Identification of novel lncRNAs associated with sensitivity of HIV antiretroviral therapy: A two-stage matched case-control study.

BACKGROUND: To identify long non-coding RNAs (lncRNAs) that may be used as potential biomarkers of sensitivity to antiretroviral therapy (ART) against human immunodeficiency virus (HIV) infection. METHOD: A two-stage matched case-control study was conducted. First, in the screening stage, peripheral blood lymphocytes (PBLs) of six subjects receiving lamivudine-based ART (3 ART-resistant and 3 ART-sensitive subjects with matching durations of ART) were subjected to comprehensive microarray expression profiling in order to screen out lncRNAs associated with ART sensitivity. Secondly, during the validation stage, promising lncRNAs were evaluated via a 1:4 matched case-control study using 50 subjects (10 ART-resistant and 40 ART-sensitive subjects with matching durations of ART). RESULTS: Seven lncRNAs were screened out (P < 1.06 × 10-3) in the first stage. Among these, two lncRNAs (n341598 and n407911) survived validation conducted at the second stage (n341598: P < 0.001; n407911: P = 0.007), while another lncRNA n406445 showed marginally significant (P = 0.049). All three showed higher expression in ART-resistant subjects compared to that in ART-sensitive subjects. The area under the ROC curve (AUC) for n341598 was 0.867 (95 % CI: 0.796-0.966; P < 0.001), which was better than that for n406445 (0.702) and n407911 (0.780). Meanwhile, the AUC for n341598 was better than that of any combination of the three lncRNAs. CONCLUSION: Our study identified three highly expressed lncRNAs in patients with HIV ART-resistant, among which the lncRNA n341598 may be utilized as an optimal biomarker to distinguish ART-resistant and ART-sensitive patients. Further studies aimed at revealing the molecular mechanisms underlying the regulation of ART sensitivity by n341598 are warranted to complement our findings.

A Novel apaQTL-SNP for the Modification of Non-Small-Cell Lung Cancer Susceptibility across Histological Subtypes.

Background: Alternative polyadenylation (APA) events may be modulated by single nucleotide polymorphisms (SNPs). Therefore, this study aims to evaluate the association between APA quantitative trait loci (apaQTLs)-related SNPs (apaQTL-SNPs) and non-small-cell lung cancer (NSCLC) risk. Methods: APA-related genes associated with NSCLC (LUAD and LUSC) were first identified, and the respective apaQTL-SNPs of those genes were selected. Then, a two-phase case-control study was performed to evaluate the association between candidate apaQTL-SNPs and NSCLC risk. Results: A total of 7 LUAD- and 21 LUSC-associated apaQTL-SNPs were selected. In the first phase, the apaQTL-SNP rs10138506 was significantly associated with LUAD risk (p < 0.05), whereas the other two apaQTL-SNPs (rs1130698 and rs1130719) were significantly associated with LUSC risk (p < 0.05). In the second phase, the variant G allele of rs10138506 was still significantly associated with an increased risk of LUAD (OR = 1.42, 95%CI = 1.02−1.98, p = 0.038). Functional annotation indicated that the variant G allele of rs10138506 was significantly associated with a higher PDUI value of CHURC1. Meanwhile, 3'RACE experiments verified the presence of two poly(A) sites (proximal and distal) in CHURC1, while qRT-PCR results indicated that different genotypes of rs1127968 which, in perfect LD with rs10138506, can mediate changes in the lengths of the 3'UTR of CHURC1 isoforms. Conclusion: The variant G allele of rs10138506 in CHURC1 was correlated with a longer 3'UTR of CHURC1 mRNA and an increased LUAD risk. Further studies should evaluate the interaction between rs10138506 and different 3'UTR lengths of CHURC1 that regulate LUAD development.

Tetrandrine Treatment May Improve Clinical Outcome in Patients with COVID-19.

Background and objectives: The COVID-19 pandemic continues worldwide, and there is no effective treatment to treat it. Chinese medicine is considered the recommended treatment for COVID-19 in China. This study aimed to examine the effectiveness of tetrandrine in treating COVID-19, which is originally derived from Chinese medicine. Materials and Methods: A total of 60 patients, categorized into three types (mild, moderate, severe), from Daye Hospital of Chinese Medicine with a diagnosis of COVID-19 were included in this study. Demographics, medical history, treatment, and results were collected. We defined two main groups according to the clinical outcome between improvement and recovery. All underlying factors including clinical outcomes were assessed in the total number of COVID-19 patients and moderate-type patients. Results: In a total of 60 patients, there were significant differences in the clinical outcome underlying treatment with antibiotics, tetrandrine, and arbidol (p < 0.05). When the comparison was limited to the moderate type, treatment with tetrandrine further increased recovery rate (p = 0.007). However, the difference disappeared, and no association was indicated between the clinical outcome and the treatment with and without antibiotic (p = 0.224) and arbidol (p = 0.318) in the moderate-type patients. In all-type and moderate-type patients, tetrandrine improved the rate of improvement in cough and fatigue on day 7 (p < 0.05). Conclusions: Tetrandrine may improve clinical outcome in COVID-19 patientsand could be a promising potential natural antiviral agent for the prevention and treatment of COVID-19.

Novel Functional eQTL-SNPs Associated With Susceptibility to Mycoplasma pneumoniae Pneumonia in Children.

Background: The functional causal single-nucleotide polymorphisms (SNPs) associated with susceptibility to Mycoplasma pneumoniae Pneumonia (MPP) have scarcely been identified. In this study, we aimed to analyze the association between the functional expression quantitative trait locus (eQTL)-SNPs and the risk of MPP. Methods: First, we identified reported genes associated with MPP from the human disease database, MalaCards. After investigating multiple databases, we systematically selected seven functional eQTL-SNPs (rs2070874, rs360720, rs8032531, rs4316, rs4353, rs7258241, and rs2250656). Finally, the selected eQTL-SNPs were genotyped using the TaqMan genotyping technology, and compared between 100 children with MPP and 178 healthy controls. Results: We found that three eQTL-SNPs (rs8032531 in CD276 and rs4316 and rs4353 in ACE) were significantly associated with susceptibility to MPP. Joint analysis of the three eQTL-SNPs revealed that the risk of MPP increased with an increase in the number of risk alleles present. Plasma protein expression levels of CD276 and ACE were distinctively higher in children with MPP than in healthy children (CD276: P < 0.001; ACE: P = 0.001). Conclusion: Functional eQTL-SNPs in CD276 and ACE may affect the susceptibility to MPP. The risk of developing MPP is higher in patients harboring a greater number of unfavorable alleles of the aforementioned SNPs.

A novel circRNA-SNP may increase susceptibility to silicosis.

In this study, we aimed to reveal the association between circRNA-related single nucleotide polymorphisms (SNPs) with the susceptibility of silicosis. To achieve this goal, a silicosis-related GWAS was constructed to select the candidate SNPs, and circBase database was utilized to select the promising SNPs which may locate on circRNAs. In addition, the eQTL analysis between the SNPs and located genes was performed to select the candidate SNPs. Finally, the association between candidate SNPs with the susceptibility of silicosis was validated. As a result, we firstly selected 10,922 SNPs with P < 1 × 10-3 through the silicosis-related GWAS. Among which, 1,752 SNPs were identified that may locate on 2,660 circRNAs. After the MAF evaluation and the sequences checking, we obtained 94 SNPs and related 105 circRNAs. EQTL analysis indicated that 7 circRNA-SNPs might regulate the expression of located genes. Subsequently, a strong association was found between variant A of rs17115143 and silicosis risk in the validation stage (OR= 1.68, P = 0.032). Combination of the GWAS data and Taqman genotyping data also revealed a strong association between rs17115143 and silicosis risk in both dominant and additive models (dom: OR= 1.96, P = 3.98 × 10-4; add: OR= 1.40, P = 3.06 × 10-4). In conclusion, the variant A allele of circRNA-SNP rs17115143 could be a risk factor in the progression of silicosis. And related 6 circRNAs may function as novel biomarkers for the diagnostic of silicosis. Further researches to explore the biological mechanisms of rs17115143 related 6 circRNAs in the regulation of silicosis are warranted.

Peripheral blood circular RNA hsa_circ_0058493 as a potential novel biomarker for silicosis and idiopathic pulmonary fibrosis.

Existing studies reported that some circular RNAs (circRNAs) play vital roles in the development of pulmonary fibrosis. However, few studies explored the biomarker potential of circRNAs for pulmonary fibrosis based on population data. Therefore, we aimed to identify peripheral blood circRNAs as potential biomarkers for diagnosing silicosis and idiopathic pulmonary fibrosis (IPF). In brief, an RNA-seq screening based on 4 silicosis cases and 4 controls was initially performed. Differentially expressed circRNAs were combined with the human serum circRNA dataset to identify overlapping serum-detectable circRNAs, followed by validation using the GEO dataset (3 IPF cases and 3 controls) and subsequent qRT-PCR, including 84 additional individuals. Following the above steps, 243 differentially expressed circRNAs were identified during the screening stage, with fold changes ≥ 1.5 and P < 0.05. Of note, the human serum circRNA dataset encompassed 28 of 243 circRNAs. GEO (GSE102660) validation revealed two highly expressed circRNAs (P < 0.05) in the IPF case group. Furthermore, at the enlarged sample validation stage, hsa_circ_0058493 was highly expressed in both silicosis and IPF cases (silicosis: P = 1.16 × 10-6; IPF: P = 7.46 × 10-5). Additionally, hsa_circ_0058493 expression was significantly increased in MRC-5 cells upon TGF-ß1 treatment, while hsa_circ_0058493 knockdown inhibited the expression of fibrotic molecules by affecting the epithelial-mesenchymal transition process. These shreds of evidence indicated that hsa_circ_0058493 might serve as a novel biomarker for diagnosing silicosis and IPF.

Optimum birth interval (36-48 months) may reduce the risk of undernutrition in children: A meta-analysis.

Background: Although some studies have highlighted short birth interval as a risk factor for adverse child nutrition outcomes, the question of whether and to what extent long birth interval affects better nutritional outcomes in children remains unclear. Methods: In this quantitative meta-analysis, we evaluate the relationship between different birth interval groups and child nutrition outcomes, including underweight, wasting, and stunting. Results: Forty-six studies with a total of 898,860 children were included in the study. Compared with a short birth interval of <24 months, birth interval of ≥24 months and risk of being underweight showed a U-shape that the optimum birth interval group of 36-48 months yielded the most protective effect (OR = 0.54, 95% CI = 0.32-0.89). Moreover, a birth interval of ≥24 months was significantly associated with decreased risk of stunting (OR = 0.61, 95% CI = 0.55-0.67) and wasting (OR = 0.63, 95%CI = 0.50-0.79) when compared with the birth interval of <24 months. Conclusion: The findings of this study show that longer birth intervals (≥24 months) are significantly associated with decreased risk of childhood undernutrition and that an optimum birth interval of 36-48 months might be appropriate to reduce the prevalence of poor nutritional outcomes in children, especially underweight. This information would be useful to government policymakers and development partners in maternal and child health programs, especially those involved in family planning and childhood nutritional programs.

A novel regQTL-SNP and the risk of lung cancer: a multi-dimensional study.

RegQTL, a novel concept, indicates that different genotypes of some SNPs have differential effects on the expression patterns of miRNAs and their target mRNAs. We aimed to identify the association between regQTL-SNPs and lung cancer risk and to explore the underlying mechanisms. The two-stage case-control study included the first stage in a Chinese population (626 lung cancer cases and 667 healthy controls) and the second stage in a European population (18,082 lung cancer cases and 13,780 healthy controls). Functional annotations were conducted based on the GTEx and the TCGA databases. Functional experiments were performed to explore the underlying biological mechanisms in vitro and vivo. After strict screening, five candidate regQTL-SNPs (rs7110737, rs273957, rs6593210, rs3768617, and rs6836432) were selected. Among them, the variant T allele of rs3768617 in LAMC1 was found to significantly increase the risk of lung cancer (first stage: P = 0.044; second stage: P = 0.007). The eQTL analysis showed that LAMC1 expression level was significantly higher in subjects with the variant T allele of rs3768617 (P = 1.10 × 10-14). In TCGA paired database, the regQTL annotation indicated the different expression patterns between LAMC1 and miRNA-548b-3p for the distinct genotypes of rs3768617. Additionally, LAMC1 knockdown significantly inhibited malignant phenotypes in lung cancer cell lines and suppressed tumor growth. A novel regQTL-SNP, rs3768617, might affect lung cancer risk by modulating the expression patterns of miRNA-548b-3p and LAMC1. RegQTL-SNPs could provide a new perspective for evaluating the regulatory function of SNPs in lung cancer development.

Integrating RNA-Seq With GWAS Reveals a Novel SNP in Immune-Related HLA-DQB1 Gene Associated With Occupational Pulmonary Fibrosis Risk: A Multi-Stage Study.

Objective: To evaluate the association between single-nucleotide polymorphisms (SNPs) in RNA-seq identified mRNAs and silicosis susceptibility. Methods: A comprehensive RNA-seq was performed to screen for differently expressed mRNAs in the peripheral blood lymphocytes of eight subjects exposed to silica dust (four silicosis cases and four healthy controls). Following this, the SNPs located on the shortlisted mRNAs, which may affect silicosis susceptibility, were screened through silicosis-related genome-wide association studies (GWAS) (155 silicosis cases and 141 healthy controls), whereas functional expression quantitative trait locus (eQTL)-SNPs were identified using the GTEx database. Finally, the association between functional eQTL-SNPs and silicosis susceptibility (194 silicosis cases and 235 healthy controls) was validated. Results: A total of 70 differentially expressed mRNAs (fold change > 2 or fold change < 0.5, P < 0.05) was obtained using RNA-seq. Furthermore, 476 SNPs located on the shortlisted mRNAs, which may affect silicosis susceptibility (P < 0.05) were obtained using GWAS, whereas subsequent six functional eQTL-SNPs were identified. The mutant A allele of rs9273410 in HLA-DQB1 indicated a potential increase in silicosis susceptibility in the validation stage (additive model: odds ratio (OR)= 1.31, 95% confidence interval (CI) = 0.99-1.74, P = 0.061), whereas the combination of GWAS and the validation results indicated that the mutant A allele of rs9273410 was associated with increased silicosis susceptibility (additive model: OR = 1.35, 95% CI =1.09-1.68, P = 0.006). Conclusion: The mutant A allele of rs9273410 was associated with increased silicosis susceptibility by modulating the expression of HLA-DQB1.

miR-608 rs4919510 Polymorphism May Affect Susceptibility to Colorectal Cancer by Upregulating MRPL43 Expression.

There are many studies on the association between miR-608 rs4919510 polymorphism and susceptibility to colorectal cancer (CRC). However, the role of rs4919510 in CRC development and its underlying mechanism remain unclear. We first evaluated the gene that may be regulated by the variation of rs4919510 through a two-stage expression quantitative trait loci analysis and then compared the expression of that identified gene in CRC tissues and adjacent nontumor tissues. Next, methyl thiazolyl tetrazolium (MTT) assay, transwell assay, and flow cytometry analyses were performed to investigate the in vitro capacity of cell proliferation, migration, invasion, apoptosis, and cell cycle of CRC cells, respectively. Finally, through bioinformatics prediction, we contrasted the regulatory network and identified microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) that could regulate the obtained gene. We found that the variant G allele of rs4919510 located in miR-608 was associated with a potentially increased expression of MRPL43 in colon tissues (p = 0.065). Moreover, the results of functional experiments suggested that knockdown of the MRPL43 gene could inhibit the growth of the CRC HCT-116 cell line and promote apoptosis. Additionally, the cell cycle of CRC HCT-116 cell line was significantly arrested at the G2 phase. Next, we obtained a competing endogenous RNA regulatory network of MRPL43 with 17 pairs of miRNAs-lncRNAs by bioinformatics prediction, out of which, survival analysis indicated that different expression levels of miR-193b-3p (p = 0.0269) and miR-194-3p (p = 0.0113) were associated with overall survival in CRC patients. The rs4919510 variant G allele in miR-608 may increase the proliferation, invasion, and migration ability and decrease the apoptosis of CRC HCT-116 cell line by upregulating the expression of MRPL43, ultimately may affect the risk of CRC. Moreover, miR-193b-3p and miR-194-3p that target MRPL43 may serve as potential predictive biomarkers of CRC survival.