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Two Novel Frameshift Mutations in the GLI3 Gene Underlie Non-Syndromic Polydactyly in Chinese Families.

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.

Allergic Rhinitis and Cancer Risk: A Two-Sample Mendelian Randomization Study.

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.

Associations Between Osteopontin Variants and Systemic Lupus Erythematosus: A Meta-Analysis.

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.

Could Aneurysm and Atherosclerosis-Associated MicroRNAs (miR 24-1-5p, miR 34a-5p, miR 126-5p, miR 143-5p, miR 145-5p) Also Be Associated with Coronary Artery Ectasia?

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.

Clinical Characteristics and Genotyping of Pediatric Adenovirus Pneumonia Disease and Coinfection in Southeast China.

Introduction: Human adenovirus (HAdV) is a common pathogen that can cause acute respiratory infections (ARIs) in children. Adenovirus pneumonia is the most severe respiratory disease associated with HAdV. Objective: We aimed to investigate the clinical characteristics of children hospitalized with adenovirus pneumonia in Quanzhou, China, in 2019. We also sought to determine the viral genotype in these cases and explore cases associated with severe adenovirus pneumonia. Methods: We collected oropharyngeal swabs from 99 children who were hospitalized with pneumonia in Quanzhou Women and Children's Hospital, these samples were tested for the presence of HAdV. Genotyping of the viruses was performed by real-time polymerase chain reaction. Logistic regression analysis was employed to analyze risk factors related to severe adenovirus pneumonia. The epidemiological data were examined using the Statistical Package for Social Sciences software (SPSS). Results: Among the 99 patients in our study, the median age was 21 months. We observed a 4% mortality rate among those diagnosed with adenovirus pneumonia. Adenovirus pneumonia often presents as a coinfection. Lactate dehydrogenase and neutrophil percentages of WBC's were significantly increased in patients with severe adenovirus pneumonia compared with mild HAdV disease. The predominant viral genotypes identified were type 3 and type 7. Conclusions: In the Quanzhou area of southeast China, the incidence of adenovirus pneumonia was found to be high among children younger than two years old. Type 7 HAdV was identified as the primary pathogen. A long duration of fever, dyspnea and digestive system complications were risk factors for severe adenovirus pneumonia after HAdV infection. Clinical Trial Registration number: ChiCTR2200062358.

Association of Apolipoprotein A5 Gene Variants with Hyperlipidemic Acute Pancreatitis in Southeastern China.

Background: Apolipoprotein A5 (APOA5) is involved in serum triglyceride (TG) regulation. Several studies have reported that the rs651821 locus in the APOA5 gene is associated with serum TG levels in the Chinese population. However, no research has been performed regarding the association between the variants of rs651821 and the risk of hyperlipidemic acute pancreatitis (HLAP). Methods: A case-control study was conducted and is reported following the STROBE guidelines. We enrolled a total of 88 participants in this study (60 HLAP patients and 28 controls). APOA5 was genotyped using PCR and Sanger sequencing. Logistic regression models were conducted to calculate odds ratios and a 95% confidence interval. Results: The genotype distribution of the rs651821 alleles in both groups follow the Hardy-Weinberg distribution. The frequency of the "C" allele in rs651821 was increased in HLAP patients compared to controls. In the recessive model, subjects with the "CC" genotype had an 8.217-fold higher risk for HLAP (OR = 8.217, 95% CI: 1.023-66.01, p = 0.046) than subjects with the "TC+TT" genotypes. After adjusting for sex, the association remained significant (OR = 9.898, 95% CI: 1.176-83.344, p = 0.035). Additionally, the "CC" genotype was related to an increased TG/apolipoprotein B (APOB) ratio and fasting plasma glucose (FPG) levels. Conclusions: Our findings suggest that the C allele of rs651821 in APOA5 increases the risk of HLAP in persons from Southeastern China.

Open Access
The Ratio of miR-122 to miR-20a (miR-122/miR-20a) Is a Useful Minimally Invasive Biomarker for Non-Alcoholic Fatty Liver Disease Detection.

Background: The increasing prevalence of non-alcoholic fatty liver disease (NAFLD) has become a global health problem. NAFLD has few initial symptoms and may be difficult to detect early, so there is need for a minimally invasive early detection marker. We hypothesized that miR-122 and miR-20a levels combined, as the miR-122/miR-20a ratio might detect NAFLD more sensitively. Methods: This study involved 167 participants with low alcohol intake. Those who had an increase in echogenicity of the liver parenchyma and hepato-renal contrast on ultrasonography were classified as the NAFLD group (n = 44), which was further classified into mild (n = 26) and severe (n = 18) groups based on echogenic intensity and hepatic vessel and diaphragm visualization. Participants without fatty liver were included in the normal group, except for those with an abnormal body mass index, glycated hemoglobin, and systolic blood pressure (n = 123) values. Serum miR-122 and miR-20a expression levels in participants were measured by real-time polymerase chain reaction, and the miR-122/miR-20a was calculated. Results: In the NAFLD group, miR-122 expression was significantly higher and the miR-20a was significantly lower than in the normal group, in agreement with previous studies. miR-122/miR-20a was also significantly higher in the NAFLD group. Receiver operating characteristic curve analysis was performed with miR-122/miR-20a as an NAFLD detection marker, and the area under the curve of miR-122/miR-20a was significantly larger than that of miR-122 or miR-20a alone. Conclusions: The miR-122/miR-20a ratio, combined with miR-122 and miR-20a levels, is a useful biomarker to detect NAFLD with high sensitivity.

Circulating Plasma miR-122 and miR-583 Levels Are Involved in Chronic Hepatitis B Virus Pathogenesis and Serve As Novel Diagnostic Biomarkers.

Background: MicroRNAs regulate many biological processes and are involved in the pathogenesis of many diseases including chronic hepatitis B (CHB). Moreover, besides investigation of their roles in hepatitis B virus (HBV) infection, a noninvasive, sensitive, and specific biomarker is essential in the diagnosis of liver diseases. This study was designed to evaluate the role of miR-122, miR-583, and miR-24 in the pathogenesis of CHB both in active chronic hepatitis (ACH) patients and in inactive carriers (IC). Materials and Methods: Plasma samples and all relevant clinical features were collected from 43 patients with CHB (28 ACH and 15 IC) and 43 healthy controls. Quantitative real-time PCR was performed to detect the plasma levels of miR-122, miR-583, and miR-24. Results: Results show miR-122 (p = 0.0001) and miR-583 (p = 0.006) but not miR-24 (p = 0.65) were upregulated in patients with CHB versus the control group. Interestingly, there was a significant increase in the plasma expression of miR-583 in IC versus ACH. Moreover, receiver operating characteristic curve analysis determined plasma levels of miR-122 (area under the ROC curve [AUC] = 0.89, p < 0.0001, sensitivity: 100%, specificity: 62.5%) and miR-583 (AUC = 0.71, p = 0.0007, sensitivity: 90%, specificity: 47.62%) as sensitive biomarkers to discriminate CHB patients from controls. Conclusion: Our data showed an increase in the plasma levels of miR-583 in IC versus ACH patients. Moreover, we demonstrated that miR-122 and miR-583 may serve as potential biomarkers for CHB diagnosis and activity.

A Novel Pair of Compound Heterozygous Mutation of EYS in a Han Chinese Family with Retinitis Pigmentosa.

Background: Retinitis pigmentosa (RP) is a complex inherited and progressive degenerative retinal disease. The eyes shut homolog (EYS) is frequently associated with RP is surprisingly high. Exploring the function of EYS is quite difficult due to the unique gene size and species specificity. Gene therapy may provide a breakthrough to treat this disease. Therefore, exploring and clarifying pathogenic mutations of EYS-associated RP has important guiding significance for clinical treatment. Methods: Clinical and molecular genetic data for EYS-associated RP were retrospectively analyzed. Sanger sequencing was applied to identify novel mutations in these patients. Candidate pathogenic variants were subsequently evaluated using bioinformatic tools. Results: A novel pair of compound heterozygous mutations was identified: a novel stop-gain mutation c.2439C>A (p.C813fsX) and a frameshift deletion mutation c.6714delT (p. P2238fsX) of the EYS gene in the RP family. Both of these mutations were rare or absent in the 1000 Genomes Project, dbSNP, and Genome Aggregation Database (gnomAD). These two mutations would result in a lack of multiple functionally important epidermal growth factor-like and Laminin G-like coding regions in EYS. Conclusions: A novel compound heterozygote of the EYS gene in a Chinese family with an autosomal inheritance pattern of RP was identified. Identifying more pathogenic mutations and expanding the mutation spectrum of the EYS gene will contribute to a more comprehensive understanding of the molecular pathogenesis of RP disease that could be gained in the future. It also could provide an important basis for the diagnosis, clinical management, and genetic counseling of the disease.