Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 47
Filter
1.
J Cell Biochem ; : e30621, 2024 Jun 26.
Article in English | MEDLINE | ID: mdl-38924128

ABSTRACT

Activating transcription factor 6 (ATF6) and its downstream genes are involved in progression of hepatocellular carcinoma (HCC). Herein, we demonstrated that sulfhydration of Ras-related protein Rab-7a (RAB7A) was regulated by ATF6. High expression of RAB7A indicated poor prognosis of HCC patients. RAB7A overexpression contributed to proliferation, colony formation, migration, and invasion of HepG2 and Hep3B cells. Furthermore, we found that RAB7A enhanced aerobic glycolysis in HepG2 cells, indicating a higher degree of tumor malignancy. Mechanistically, RAB7A suppressed Yes-associated protein 1 (YAP1) binding to 14-3-3 and conduced to YAP1 nuclear translocation and activation, promoting its downstream gene expression, thereby promoting growth and metastasis of liver cancer cells. In addition, knocking down RAB7A attenuated the progression of orthotopic liver tumors in mice. These findings illustrate the important role of RAB7A in regulating HCC progression. Thus, RAB7A may be a potential innovative target for HCC treatment.

2.
Mol Ther Nucleic Acids ; 33: 164-179, 2023 Sep 12.
Article in English | MEDLINE | ID: mdl-37456776

ABSTRACT

We have shown previously that polymorphism of activating transcription factor 6 (ATF6) is associated with susceptibility to hepatocellular carcinoma (HCC). Therefore, genes down-regulated by ATF6 might play a tumor-suppressing role. In the present study, we identified that expression of protein phosphatase magnesium- or manganous-dependent 1H (PPM1H) mRNA and protein can be inhibited by ATF6 in hepatoma cells and mice with liver Atf6 knockdown. Tumor tissues from 134 HCC patients were analyzed by immunohistochemistry, and PPM1H exhibited higher expression levels in adjacent para-cancer tissues than in HCC tissues. Therefore, patients with higher expression of PPM1H had a better prognosis. PPM1H inhibited proliferation, migration, and invasion of hepatoma cells. In addition, PPM1H inhibited induced HCC nodule formation as well as tumor xenograft growth in diethylnitrosamine/CCl4-induced HCC mouse model and nude mouse tumorigenicity assay, respectively. A 3D model of PPM1H was obtained by homology multi-template modeling, and ribosomal protein S6 kinase B1 (RPS6KB1) in the bone morphogenetic protein (BMP)/transforming growth factor ß (TGF-ß) pathway was screened out as the potential substrate of PPM1H by Rosetta. PPM1H could directly dephosphorylate p-RPS6KB1. To conclude, we discovered RPS6KB1 as a new PPM1H dephosphorylation substrate. PPM1H exhibited a suppressive effect on HCC progression by dephosphorylating p-RPS6KB1.

3.
Biochem Biophys Res Commun ; 615: 109-115, 2022 07 30.
Article in English | MEDLINE | ID: mdl-35609415

ABSTRACT

Endoplasmic reticulum stress (ER stress) plays a crucial role in the process of Alzheimer's disease (AD). Activating transcription factor 6 (ATF6) is a crucial sensor of ER stress. In AD patients, the homeostasis of the endogenous signal H2S produced by cystathionine γ-lyase (CTH) is in disbalance. However, the role of ATF6 and CTH in AD is rarely reported. Herein, we found that ATF6 and CTH were reduced in AD patients and APP/PS1 mice by immunohistochemistry and western blots. In LN229 and U87 MG cells, knockdown of ATF6 attenuated CTH expression, whereas overexpression of ATF6 resulted in upregulation of CTH. Brain-specific ATF6 knockout mice expressed significantly down-regulated CTH in the hippocampus and cortex compared to wild-type mice. Mechanistically, ATF6 and CTH increased H2S generation and autophagy-related proteins. Further we observed that CTH promoted the sulfhydration of αSNAP. This is probably to be the specific mechanism by which AFT6 promotes autophagy. Through in vivo studies, we found that αSNAP sulfhydration expression was significantly lower in ATF6 knockout mice than in wild-type mice. Decreased ATF6 impaired spatial memory retention, while addition of CTH rescued memory loss. Together, we demonstrate that ATF6 positively regulates the expression of CTH, which is closely related to the rescue of AD. Targeting the ATF6/CTH signal pathway may provide a new strategy for the treatment of AD.


Subject(s)
Activating Transcription Factor 6/metabolism , Alzheimer Disease , Activating Transcription Factor 6/genetics , Alzheimer Disease/genetics , Animals , Autophagy , Cystathionine , Cystathionine gamma-Lyase/genetics , Cystathionine gamma-Lyase/metabolism , Humans , Mice , Mice, Knockout
4.
Andrologia ; 54(3): e14350, 2022 Apr.
Article in English | MEDLINE | ID: mdl-34904262

ABSTRACT

Activating transcription factor 6 (ATF6), also known as ACHM7, ATF6A, encodes a transcription factor that activates target genes for the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress. It functions as nuclear transcription factor via a cis-acting ER stress response element (ERSE) that is presented in the promoters of genes encoding ER chaperones. Studies have shown that endoplasmic reticulum stress (ERS) can cause damage to spermatozoa and testes, leading to male sterility. And we find that the expression of ATF6 in spermatozoa of some infertile patients is significantly reduced. Then, we construct the Atf6 knockout mice model and interestingly find a decline in male fertility. The downstream gene testis-specific serine/threonine-protein kinase 4 (Tssk4) is screened based on transcriptome sequencing. We use Western blot and real-time PCR to confirm this result in both 293T cells and Atf6 knockout mice. TSSK4 is essential in male germ cell genesis and sperm maturation. Our results suggest that the expression of TSSK4 may be regulated by ATF6. The effect of Atf6 knockout on the reproductive development of male mice may be related to the low expression of TSSK4, which further verify that there may be some relationship between ERS and male reproduction.


Subject(s)
Activating Transcription Factor 6 , Endoplasmic Reticulum , Activating Transcription Factor 6/genetics , Activating Transcription Factor 6/metabolism , Animals , Endoplasmic Reticulum/metabolism , Humans , Male , Mice , Mice, Knockout , Spermatogenesis/genetics , Transcription Factors/genetics
5.
Mol Ther ; 29(3): 1335-1348, 2021 03 03.
Article in English | MEDLINE | ID: mdl-33279720

ABSTRACT

The partial response of chronic hepatitis B virus (CHB) patients to interferon-α (IFN-α) therapy remains elusive, which requires a better understanding of the involved molecular mechanism. In our study, bioinformatics analysis was applied to relate IFN-α regulated candidate genes and RNA editing sites by RNA sequencing. Mitochondrial antiviral signaling protein (MAVS) antiviral effect was confirmed in HepG2.2.15 cells and in two mouse models. The associations between polymorphisms in MAVS gene and response to IFN-α therapy were confirmed in CHB patients. We found that IFN-α downregulates MAVS via RNA editing that was mediated by adenosine deaminase acting on RNA (ADAR1). ADAR1 inhibited MAVS expression via a human antigen R (HuR)-mediated post-transcriptional regulation. MAVS exerted an antiviral activity and reduced the level of hepatitis B virus (HBV) markers in vitro and in vivo. IFN-α antiviral effects were significantly enhanced by MAVS co-transfection. Hepatitis B core protein (HBc) interacted with SP1 to inhibit the promoter activity of MAVS that regulates its expression. CHB patients with a rs3746662A allele had higher MAVS expression and thus were more responsive to IFN-α treatment. In this work, we demonstrated that the decrease of MAVS expression is mediated by the IFN-α-ADAR1 axis. This study also highlighted the potential for the clinical application of MAVS in combination with IFN-α for the treatment of HBV infection.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Adenosine Deaminase/metabolism , Gene Expression Regulation/drug effects , Hepatitis B virus/drug effects , Hepatitis B, Chronic/drug therapy , Interferon-alpha/pharmacology , RNA Editing , RNA-Binding Proteins/metabolism , Adaptor Proteins, Signal Transducing/genetics , Adenosine Deaminase/genetics , Animals , Antiviral Agents/pharmacology , Hep G2 Cells , Hepatitis B virus/isolation & purification , Hepatitis B, Chronic/immunology , Hepatitis B, Chronic/metabolism , Hepatitis B, Chronic/pathology , Humans , Immunity, Innate , Mice , Mice, Transgenic , RNA-Binding Proteins/genetics , Signal Transduction
6.
Int J Neurosci ; 130(10): 1015-1023, 2020 Oct.
Article in English | MEDLINE | ID: mdl-31928492

ABSTRACT

OBJECTIVES: Amyloid plaques are the most important pathological hallmarks of Alzheimer's disease. The deposition of amyloid plaques will cause ER Stress. Activating Transcription Factor 6(ATF6) is a sensor of ER Stress. However, the role of ATF6 in Alzheimer's disease has not been reported yet. METHODS: The levels of ß-site APP-cleaving enzyme 1 (BACE1) and Aß1-42 were detected by Western blot, ELISA and Thioflavin S staining. Y maze and Morris water maze tests were used to detect the learning and memory functions. Dual luciferase assay was used to test the promoter activity of BACE1 and ADAM17. RESULTS: In our study, we found that the expression of ATF6 was reduced in APPswe/PSNdE9 (APP/PS1) Alzheimer's disease model mice compared with wild type mice. Furthermore, in LN229 cell, we found that ATF6 reduced the expression of full length amyloid precursor protein (APP) in protein level. At the same time, the overexpression of ATF6 strikingly reduced the level of Aß1-42. Interestingly, ATF6 also downregulated the promoter activity of BACE1. And some behavioral experiments like Y maze and Morris water maze test indicated that ATF6 could protect retention of spatial memory in APP/PS1 mice. CONCLUSION: Our findings indicated that ATF6 rescued the amyloid pathology by downregulating BACE1. Therefore, we suggest that ATF6 could be a potential hub for targeting treatment of the Alzheimer's disease.


Subject(s)
Activating Transcription Factor 6/metabolism , Alzheimer Disease/metabolism , Alzheimer Disease/physiopathology , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Aspartic Acid Endopeptidases/metabolism , Peptide Fragments/metabolism , Spatial Memory/physiology , Animals , Behavior, Animal/physiology , Disease Models, Animal , Down-Regulation , Maze Learning/physiology , Mice , Mice, Transgenic
7.
Neurobiol Dis ; 121: 274-285, 2019 01.
Article in English | MEDLINE | ID: mdl-30347267

ABSTRACT

Proline-rich transmembrane protein 2 (PRRT2) was identified as the causative gene of paroxysmal kinesigenic choreoathetosis (PKC) as well as various other neurological diseases. However, the molecular mechanisms of how mutant PRRT2 leads to abnormal synaptic function and triggers PKC are still obscure. We generated a Prrt2 truncated mutant rat model which shows spontaneous PKC-like attacks with a relative low frequency as well as increased susceptibility to pentylenetetrazol (PTZ)-induced seizures. We demonstrate that PRRT2 is expressed on both pre- and post-synaptic membranes in the M1 cortex. PRRT2 negatively regulates SNARE complex assembly through interaction with SNAP25, STX1A, and VAMP2. In the M1 cortex of the rat model, release of amino acid neurotransmitters is increased. Protein levels of glutamate receptor subunit GRIA1 are significantly increased in PRRT2 mutant rats, while GABA receptor subunits GABRA1 are significantly reduced. Both frequency and amplitude of mEPSC are significantly increased, while amplitude of mIPSC is decreased and the ratio of mEPSC/mIPSC is significantly increased. The balance between excitatory and inhibitory neuronal activity is disrupted, which could lead to abnormal neuronal hyperexcitability. These results provide new insights into the function of PRRT2 in synaptic transmission and movement control, as well as the pathogenic mechanism underlying PKC.


Subject(s)
Dystonia/metabolism , Membrane Proteins/metabolism , Motor Cortex/metabolism , Nerve Tissue Proteins/metabolism , Presynaptic Terminals/metabolism , Animals , Disease Models, Animal , Dystonia/chemically induced , Female , Male , Membrane Proteins/genetics , Motor Cortex/ultrastructure , Nerve Tissue Proteins/genetics , Pentylenetetrazole/administration & dosage , Presynaptic Terminals/ultrastructure , Rats, Sprague-Dawley , SNARE Proteins/metabolism , Synaptic Potentials , Synaptic Vesicles/metabolism
8.
Oncol Lett ; 14(4): 4403-4409, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28943956

ABSTRACT

Hepatocellular carcinoma (HCC) accounts for a proportion of cancer-associated mortalities worldwide. Hepatitis B virus (HBV) infection is a major cause of HCC in China. Thapsigargin (TG) is a potential antitumor prodrug, eliciting endoplasmic reticulum (ER) stress via the inhibition of the ER calcium pump, effectively inducing apoptosis. The present study therefore examined the role of HBV in TG-induced apoptosis using two HCC cell lines, HBV positive HepG2.2.15 and HBV negative HepG2. When these two cell lines were treated with TG, HepG2.2.15 was less susceptible to apoptosis than HepG2. This phenomenon was confirmed by an MTT assay and Annexin V-FITC/propidium iodide staining. Reverse transcription quantitative polymerase chain reaction and western blotting were used to detect the expression levels of genes in the ER stress pathway subsequent to treatment with TG. Notably, the mRNA and protein levels of the apoptosis factor DNA damage inducible transcript 3 (CHOP) increased significantly in the HepG2 cells compared with the HepG2.2.15 cells. Additionally, the HepG2.2.15 cells treated with interferon-α exhibited higher levels of CHOP compared with the untreated cells. The overexpression or knockdown of CHOP microRNA in HepG2.2.15 or HepG2 cells may reduce the difference in apoptosis status between the two cell lines. These results suggest that HBV may inhibit the apoptosis induced by ER stress. These findings may be useful in the development of selective therapies for patients with HBV-positive tumors.

9.
Int Immunopharmacol ; 48: 76-83, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28477473

ABSTRACT

The major histocompatibility complex (MHC) is the connection between innate immunity and acquired immune system. Recently, many studies reported that the immunoresponsive gene 1 (IRG1) play an important role on innate immunity including reactive oxygen species (ROS), antiviral effect and expression of inflammatory factors. However, the function of IRG1 in antigen presenting remains unclear. In this study, we found that overexpressed-IRG1 promoted MHC I level instead of MHC II in macrophages membrane. Besides, IRG1 increased expression of some transporter proteins associated with antigen processing involving TAP1, PSMB9 depending on ROS. By detecting the activation of glucose-6-phosphate dehydrogenase (G6PD), we confirmed that IRG1 could increase ROS level by promoting pentose phosphate pathway (PPP). DPI, an inhibitor of NADPH oxidase (NOX), also significant attenuated TAP1 and MHC I level in IRG1-overexpressed macrophages. Finally, results showed that phosphorylation of STAT1/3 involved in IRG1-mediated TAP1 and MHC I expression. In conclusion, IRG1 increased MHC class I level in macrophages through STAT1/3-TAP1 axis depending on PPP and NOX mediated ROS.


Subject(s)
Histocompatibility Antigens Class I/metabolism , Macrophages/metabolism , Proteins/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 2/genetics , Carboxy-Lyases , Cell Line , Cysteine Endopeptidases/genetics , Humans , Immunoglobulin G/metabolism , NADPH Oxidase 1 , NADPH Oxidases/metabolism , Proteins/genetics , RNA, Messenger/metabolism , Reactive Oxygen Species/metabolism , STAT1 Transcription Factor/genetics , STAT1 Transcription Factor/metabolism , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism
10.
Oncol Lett ; 14(6): 8227, 2017 12.
Article in English | MEDLINE | ID: mdl-29344266

ABSTRACT

[This corrects the article DOI: 10.3892/ol.2017.6666.].

11.
J Med Virol ; 89(7): 1215-1223, 2017 07.
Article in English | MEDLINE | ID: mdl-28004399

ABSTRACT

Vaccination against the hepatitis B virus (HBV) is extensively used as an effective method to prevent HBV infection. However, nearly 10% of healthy adults fail to produce a protective level of antibodies against the hepatitis B vaccine, and multiple genetic variants are known to affect the immune response to the hepatitis B vaccine. The aim of the present study was to investigate the association between polymorphisms in immunoresponsive gene 1 (IRG1) gene and the immune response to hepatitis B vaccination in a Chinese Han population. Four single nucleotide polymorphisms (SNPs) located in the IRG1 gene were genotyped in 1230 high-responders and 451 non-responders to hepatitis B vaccination. The SNPs rs17470171 and rs17385627 were associated with the immune response to hepatitis B vaccination (P = 0.014 and 0.029, respectively). In addition, the haplotypes G-A-A-A (rs614171-rs17470171-rs9530614-rs17385627, P = 0.0042, OR = 0.68) and A-A (rs17470171-rs17385627, P = 0.0065, OR = 0.72) exerted a protective role in the immune response to hepatitis B vaccination. Allele 'A' of rs17470171 and allele 'A' of rs17385627 show higher levels of expression for the IRG1 gene compared with allele 'C' of rs17470171 and allele 'T' of rs17385627 as demonstrated by luciferase reporter and overexpression assays. In addition, we observed that IRG1 inhibited the HBV life cycle and that IRG1 rs17385627 allele 'A' was more effective than rs17385627 allele 'T' at eliminating HBV in HepG2.2.15 cells. These findings suggest that polymorphisms in the IRG1 gene are associated with the immune response to hepatitis B vaccination. The antiviral effect of IRG1 was confirmed using HBV infection cell models.


Subject(s)
Alleles , Hepatitis B Vaccines/immunology , Polymorphism, Single Nucleotide , Proteins/genetics , Adult , Asian People , Carboxy-Lyases , Female , Gene Frequency , Genetic Predisposition to Disease/ethnology , Genotype , Haplotypes , Hep G2 Cells , Hepatitis B Vaccines/administration & dosage , Hepatitis B virus/immunology , Hepatitis B virus/physiology , Hepatitis B, Chronic/ethnology , Hepatitis B, Chronic/genetics , Hepatitis B, Chronic/immunology , Hepatitis B, Chronic/prevention & control , Humans , Male , Middle Aged
12.
Nat Commun ; 7: 11664, 2016 05 31.
Article in English | MEDLINE | ID: mdl-27244555

ABSTRACT

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.


Subject(s)
Carrier Proteins/genetics , Chromosomes, Human, Pair 8/genetics , Genetic Predisposition to Disease , Hepatitis B virus/physiology , Hepatitis B, Chronic/genetics , Adult , Aged , Asian People/genetics , Carrier Proteins/immunology , Case-Control Studies , Cell Line , Female , Genetic Loci/genetics , Genome-Wide Association Study , Hepatitis B Surface Antigens/isolation & purification , Hepatitis B virus/isolation & purification , Hepatitis B, Chronic/blood , Hepatitis B, Chronic/immunology , Hepatitis B, Chronic/virology , Hepatocytes , Humans , Interferon Regulatory Factor-3/immunology , Interferon Regulatory Factor-3/metabolism , Liver/cytology , Liver/immunology , Liver/virology , Male , Middle Aged , Polymorphism, Single Nucleotide , Serologic Tests , Viral Load/immunology , Virus Replication/immunology , Young Adult
13.
Hepatology ; 63(4): 1102-11, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26704347

ABSTRACT

UNLABELLED: Interferon (IFN)-α is a first-line therapy for chronic hepatitis B (CHB) patients but only initiates a response in a minority of patients. A genetic variant, rs7574865 in STAT4, was recently reported to be associated with risk of developing CHB and hepatitis B virus-related hepatocellular carcinoma. We aimed to determine whether this variant is associated with the response to IFNα treatment for hepatitis B e antigen (HBeAg)-positive CHB patients. We studied 466 HBeAg-positive CHB patients who received either IFNα-2b (n = 224) or pegylated IFNα-2a (n = 242) therapy for 48 weeks and were followed for an additional 24 weeks. The rate of sustained virologic response (SVR), defined as HBeAg seroconversion along with hepatitis B virus DNA level <2000 copies/mL at week 72, was compared among patients with different genotypes of rs7574865. After 48 weeks of treatment and 24 weeks off treatment, the SVR rates in the IFNα-2b and pegylated IFNα-2a therapy groups were 30.4% and 28.9%, respectively. Compared to the rs7574865 GT/TT genotype, the GG genotype (a risk factor of CHB and hepatitis B virus-related hepatocellular carcinoma) was significantly associated with a reduced SVR rate in both patients who received IFNα-2b therapy (21.1% versus 37.2%, P = 0.01) and those who received pegylated IFNα-2a therapy (18.0% versus 41.2%, P = 9.74 × 10(-5) ). In joint analysis of the 466 patients, the GG genotype was associated with an approximately half SVR rate compared to the GT/TT genotype (19.3% versus 39.1%, P = 4.15 × 10(-6) ). A multivariate logistic regression model including rs7574865 and clinical variables showed that rs7574865 was the most significant factor for the prediction of SVR. CONCLUSION: STAT4 rs7574865 is a reliable predictor of response to IFNα therapy for HBeAg-positive CHB patients and may be used for optimizing the treatment of CHB.


Subject(s)
Genetic Variation , Hepatitis B e Antigens/drug effects , Hepatitis B, Chronic/drug therapy , Hepatitis B, Chronic/genetics , Interferon-alpha/therapeutic use , STAT4 Transcription Factor/genetics , Adult , Aged , China , Cohort Studies , Confidence Intervals , Databases, Factual , Female , Follow-Up Studies , Genotype , Hepatitis B e Antigens/immunology , Hepatitis B, Chronic/diagnosis , Humans , Male , Middle Aged , Odds Ratio , Polymorphism, Single Nucleotide , Retrospective Studies , Risk Assessment , Severity of Illness Index , Statistics, Nonparametric , Treatment Outcome
14.
Int J Neurosci ; 126(5): 436-41, 2016.
Article in English | MEDLINE | ID: mdl-26000807

ABSTRACT

Various studies suggested that brain-derived neurotrophic factor (BDNF) gene polymorphisms contributed to the development of many neurological disorders. However, whether BDNF Val66Met polymorphism is associated with epilepsy remains controversial. In our study, we tried to investigate the effects of this functional polymorphism on the occurrence of temporal lobe epilepsy (TLE) and its clinical phenotypes. Case-control studies were employed to study the association between BDNF Val66Met polymorphism and TLE, as well as its clinical phenotypes, and magnetic resonance imaging examinations and voxel-based morphometry analyses were carried out for further study. Our results showed that the frequency of Met allele was found to be lower in the TLE patients compared with the control subjects (43.9% vs. 48.6%, P = 0.012, OR = 1.21, 95% CI = 1.04-1.41), and the frequency of Met66 allele carriers in the TLE with hippocampal sclerosis was significantly lower than those non-carriers (20.5% vs. 29.1%, P = 0.040). However, we failed to find the difference between different genotypes and hippocampal asymmetry. Our findings suggested that BDNF Val66Met polymorphism might be correlated with epileptogenesis, and Met66 allele might play a protective role against the occurrence of TLE.


Subject(s)
Brain-Derived Neurotrophic Factor/genetics , Epilepsy, Temporal Lobe/genetics , Genotype , Hippocampus/pathology , Polymorphism, Single Nucleotide , Adolescent , Adult , Alleles , Case-Control Studies , Child , Epilepsy, Temporal Lobe/pathology , Female , Gene Frequency , Humans , Magnetic Resonance Imaging , Male , Young Adult
15.
J Genet ; 94(4): 637-42, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26690518

ABSTRACT

Temporal lobe epilepsy (TLE) is the most common epilepsy subtype with complex genetic structure. A recent study in four populations (Ireland, UK, Australia and Finland) reported an allelic association between betaine/GABA transporter-1(BGT-1 or SLC6A12) and mesial temporal lobe epilepsy with hippocampal sclerosis. To demonstrate the association between SLC6A12 gene polymorphisms and TLE, TaqMan method was used to genotype five single-nucleotide polymorphisms of SLC6A12 gene in 358 TLE patients and 596 nonepileptic control subjects of Chinese Han origin. Real-time PCR was used to detect the effects of variations on gene expression associated with TLE. Though, the single-marker analysis did not demonstrate allelic association with TLE, rs542736-rs557881 interaction showed significant association. The SLC6A12 expression levels in peripheral blood mononuclear cells were significantly higher in TLE patients than in control subjects and were correlated to rs542736 G-rs557881 A haplotypes. Our preliminary results suggested combined effect of two common polymorphisms on SLC6A12 gene may be associated with TLE, but the precise mechanism needs further investigation.


Subject(s)
Carrier Proteins/genetics , Epilepsy, Temporal Lobe/genetics , Genetic Predisposition to Disease/genetics , Polymorphism, Single Nucleotide/genetics , Adult , Asian People/genetics , Case-Control Studies , Female , GABA Plasma Membrane Transport Proteins , Humans , Male
16.
Sci Rep ; 5: 16278, 2015 Nov 05.
Article in English | MEDLINE | ID: mdl-26538132

ABSTRACT

Recent genome-wide associated studies (GWASs) have revealed several common loci associated with the risk of hepatitis B virus (HBV)- or hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). We selected 15 single nucleotide polymorphisms (SNPs) identified through GWASs on HBV- or HCV-related HCC, and genotyped them in two independent Chinese cohorts of chronic HBV carriers, including 712 LC cases and 2601 controls. The association of each SNP with the risk of HBV-related LC was assessed by meta-analysis of the two cohorts. Of the 12 SNPs reported in HBV-related HCC GWASs, five SNPs (rs7574865 in STAT4, rs9267673 near C2, rs2647073 and rs3997872 near HLA-DRB1 and rs9275319 near HLA-DQ), were found to be significantly associated with the risk of HBV-related LC (rs7574865: P = 1.79 × 10(-2), OR = 1.17, 95% CI = 1.03-1.34; rs9267673: P = 4.91 × 10(-4), OR = 1.37, 95% CI = 1.15-1.63; rs2647073: P = 3.53 × 10(-5), OR = 1.63, 95% CI = 1.29-2.06; rs3997872: P = 4.22 × 10(-4), OR = 1.86, 95% CI = 1.32-2.62; rs9275319: P = 1.30 × 10(-2), OR = 1.32, 95% CI = 1.06-1.64). However, among the three SNPs associated with the risk of HCV-related HCC in previous GWASs, none of them showed significant association with the risk of HBV-related LC. Our results suggested that genetic variants associated with HBV-related hepatocarcinogenesis may already play an important role in the progression from CHB to LC.


Subject(s)
HLA-DQ Antigens/genetics , HLA-DRB1 Chains/genetics , Hepatitis B virus/metabolism , Liver Cirrhosis/genetics , Liver Cirrhosis/virology , Polymorphism, Single Nucleotide/genetics , STAT4 Transcription Factor/genetics , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/virology , Case-Control Studies , China , Female , Genetic Predisposition to Disease/genetics , Genome-Wide Association Study/methods , Genotype , Hepatitis B, Chronic/genetics , Hepatitis B, Chronic/virology , Humans , Liver Neoplasms/genetics , Liver Neoplasms/virology , Male , Middle Aged , Risk
17.
Chin Med J (Engl) ; 128(14): 1873-8, 2015 Jul 20.
Article in English | MEDLINE | ID: mdl-26168825

ABSTRACT

BACKGROUND: Fetal insulin hypothesis was proposed that the association between low birth weight and type 2 diabetes is principally genetically mediated. The aim of this study was to investigate whether common variants in genes CDKAL1, HHEX, ADCY5, SRR, PTPRD that predisposed to type 2 diabetes were also associated with reduced birthweight in Chinese Han population. METHODS: Twelve single nucleotide polymorphisms (rs7756992/rs10946398 in CDKAL1, rs1111875 in HHEX, rs391300 in SRR, rs17584499 in PTPRD, rs1170806/rs9883204/rs4678017/rs9881942/rs7641344/rs6777397/rs6226243 in ADCY5) were genotyped in 1174 unrelated individuals born in Peking Union Medical College Hospital from 1921 to 1954 by TaqMan allelic discrimination assays, of which 645 had normal glucose tolerance, 181 had developed type 2 diabetes and 348 impaired glucose regulation. Associations of these 12 genetic variants with birthweight and glucose metabolism in later life were analyzed. RESULTS: Birthweight was inversely associated with CDKAL1-rs10946398 (ß = -41 g [95% confidence interval [CI]: -80, -3], P = 0.034), common variants both associated with increased risk of impaired glucose metabolism and decreased insulin secretion index later in life. After adjusting for sex, gestational weeks, parity and maternal age, the risk allele of CDKAL1-rs7756992 was associated with reduced birthweight (ß = -36 g [95% CI: -72, -0.2], P = 0.048). The risk allele in SRR showed a trend toward a reduction of birthweight (P = 0.085). CONCLUSIONS: This study identified the association between type 2 diabetes risk variants in CDKAL1 and birthweight in Chinese Han individuals, and the carrier of risk allele within SRR had the trend of reduced birthweight. This demonstrates that there is a clear overlap between the genetics of type 2 diabetes and fetal growth, which proposes that lower birth weight and type 2 diabetes may be two phenotypes of one genotype.


Subject(s)
Birth Weight/genetics , Cyclin-Dependent Kinase 5/genetics , Diabetes Mellitus, Type 2/genetics , Adenylyl Cyclases/genetics , Aged , Alleles , Asian People/genetics , Female , Genetic Predisposition to Disease/genetics , Homeodomain Proteins/genetics , Humans , Infant, Low Birth Weight , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , Receptor-Like Protein Tyrosine Phosphatases, Class 2/genetics , Transcription Factors/genetics , tRNA Methyltransferases
18.
Int J Mol Sci ; 16(5): 9134-51, 2015 Apr 23.
Article in English | MEDLINE | ID: mdl-25915028

ABSTRACT

Paroxysmal kinesigenic choreoathetosis (PKC) is an inherited disease of the nervous system. We previously identified PRRT2 as the causative gene of PKC. However, as little is known about the function of PRRT2, elucidating its function will benefit not only PKC studies, but also many other related disorders. Here, we reveal higher levels of glutamate in the plasma of PKC patients and the culture medium of neurons following knock-out Prrt2 expression. Using double immunostaining assays we confirm Prrt2 is located at the glutamatergic neurons in accordance with its function. Our co-immunoprecipitation assays reveal mutant PRRT2 interferes with SNAP25 and GRIA1 interactions, respectively. Furthermore, using live-labeling techniques, we confirmed co-transfection with mutant PRRT2 caused an increase in GRIA1 distribution on the cell surface. Therefore, our results suggest that mutant PRRT2, probably through its weakened interaction with SNAP25, affects glutamate signaling and glutamate receptor activity, resulting in the increase of glutamate release and subsequent neuronal hyperexcitability.


Subject(s)
Glutamates/metabolism , Membrane Proteins/genetics , Mutation , Nerve Tissue Proteins/genetics , Signal Transduction , Adolescent , Adult , Age of Onset , Animals , Aspartic Acid/metabolism , Case-Control Studies , Cell Line , Cell Membrane/metabolism , Cells, Cultured , Child , Dystonia/genetics , Dystonia/metabolism , Female , Gene Knockout Techniques , Glycine/metabolism , Humans , Male , Membrane Proteins/metabolism , Mice , Nerve Tissue Proteins/metabolism , Neurons/metabolism , Protein Binding , Receptors, AMPA/metabolism , Young Adult
19.
Hepatology ; 62(1): 118-28, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25802187

ABSTRACT

UNLABELLED: Hepatitis B virus affects more than 2 billion people worldwide, 350 million of which have developed chronic hepatitis B (CHB). The genetic factors that confer CHB risk are still largely unknown. We sought to identify genetic variants for CHB susceptibility in the Chinese population. We undertook a genome-wide association study (GWAS) in 2,514 CHB cases and 1,130 normal controls from eastern China. We replicated 33 of the most promising signals and eight previously reported CHB risk loci through a two-stage validation totaling 6,600 CHB cases and 8,127 controls in four independent populations, of which two populations were recruited from eastern China, one from northern China and one from southern China. The joint analyses of 9,114 CHB cases and 9,257 controls revealed significant association of CHB risk with five novel loci. Four loci are located in the human leukocyte antigen (HLA) region at 6p21.3, including two nonsynonymous variants (rs12614 [R32W] in complement factor B [CFB], Pmeta =1.28 × 10(-34) ; and rs422951 [T320A] in NOTCH4, Pmeta = 5.33 × 10(-16) ); one synonymous variant (rs378352 in HLA-DOA corresponding to HLA-DOA*010101, Pmeta = 1.04 × 10(-23) ); and one noncoding variant (rs2853953 near HLA-C, Pmeta = 5.06 × 10(-20) ). Another locus is located at 20q13.1 (rs1883832 in the Kozak sequence of CD40, Pmeta = 2.95 × 10(-15) ). Additionally, we validated seven of eight previously reported CHB susceptibility loci (rs3130542 at HLA-C, rs1419881 at TCF19, rs652888 at EHMT2, rs2856718 at HLA-DQB1, rs7453920 at HLA-DQB2, rs3077 at HLA-DPA1, and rs9277535 at HLA-DPA2, which are all located in the HLA region, 9.84 × 10(-71) ≤ Pmeta ≤ 9.92 × 10(-7) ). CONCLUSION: Our GWAS identified five novel susceptibility loci for CHB. These findings improve the understanding of CHB etiology and may provide new targets for prevention and treatment of this disease.


Subject(s)
CD40 Antigens/genetics , Complement Factor B/genetics , HLA-C Antigens/genetics , Hepatitis B, Chronic/genetics , CD40 Antigens/blood , Complement Factor B/metabolism , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Linkage Disequilibrium , Male , Middle Aged
20.
J Med Virol ; 86(7): 1105-12, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24664813

ABSTRACT

No response to hepatitis B vaccination is a complex phenomenon, which is induced by the combinations of environmental and genetic factors. The aim of the study was to investigate the association between the polymorphisms of the butyrophilin-like 2 (BTNL2) gene and the immune response to hepatitis B vaccination in a Chinese Han population. A total of 7 single nucleotide polymorphisms in the BTNL2 gene were analyzed in 566 non-responders and 1,040 high-responders to hepatitis B vaccination. The alleles T, T, C, A, G of rs3763316, rs3763311, rs9268494, rs3806156, and rs2076530 were associated with no response to hepatitis B vaccination (P = 0.015, odds ratio (OR) = 1.20; P = 0.029, OR = 1.18; P = 2.00E-07, OR = 1.58; P = 0.002, OR = 1.27; P = 2.90E-06, OR = 1.41, respectively). Whereas, the alleles T, C of rs9268501 and rs3763313 played significantly protective roles in the immune response to hepatitis B vaccination (P = 0.007, OR = 0.81; P = 0.004, OR = 0.74). Besides, the risks of no response to hepatitis B vaccination were increased significantly among individuals harbored the haplotypes of G-T-A-T-C-A-G (P = 0.038, OR = 1.48), G-T-A-T-C (P < 0.0001, OR = 2.34), A-A (P < 0.0001, OR = 4.08), and C-G (P < 0.0001, OR = 4.75). However, the haplotype of G-C-A-T-C (P = 1.00E-04, OR = 0.54) exhibited a protective role in the immune response to hepatitis B vaccination in the study. These findings suggest that polymorphisms in the BTNL2 gene might play a vital role in determining the outcome of the immune response to hepatitis B vaccination.


Subject(s)
Hepatitis B Vaccines/immunology , Membrane Glycoproteins/genetics , Membrane Glycoproteins/immunology , Polymorphism, Single Nucleotide , Vaccination/methods , Adult , Butyrophilins , Case-Control Studies , China , Female , Gene Frequency , Hepatitis B Vaccines/administration & dosage , Humans , Male , Middle Aged
SELECTION OF CITATIONS
SEARCH DETAIL
...