Only a small proportion of genetic variation in serum ferritin has been explained by variant genetic studies, and genome-wide association study (GWAS) for serum ferritin has not been investigated widely in Chinese population. We aimed at exploring the novel genetic susceptibility to serum ferritin, and performed this two stage GWAS in a healthy Chinese population of 3,495 men aged 20-69 y, including 1,999 unrelated subjects in the first stage and 1,496 independent individuals in the second stage. Serum ferritin was measured with electrochemiluminescence immunoassay, and DNA samples were collected for genotyping. A total of 1,940,243 SNPs were tested by using multivariate linear regression analysis. After adjusting for population stratification, age and BMI, the rs5742933 located in the 5'UTR region of PMS1 gene on chromosome 2 was the most significantly associated with ferritin concentrations (P-combined  = 2.329×10(-10)) (β  =  -0.11, 95% CI: -0.14, -0.07). Moreover, this marker was about 200 kb away from the candidate gene SLC40A1 which is responsible for iron export. PMS1 gene was the novel genetic susceptibility to serum ferritin in Chinese males and its relation to SLC40A1 needs further study.

Manganese (Mn) is an essential trace element, while excessive expose may induce neurotoxicity. Recently, lncRNAs have been extensively studied and it has been confirmed that lncRNAs participate in neural functions and aberrantly expressed lncRNAs are involved in neurological diseases. However, the pathological effects of lncRNAs on Mn-induced neurotoxicity remain unclear. In this study, the expression profiles of lncRNAs and messenger RNAs (mRNAs) were identified in Mn-treated hippocampal neurons and control neurons via microarray. Bioinformatic methods and intersection analysis were also employed. Results indicated that 566, 1161, and 1474 lncRNAs meanwhile 1848, 3228, and 4022 mRNAs were aberrantly expressed in low, intermediate, and high Mn-exposed groups compared with the control group, respectively. Go analysis determined that differentially expressed mRNAs were targeted to biological processes, cellular components, and molecular functions. Pathway analysis indicated that these mRNAs were enriched in insulin secretion, cell cycle, and DNA replication. Intersection analysis denominated that 135 lncRNAs and 373 mRNAs were consistently up-regulated while 150 lncRNAs and 560 mRNAs were consistently down-regulated. Meanwhile, lncRNA BC079195 was significantly up-regulated while lncRNAs uc.229- and BC089928 were significantly down-regulated in three comparison groups. The relative expression levels of 3 lncRNAs and 4 mRNAs were validated through qRT-PCR. To the best of our knowledge, this study is the first to identify the expression patterns of lncRNAs and mRNAs in hippocampal neurons of Sprague-Dawley rats. The results may provide evidence on underlying mechanisms of Mn-induced neurotoxicity, and aberrantly expressed lncRNAs/mRNAs may be useful in further investigations to detect early symptoms of Mn-induced neuropsychiatric disorders in the central nervous system.

Hepatitis B virus (HBV) infection is a common infectious disease. Here we perform a genome-wide association study (GWAS) among Chinese populations to identify novel genetic loci involved in persistent HBV infection. GWAS scan is performed in 1,251 persistently HBV infected subjects (PIs, cases) and 1,057 spontaneously recovered subjects (SRs, controls), followed by replications in four independent populations totally consisting of 3,905 PIs and 3,356 SRs. We identify a novel locus at 8p21.3 (index rs7000921, odds ratio=0.78, P=3.2 × 10(-12)). Furthermore, we identify significant expression quantitative trait locus associations for INTS10 gene at 8p21.3. We demonstrate that INST10 suppresses HBV replication via IRF3 in liver cells. In clinical plasma samples, we confirm that INST10 levels are significantly decreased in PIs compared with SRs, and negatively correlated with the HBV load. These findings highlight a novel antiviral gene INTS10 at 8p21.3 in the clearance of HBV infection.

The gut microbiome in humans is associated with geography, diet, lifestyles and so on, but its relationship with some isolated populations is not clear. We used the 16sRNA technique to sequence the fecal microbiome in the Chinese isolated Yao population and compared it with the major minority Zhuang and the major ethnic Han populations living in the same rural area. Information about diet frequency and health status and routine serum measurements were collected. The unweighted UniFrac principal coordinates analysis showed significant structural differences in fecal microbiota among the three ethnic groups. Statistically significant differences were observed in the community richness estimator (chaos) and the diversity estimator (Shannon) among the three groups. At the genus level, the fecal samples of the isolated Yao population presented the lowest relative abundance of the Megamonas genus, which was potentially related to the high frequency of bean consumption in the diet. Two enterotypes were identified in the overall fecal microbiota in the three populations. In the isolated Yao population, a higher Bacteroides abundance was observed, but the Prevotella abundance decreased with increased alcohol consumption.

Some studies have reported that hepatitis B virus (HBV) infection affects the risk of nonalcoholic fatty liver disease (NAFLD). However, this association is controversial. We conducted a systematic review and meta-analysis to investigate the relationship between HBV infection and NAFLD. Relevant studies published before May 2017 were identified by searching PubMed, EMBASE, and ISI Web of Science. We used the random-effects model proposed by DerSimonian and Laird to quantify the relationship between HBV infection and risk of NAFLD. We also conducted subgroup and sensitivity analyses to validate the stability of the results. Five articles, comprising 8,272 HBV-infected patients and 111,631 uninfected controls, were included in our research. Our meta-analysis suggested that the risk of NAFLD was significantly lower in HBV-infected patients than in uninfected controls, with heterogeneity between studies (summary odds ratio [OR] = 0.71; confidence interval [CI] = 0.53-0.90; I2 = 75.2%). However, the inverse relationship was observed in only cohort (OR = 0.83; 95% CI = 0.73-0.94) and cross-sectional studies (OR = 0.63; 95% CI = 0.47-0.79), not case-control studies (OR = 3.96; 95% CI = 2.10-7.48). In conclusion, HBV infection was inversely associated with the risk of NAFLD.

TP53 mutation is the most common mutation in hepatocellular carcinoma (HCC), and it affects the progression and prognosis of HCC. We investigated how TP53 mutation regulates the HCC immunophenotype and thus affects the prognosis of HCC.

Most cases of hepatocellular carcinoma (HCC) are already advanced at the time of diagnosis, which limits treatment options. Challenges in early-stage diagnosis may be due to the genetic complexity of HCC. Gene fusion plays a critical function in tumorigenesis and cancer progression in multiple cancers, yet the identities of fusion genes as potential diagnostic markers in HCC have not been investigated. Here, we employed STAR-Fusion and identified 43 recurrent fusion events in our own and four public RNA-seq datasets. We identified 2354 different gene fusions in two hepatitis B virus (HBV)-HCC patients. Validation analysis against the four RNA-seq datasets revealed that only 1.8% (43/2354) were recurrent fusions. Comparison with the four fusion databases demonstrated that 19 recurrent fusions were not previously annotated to diseases and three were annotated as disease-related fusion events. Finally, we validated six of the novel fusion events, including RP11-476K15.1-CTD-2015H3.2, by RT-PCR and Sanger sequencing of 14 pairs of HBV-related HCC samples. In summary, our study provides new insights into gene fusions in HCC and may contribute to the development of anti-HCC therapy.

rs2274911 (Pro91Ser, G > A) is a missense mutation located on the second exon of the GPRC6A gene. Increasing evidence revealed a significant association between the A allele of rs2274911 and male diseases, such as oligospermia, cryptorchidism, and prostate tumor. However, the function of rs2274911 in healthy males is unclear.

Intraductal papillary neoplasm of the bile duct (IPNB) has been widely recognized. However, the knowledge of intracystic papillary neoplasm of the gallbladder (IPNG) including papillary adenoma and adenocarcinoma is not well defined. In this study, we compared the clinicopathological and immunohistochemical features between 32 IPNG cases and 32 IPNB cases. IPNG-1 (low-high grade dysplasia) exhibited an earlier onset age, smaller tumor size and lower level of CK20 expression compared to IPNG-2 (invasive carcinoma). Histologically, pancreaticobiliary and intestinal subtype accounted for nearly half of IPNG or IPNB (44.4% and 48.1% vs. 44.0% and 44.0%), respectively. Immunohistochemically, 88.9% of IPNG and 92.0% of IPNB cases were positive for MUC1, and 96.3% and 92.0% for CK7, respectively. CDX2 and MUC2 were more highly expressed in the intestinal subtype than in other subtypes. CK20 expression increased in parallel with tumor progression. In addition, 53.1% of IPNG cases and 68.6% of IPNB cases exhibited invasive carcinoma, and showed significant survival advantages to conventional gallbladder adenocarcinoma and cholangiocarcinoma, respectively. In conclusion, papillary adenoma and adenocarcinoma of the gallbladder can be recognized as different pathological stages of IPNG, and they share pathological features with IPNB.

The RTK/ERK signaling pathway has been implicated in prostate cancer progression. However, the genetic relevance of this pathway to aggressive prostate cancer at the SNP level remains undefined. Here we performed a SNP and gene-based association analysis of the RTK/ERK pathway with aggressive prostate cancer in a cohort comprising 956 aggressive and 347 non-aggressive cases. We identified several loci including rs3217869/CCND2 within the pathway shown to be significantly associated with aggressive prostate cancer. Our functional analysis revealed a statistically significant relationship between rs3217869 risk genotype and decreased CCND2 expression levels in a collection of 119 prostate cancer patient samples. Reduced expression of CCND2 promoted cell proliferation and its overexpression inhibited cell growth of prostate cancer. Strikingly, CCND2 downregulation was consistently observed in the advanced prostate cancer in 18 available clinical data sets with a total amount of 1,095 prostate samples. Furthermore, the lower expression levels of CCND2 markedly correlated with prostate tumor progression to high Gleason score and elevated PSA levels, and served as an independent predictor of biochemical relapse and overall survival in a large cohort of prostate cancer patients. Together, we have identified an association of genetic variants and genes in the RTK/ERK pathway with prostate cancer aggressiveness, and highlighted the potential importance of CCND2 in prostate cancer susceptibility and tumor progression to metastasis.

Phenomics provides new technologies and platforms as a systematic phenome-genome approach. However, few studies have reported on the systematic mining of shared genetics among clinical biochemical indices based on phenomics methods, especially in China. This study aimed to apply phenomics to systematically explore shared genetics among 29 biochemical indices based on the Fangchenggang Area Male Health and Examination Survey cohort.

GTSE1 is well correlated with tumor progression; however, little is known regarding its role in liver cancer prognosis. By analyzing the hepatocellular carcinoma (HCC) datasets in GEO and TCGA databases, we showed that high expression of GTSE1 was correlated with advanced pathologic stage and poor prognosis of HCC patients. To investigate underlying molecular mechanism, we generated GTSE1 knockdown HCC cell line and explored the effects of GTSE1 deficiency in cell growth. Between GTSE1 knockdown and wild-type HCC cells, we identified 979 differentially expressed genes (520 downregulated and 459 upregulated genes) in the analysis of microarray-based gene expression profiling. Functional enrichment analysis of DEGs suggested that S phase was dysregulated without GTSE1 expression, which was further verified from flow cytometry analysis. Moreover, three other DEGs: CDC20, PCNA, and MCM6, were also found contributing to GTSE1-related cell cycle arrest and to be associated with poor overall survival of HCC patients. In conclusion, GTSE1, together with CDC20, PCNA, and MCM6, may synergistically promote adverse prognosis in HCC by activating cell cycle. Genes like GTSE1, CDC20, PCNA, and MCM6 may be promising prognostic molecular biomarkers in liver cancer.

To explore and understand the competitive mechanism of ceRNAs in intrahepatic cholangiocarcinoma (ICC), we used bioinformatics analysis methods to construct an ICC-related ceRNA regulatory network (ceRNET), which contained 340 lncRNA-miRNA-mRNA regulatory relationships based on the RNA expression datasets in the NCBI GEO database. We identified the core regulatory pathway RP11-328K4.1-hsa-miR-27a-3p-PROS1, which is related to ICC, for further validation by molecular biology assays. GO analysis of 44 differentially expressed mRNAs in ceRNET revealed that they were mainly enriched in biological processes including "negative regulation of epithelial cell proliferation" and "positive regulation of activated T lymphocyte proliferation." KEGG analysis showed that they were mainly enriched in the "complement and coagulation cascade" pathway. The molecular biology assay showed that lncRNA RP11-328K4.1 expression was significantly lower in the cancerous tissues and peripheral plasma of ICC patients than in normal controls (p<0.05). In addition, hsa-miR-27a-3p was found to be significantly upregulated in the cancer tissues and peripheral plasma of ICC patients (p<0.05). Compared to normal controls, the expression of PROS1 mRNA was significantly downregulated in ICC patient cancer tissues (p<0.05) but not in peripheral plasma (p>0.05). Furthermore, ROC analysis revealed that RP11-328K4.1, hsa-miR-27a-3p, and PROS1 had significant diagnostic value in ICC. We concluded that the upregulation of lncRNA RP11-328K4.1, which might act as a miRNA sponge, exerts an antitumor effect in ICC by eliminating the inhibition of PROS1 mRNA expression by oncogenic miRNA hsa-miR-27a.

Fat mass and obesity-associated (FTO) gene is an obesity susceptibility gene and its relationship with the nonalcoholic fatty liver disease (NAFLD) remains unclear. This study aims to investigate the relationships of FTO gene variations with NAFLD risk in a Chinese male population.

Abnormal activation of the coagulation system has been reported in patients with malignancies, but its prognostic significance in biliary tract cancer (BTC) remains unclear. This study aims to analyze and compare the prognostic value of coagulation indices in patients with BTC.

Purpose: The albumin-to-γ-glutamyltransferase ratio (AGR), a novel inflammation-related index, has been reported to have prognostic importance in several malignancies but not yet in gallbladder cancer (GBC). This study intended to assess the prognostic value of AGR in GBC and to develop a nomogram based on AGR for predicting overall survival (OS) in GBC patients after surgery. Methods: Medical records of 140 qualified GBC patients between July 2003 and June 2017 were retrospectively analyzed. The function "surv_cutpoint" in the R package "survminer" was implemented to discover the optimal cut-off value of AGR. A nomogram on the fundamental of Cox model was established in the training cohort and was internally validated using calibration curves, Harrell's concordance index, time-dependent AUC plots and decisive curve analyses. Results: The optimal AGR cut-off value concerning overall survival was 2.050. Univariate and multivariate analyses demonstrated that AGR (HR=0.354, P=0.004), T stage (HR=3.114, P=0.004), R0 resection (HR=0.448, P=0.003), BMI (HR=0.470, P=0.002) and CA19-9 (HR=1.704, P=0.048) were independent predictors for OS. The nomogram combining these prognostic factors showed considerable prognostic performance in term of consistency, discrimination and net benefit. Conclusion: AGR has independent prognostic value for OS in GBC patients receiving surgery. A nomogram incorporating AGR, T stage, R0 resection, CA19-9 and BMI achieved enhanced prognostic ability.

Glioma is regarded as an aggressive lethal primary brain tumor. Jumonji domain containing 1C (JMJD1C) is a H3K9 demethylase which participates in the progression of various tumors, but its specific function and underlying mechanism in glioma development remain undefined, which is the purpose of our work. We initially assessed JMJD1C expression in glioma tissues and cells using the assays of RT-qPCR and immunohistochemistry. Meanwhile, the H3K9 level at the microRNA (miR)-302a promoter region was measured by chromatin immunoprecipitation assay, while luciferase-based reporter assay was performed for validation of the binding affinity between miR-302a and methyltransferase-like 3 (METTL3). The effect of METTL3 on suppressor of cytokine signaling 2 (SOCS2) was subsequently analyzed by MeRIP-RT-qPCR. Finally, a xenograft tumor model was established in nude mice, followed by measurement of tumor-associated macrophages using flow cytometry. JMJD1C was poorly expressed in glioma tissues. Furthermore, JMJD1C increased miR-302a expression through promoting H3K9me1 demethylation at the miR-302a promoter region. miR-302a was identified to target METTL3, which could inhibit SOCS2 expression via m6A modification. JMJD1C promoted M1 macrophage polarization and suppressed the growth of glioma xenografts through the miR-302a/METTL3/SOCS2 axis both in vivo and in vitro. In conclusion, JMJD1C could enhance M1 macrophage polarization to inhibit the onset of glioma, bringing a new insight into the contribution of JMJD1C to the pathobiology of glioma, with possible implications for targeted therapeutic method.

Long non-coding RNAs (lncRNAs) have been manifested to manipulate diverse biological processes, including tumor-induced immune tolerance. Thus, we aimed in this study to identify the expression pattern of lncRNA homeobox A cluster antisense RNA 2 (HOXA-AS2) in glioma and decipher its role in immune tolerance and glioma progression. We found aberrant upregulation of lncRNA HOXA-AS2, lysine demethylase 2A (KDM2A), and jagged 1 (JAG1) and a downregulation of microRNA-302a (miR-302a) in glioma specimens. Next, RNA immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase reporter gene assay demonstrated that lncRNA HOXA-AS2 upregulated KDM2A expression by preventing miR-302a from binding to its 3'untranslated region. The functional experiments suggested that lncRNA HOXA-AS2 could promote regulatory T (Treg) cell proliferation and immune tolerance, which might be achieved through inhibition of miR-302a and activation of KDM2A/JAG1 axis. These findings were validated in a tumor xenograft mouse model. To conclude, lncRNA HOXA-AS2 facilitates KDM2A/JAG1 expression to promote Treg cell proliferation and immune tolerance in glioma by binding to miR-302a. These findings may aid in the development of novel antitumor targets.

Immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of many cancers. However, the limited population that benefits from ICI therapy makes it necessary to screen predictive biomarkers for stratifying patients. Currently, many biomarkers, such as tumor mutational burden (TMB), have been used in the clinic as indicative biomarkers. However, some high-TMB patients with mutations in genes that are closely related to immunotherapeutic resistance are not sensitive to ICI therapy. Thus, there is a need to move beyond TMB and identify specific genetic determinants of the response to ICI therapy. In this study, we established a comprehensive mutation-based gene set across different tumor types to predict the efficacy of ICI therapy.

Glioblastoma angiogenesis is critical for tumor growth, making it an appealing target for treatment development. BAY1143269 is a novel inhibitor of mitogen-activated protein kinase interacting serine/threonine-protein kinase 1 (MKN1) and has potent anti-cancer activity. We identified BAY1143269 as an angiogenesis inhibitor, by in vitro and in vivo glioblastoma angiogenesis models. BAY1143269 inhibited the capillary network formation of glioblastoma microvascular endothelial cells (GMECs), particularly the early stage of tubular structure formation. It also inhibited migration and proliferation, and induced apoptosis of GMECs isolated from glioblastoma patients. We found that BAY1143269 acted on GMECs by suppressing the eukaryotic translation initiation factor 4E (eIF4E) and eIF4E-mediated expression of oncogenic proteins, including those involved in cell cycle, epithelial-mesenchymal transition (EMT), and pro-survival. In addition, BAY1143269 suppressed eIF4E phosphorylation, inhibited proliferation, and induced apoptosis of glioblastoma cells. Interestingly, it reduced vascular endothelial growth factor (VEGF) level in tumor cells and culturing medium, demonstrating the inhibitory effect of BAY1143269 on tumor proangiogenic microenvironment. We finally challenged BAY1143269 on the glioblastoma xenograft mice model and observed a significant tumor growth reduction without toxicity in mice receiving oral BAY1143269. Immunoblotting analysis demonstrated significantly less phosphorylated-eIF4E (p-eIF4E), cluster of differentiation 31 (CD31) (microvascular endothelial cell marker), and VEGF in tumors from drug-treated mice. In summary, the inhibition of glioblastoma angiogenesis with BAY1143269 may provide an alternative approach for anti-glioblastoma therapy.