2259292) of MUC4 gene、seven SNPs (rs28415193、rs56047977、rs2037089、rs2075854、rs3829224、rs2672785、rs2735709) of MUC5 gene、eight SNPs (rs10902268、rs61869016、rs573849895、rs59257210、rs7396383、rs74644072、rs7481521、rs9704308) of MUC6 gene、five SNPs (rs10229731、rs73168398、rs4729655、rs55903219、rs74974199) of MUC17 gene. We amplified SNP sites by polymerase chain reaction (PCR) using specific primer sets followed by DNA sequencing.

Results: The frequencies of MUC2 rs2856111 C/T genotype (OR = 3.81, 95%CI: 1.06-13.68) was higher than the control group. MUC17 rs10229731 A/C genotype (OR = 0.33, 95%CI: 0.12-0.95), rs73168398 G/A genotype (OR = 0.26, 95%CI: 0.07-0.98), MUC6 rs10902268 G/A genotype (OR = 0.40, 95%CI: 0.17-0.95) at lower frequencies than controls. The frequencies of MUC2 rs41532344 T allele (OR = 2.55, 95%CI: 1.06-6.13), MUC4 rs712005 G allele (OR = 2.51, 95%CI: 1.20-5.22), MUC5B rs2037089 C allele (OR = 3.54, 95%CI: 1.14-11.01) and MUC5AC rs28415193 G allele (OR = 1.77, 95%CI: 1.02-3.07) were higher than the control group. MUC6 rs10902268 A allele (OR = 0.004, 95%CI: 0.00-0.27), rs61869016 C allele (OR = 0.07, 95%CI: 0.01-0.63) at lower frequencies than controls.

Conclusions: Polymorphisms in the mucin gene were linked to the formation of gallbladder stones. The MUC4 rs712005 G allele, MUC5B rs2037089 C allele, MUC2 rs41532344 T allele and MUC5AC rs28415193 G allele were found to predispose individuals to the development of the disease. MUC6 rs10902268 A allele and rs61869016 C allele were identified as protective factors. Meanwhile, MUC2 rs2856111 CT genotype was found to predispose individuals to the development of the disease. MUC17 rs10229731 AC genotype, rs73168398 GA genotype and MUC6 rs10902268 GA genotype were identified as protective factors.

Background: The clinical manifestations of PI4KA-related disorders are characterized by considerable variability, predominantly featuring neurological impairments, gastrointestinal symptoms, and a combined immunodeficiency. The aim of this study was to delineate the novel spectrum of PI4KA variants detected prenatally and to assess their influence on fetal development.

Methods: A thorough fetal ultrasound screening was conducted, supplemented by both antenatal and post-abortion magnetic resonance imaging (MRI) studies. Novel PI4KA variants were detected through clinical Whole exon sequencing (WES) and validated by Sanger sequencing. The functional consequences of these variants were evaluated using bioinformatics tools. The effects of the identified variants on splicing were analyzed through minigene splicing assays. Subsequently, both wild-type and mutant PI4KA protein fragments were purified, and their enzymatic activities were quantitatively assessed.

Results: Ultrasound imaging, MRI scans revealed a dilated small intestine with an obstruction. Compound heterozygous variants (NM_058004.3: c.2802_2863-40del and c.2819 C > T, p.Ala940Val) were identified in the PI4KA of the affected fetus through clinical trio-WES. Both variants were predicted deleterious. The PI4KA variant c.2802_2863-40del resulted in the production of three distinct mRNA isoforms. The PI4KA variant c.2819 C > T (p.Ala940Val) significantly reduced the enzyme activity.

Conclusions: This study extended the mutational spectrum of PI4KA and may provide guidance for genetic counseling. Functional studies confirmed that the identified variant induces alterations in RNA splicing and impairs enzyme activity.