Genetic testing and molecular biomarkers最新文献

Background: Colorectal cancer (CRC) is a common malignancy of the digestive system, but its specific mechanisms of occurrence and development remain incompletely understood. F-Box and leucine-rich repeat protein 7 (FBXL7) is a subunit of the Skp-cullin-F-box ubiquitin ligase, involved in cell cycle regulation, endothelial cell damage, and inflammatory immunological responses. However, the role of FBXL7 in CRC remains unknown. In this study, we investigated the clinical significance and potential mechanism of FBXL7 expression in CRC progression. Methods: We utilized data from The Cancer Genome Atlas (TCGA) and the University of California Santa Cruz Xena (UCSC Xena) database for bioinformatic analyses. Clinical CRC samples were used to confirm FBXL7 expression. Gene set enrichment analysis (GSEA) and various databases, such as TCGA, UCSC Xena, cBioPortal, University of ALabama at Birmingham CANcer data analysis portal, MethSurv, Tumor Immune Estimation Resource (TIMER), TIMER2.0, Tumor-Immune System Interaction Database, and Tumor Immune Dysfunction and Exclusion Database (TIDB), were used to investigate the role of FBXL7 in CRC. Statistical analysis was performed using R (v.3.6.3) or GraphPad Prism 8.0. Results: Our findings revealed the predictive significance of FBXL7 in CRC patients. FBXL7 expression was associated with tumor stage, lymph node stage, pathological stage, perineural invasion, and lymphatic invasion. GSEA analysis identified associations between FBXL7 and extracellular matrix organization, as well as immune-related pathways. Immunological analysis revealed a correlation between high FBXL7 expression and the development of an immunosuppressive microenvironment. Conclusion: Identifying FBXL7 as a novel biomarker for CRC could shed light on the promotion of CRC development by the immune environment.

Background: Recurrent spontaneous abortion (RSA), defined as two or more succeeding abortions during 20 weeks of gestation, affects 3-5% of pregnancies. Several studies have found that most women with RSA had at least one (and sometimes two copies) of the methylenetetrahydrofolate reductase (MTHFR) C677T variant. Materials and Methods: The study involved 118 women who had two or more spontaneous abortions (SAs) as the case group and 118 women who had at least one live birth but no SA as the control group. Clinical features such as age, body mass index (BMI), medication received, family history of abortion, and thrombophilia were investigated. Real-time PCR was used for genotyping subjects for MTHFR C677T gene polymorphism. Results: Significant differences in age, BMI, and medication received characters have been shown between those in the patients' group. For the MTHFR C677T gene, the genotypes for the patients' group were 36%, 60%, and 4%, whereas the genotypes for the control group were 30%, 58%, and 12%. In addition, the C and T allelic frequencies were 59% and 41% in the healthy control group and 67% and 33% in the patients' group, respectively. A significant association was found between the TT genotype and RSA. A 3.84-fold increased risk of RSA was associated with the TT genotype (odds ratio = 3.84, confidence interval: 1.28-10.93, p-value = 0.02). Conclusions: In this study, homozygosity for the T allele was significantly lower in the RSA-affected than in healthy women, whereas heterozygosity did not vary substantially between the two groups, which was in line with other studies.

Background: The LIPA gene encodes for lysosomal acid lipase (LAL), which catalyzes the hydrolysis of cholesterol esters and triglycerides. Variations in the LIPA gene impair LAL activity, predisposing patients to a rare metabolic disorder called LAL deficiency (LAL-D). The lack of functioning LAL promotes lipid accumulation and subsequent dyslipidemia, which can increase the likelihood of complications in both infants and adults. Although the worldwide prevalence is 1:500,000 births, the frequency in Mizrahi Jewish populations is projected to be as high as 1 in every 4200 births (Valles-Ayoub et al.) based on the LIPA p.G87V variant frequency among 162 individuals. Materials and Methods: This study was conducted to validate the previously reported prevalence of LAL-D in the Mizrahi Jewish population based on the pathogenic LIPA missense variants in exon 4 (c.260G>T; p.G87V) and exon 8 (c.894G>A; p.Gln298=) using a larger cohort of those with Middle Eastern ancestry living around Los Angeles. Among the 1184 individual samples sequenced, 660 self-reported as Mizrahi Jewish, while the remaining 524 came from other Middle Eastern groups labeled as "non-Jewish." Results: Of the 1184 samples, 22 alleles of the exon 4 variant were identified (1.85%), and 2 alleles of the exon 8 variant were identified (0.16%). For the exon 4 variant, 20 of 22 (90.9%) heterozygotes were Mizrahi Jewish, while 2 of 22 (9.09%) heterozygotes were "non-Jewish." For the exon 8 variant, 2 of 2 (100%) heterozygotes were Mizrahi Jewish. This suggests that the prevalence of LAL-D in this population is 1 in 900, which suggests that LAL-D may be 4.6% higher in the Mizrahi Jewish population in previous reports. Conclusion: These findings show increased prevalence of LIPA gene exon 4 variation p.G87V in the Middle East population when compared to the general population, indicating the need for prenatal screening in those of Mizrahi Jewish ancestry.

Background: Coronary artery ectasia (CAE), known for localized or diffuse excessive dilatation of the coronary artery, has an unknown etiology, but it has been reported that the underlying cause may be atherosclerosis and genetic changes that may affect the arterial lumen. MicroRNAs have been shown to have an effect in aneurysm diseases and are known to contribute to vascular development and atherosclerosis. The purpose of this study was to investigate whether they are also associated with CAE. Methods: This cross-sectional study consisted of 25 patients with CAE and 25 subjects with normal coronary arteries. Blood was collected and miRNA expression was detected using the Rotor-GeneQ real-time polymerase chain reaction cycler (Qiagen) to investigate expression levels of miR-24-1-5p, miR-34a-5p, miR-126-5p, miR-143-5p, and miR-145-5p. Results: Demographic variables of CAE (mean age 59.5 ± 1.7; 12 women) and controls (mean age 57.2 ± 2.1; 16 women) were similar. miR-126-5p (p = 0.014) and miR-145-5p (p = 0.003) levels were found to be <2-fold upregulated in CAE compared to controls; miR-143-5p also showed upregulation, but it was not significant (p = 0.078). Conversely, miR-24-1-5p (p = 0.032) levels were downregulated in CAE compared to controls. miR-34a-5p was also downregulated, but this was not considered significant (p = 0.185). Conclusions: According to our study findings, miR-126-5p, miR-145-5p, and miR-24-1-5p may be associated with CAE. These microRNAs could be of diagnostic and therapeutic significance for further studies of CAE involving abnormal angiogenesis and vascular disorders and potentially serve as useful biomarkers.

Objective: Polydactyly is characterized by multiple distinct heterogeneous phenotypes, the etiologies of which involve several genes. This study aimed to explore the genetic defects and further clarify the molecular mechanism of polydactyly in several Chinese families. Methods: Three families with diverse phenotypes of non-syndromic polydactyly were analyzed: two were cases of familial disease, whereas one was sporadic. PCR and Sanger sequencing were used to screen for pathogenic mutations in two known disease-associated genes, GLI3 and HOXD13, while bioinformatic analyses predicted the pathogenicity of the identified variants. Reverse transcription PCR was used to analyze the splicing effect of an intronic variant. Results: Two novel heterozygous frameshift mutations (c.4478delG/p.S1493Tfs*18; c.846_c.847insC/p.R283Qfs*21) were identified in the GLI3 gene from two of the pedigrees. Both c.4478delG and c.846_c.847insC were later confirmed in affected and unaffected members and normal controls, to truncate and disrupt the integrity of the GLI3 protein, reduce its level of expression, and disrupt its biological function through nonsense-mediated mRNA decay (NMD). In addition, a deep intron mutation (c.125-47 C>A) was detected in the GLI3 gene from the sporadic case, however, both bioinformatics analysis (HSF, splice AI, and CBS) and RT-PCR indicated that the variant c.125-47 C>A had minimal if any impact on splicing of the GLI3 gene. Conclusion: Two newly identified heterozygous frameshift mutations in the GLI3 gene were detected in two families with non-syndromic polydactyly, further extending the mutational spectrum of the GLI3 gene in non-syndromic polydactyly. Moreover, our study further expanded the phenotypic spectrum of non-syndromic polydactyly.

Background: There is increasing evidence that allergic rhinitis (AR) is associated with cancer. However, these results are inconsistent. Because of common risk factors, there may be reverse causality and confounding factors that affect our understanding of the relationship between AR and cancer. We aimed to explore the role of AR in cancer development using Mendelian randomization (MR) analysis. Materials and Methods: We performed a two-sample MR analysis using summary data from genome-wide association studies (GWAS). Single nucleotide polymorphisms (SNPs) strongly associated with AR (or hay fever) were used as instrumental variables, mainly using the inverse variance weighted analysis method, supplemented by MR Egger, maximum likelihood, weighted media, and penalized weighted media for MR analysis. Sensitivity analyses included heterogeneity and horizontal pleiotropy; and leave-one-out analyses were performed to test the robustness of our results. Results: MR analysis revealed no evidence of a causal relationship between AR and any of the examined cancers (all p > 0.05). The results using five different analytical approaches were similar. Sensitivity analyses showed no evidence of heterogeneity nor horizontal pleiotropy. According to the leave-one-out sensitivity analyses, no individual SNP was significantly influencing the causal effect of AR on cancers. Conclusions: These findings do not provide evidence to support that AR has a large impact on the risk of eight common cancers in the European population. However, we cannot rule out a very minor effect of AR on cancer. Further large-scale studies are necessary to validate our findings.

Objective: Osteopontin (OPN) increases T-cell proliferation, interferon production, and CD40 ligand expression, which leads to B-cell proliferation and antibody production. This study was designed to determine whether OPN variants are associated with susceptibility to systemic lupus erythematosus [SLE]. Methods: We searched the Medline, Embase, and KoreaMed databases for available articles. We performed a meta-analysis on the association of OPN 707 T/C (rs1126616) at exon 6, 1083 G/A (rs112772) at the 3'-untranslated region (3'-UTR), 1239 C/A (rs9138) at 3'-UTR, and 9250 T/C (rs11229919) variants in exon 7 with susceptibility to SLE. Results: Ten studies from 9 articles with 2175 SLE patients and 3233 controls were included. The meta-analysis showed a significant association between SLE and the 707 T allele of the OPN 707 T/C variant (odds ratio [OR] = 1.522, 95% confidence interval [CI] = 1.101-2.105, p = 0.044). Stratification by ethnicity indicated an association between the OPN 707 T/C variant and SLE in European and Arab populations. The meta-analysis also revealed a significant association between the OPN 9250 C allele and SLE in the Asian and Arab populations. A significant association was also identified between the +1239 C allele of the OPN 1239 C/A variant and SLE (OR = 1.192, 95% CI = 1.008-1.410, p = 0.040). The meta-analysis indicated no allelic association between SLE and OPN 1083 G/A and the OPN 1239 C/A variants. Conclusions: The OPN 707 T/C variant is associated with SLE susceptibility in European and Arab populations and the OPN 9250 T/C variant is associated with SLE susceptibility in Asian and Arab populations. In addition, associations were found between the OPN 1239 C/A variant and SLE.