Genetic variation in the interleukin-28B gene is associated with spontaneous clearance and progression of hepatitis C virus in Moroccan patients

Genetic variation in the IL28B gene has been strongly associated with treatment outcomes, spontaneous clearance and progression of the hepatitis C virus infection (HCV). The aim of the present study was to investigate the role of polymorphisms at this locus with progression and outcome of HCV infection in a Moroccan population. We analyzed a cohort of 438 individuals among them 232 patients with persistent HCV infection, of whom 115 patients had mild chronic hepatitis and 117 had advanced liver disease (cirrhosis and hepatocellular carcinoma), 68 individuals who had naturally cleared HCV and 138 healthy subjects. The IL28B SNPs rs12979860 and rs8099917 were genotyped using a TaqMan 5' allelic discrimination assay. The protective rs12979860-C and rs8099917-T alleles were more common in subjects with spontaneous clearance (77.9% vs 55.2%; p = 0.00001 and 95.6% vs 83.2%; p = 0.0025, respectively). Individuals with clearance were 4.69 (95% CI, 1.99-11.07) times more likely to have the C/C genotype for rs12979860 polymorphism (p = 0.0017) and 3.55 (95% CI, 0.19-66.89) times more likely to have the T/T genotype at rs8099917. Patients with advanced liver disease carried the rs12979860-T/T genotype more frequently than patients with mild chronic hepatitis C (OR = 1.89; 95% CI, 0.99-3.61; p = 0.0532) and this risk was even more pronounced when we compared them with healthy controls (OR = 4.27; 95% CI, 2.08-8.76; p = 0.0005). The rs8099917-G allele was also associated with advanced liver disease (OR = 2.34; 95% CI, 1.40-3.93; p = 0.0100). In the Moroccan population, polymorphisms near the IL28B gene play a role both in spontaneous clearance and progression of HCV infection

HCV-Induced Oxidative Stress: Battlefield-Winning Strategy

About 150 million people worldwide are chronically infected with hepatitis C virus (HCV). The persistence of the infection is controlled by several mechanisms including the induction of oxidative stress. HCV relies on this strategy to redirect lipid metabolism machinery and escape immune response. The 3 -hydroxysterol Δ24-reductase (DHCR24) is one of the newly discovered host markers of oxidative stress. This protein, as HCV-induced oxidative stress responsive protein, may play a critical role in the pathogenesis of HCV chronic infection and associated liver diseases, when aberrantly expressed. The sustained expression of DHCR24 in response to HCV-induced oxidative stress results in suppression of nuclear p53 activity by blocking its acetylation and increasing its interaction with MDM2 in the cytoplasm leading to its degradation, which may induce hepatocarcinogenesis

MDM2 285G>C and 344T>A gene variants and their association with hepatocellular carcinoma: a Moroccan case-control study

International audienceBackground MDM2 gene polymorphisms 285G/C and 344 T/A are two single nucleotide polymorphisms (SNPs) recently identified as important variants that could influence the expression of MDM2 gene through the modulation of transcription factors binding on the SNP309T/G. The 285C variant seems to present a geographically distinct distribution in humans and to be associated with a low cancer risk. In the present report, we studied the distribution of the three SNPs in a population with low liver cancer incidence.MethodsA group of 119 patients with hepatocellular carcinoma (HCC, 63.45 ± 12.59 year, 26-80) and another of 103 non-HCC controls (56 ± 10.82 year, 22-79) were enrolled to investigate association between MDM2 polymorphisms and susceptibility to develop HCC. The three studied SNPs (285G/C, 309 T/G and 344 T/A) were genotyped using polymerase chain reaction and sequencing techniques.ResultsGenotypes and alleles distributions of the three studied polymorphisms of MDM2 were not significantly different between cases and controls. An increased risk of HCC development was found in case of 309G allele presence albeit without reaching the significance (29.8% vs 22.3%, OR = 1.48, 95% CI, 0.96-2.27, p = 0.073). In addition, neither 285C nor 344A MDM2 variants were significantly associated with an increased risk of HCC (p = 0.688 and p = 1 respectively). Remarkably, we found that the supposedly Caucasian-specific 285C variant was present in 1% of the Moroccan population.ConclusionsThis is the first study of the MDM2 SNP285G/C and SNP344T/A polymorphisms in association with HCC development. In contrast with previous studies, showing that females carrying SNP285C variant have a significantly reduced risk of developing breast, ovarian and endometrial cancer, no significant modulation of HCC risk was found in a North-African population

Myxovirus resistance 1 gene polymorphisms and outcomes of viral hepatitis B and C infections in Moroccan patients

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Altérations somatiques du cancer primitif du foie en Russie: une étude pilote

International audiencePrimary liver cancer (PLC) is a major public health concern worldwide, ranking third among the causes of death from cancer. Molecular pathogenesis of PLC is known to be especially sensitive to ethno-environmental variations that modulate mutation spectra in tumours. Despite a high prevalence of chronic liver diseases, the molecular epidemiology of PLC is still poorly known in Russia. To characterize the major genetic features of liver tumours in Russian populations, we conducted a pilot study on 34 PLC cases (28 hepatocellular, two cholangiocellular, and four mixed cases) among patients attending the Radiology and Roentgenology Hospital in Saint Petersburg. Point mutations were searched in 9 genes that are commonly altered in PLC, viz. TP53, CTNNB1, AXIN1, H/K/N-RAS, BRAF, PTEN, and NFE2L2. The genes TP53 and AXIN1 were mutated in 16% and 10% of the cases, respectively, whereas mutations of β-catenin were present in only 7% of samples, an unusual situation for Europe but common in East Asia. No R249S mutation indicative of exposure to aflatoxin B1 was detected in TP53. A single case harboured an NFE2L2 mutation. The loss of chromosome 18q was associated with early onset of tumours (mean 50 vs 62yrs, p=0.0252) and with the patient's place of birth in Caucasus or Siberia. A lack of any risk factor was noted in 47% of the patients, whereas only 23% of the patients were infected either by hepatitis virus B or C. An extension of the present cohort as well as further molecular studies are now warranted in order to understand the processes governing liver carcinogenesis affecting Russian populations

Des effecteurs immunitaires polymorphes communs contre les hépatites B et C modulent la sensibilité à l'infection et la clairance spontanée dans une population marocaine

International audienceChronic diseases caused by hepatitis B and C viruses may evolve towards major complications as liver cirrhosis and cancer. Fortunately, only subsets among acutely infected individuals develop a persistent disease suggesting that genetic susceptibility may influence the establishment of chronicity. In the present study we aim to explore variants distribution in genes encoding for important immune response effectors in chronic hepatitis B and C. We intend to identify common features and to establish connections between single nucleotide polymorphisms (SNPs) predisposing to both chronic hepatitis and spontaneous clearance in a Moroccan population. Ten SNPs mapping on seven candidate genes (CD209, TGFβ-1, CCR5, CCL2, CXCL12, SUMO1 and UBC9) were studied in 544 Moroccan subjects grouped in chronically infected patients, spontaneously resolved individuals, liver disease progressors and healthy controls. Among significant associations found between virus infections and genetic variants, we report for the first time an association of rs4804803 (CD209) A and G variants with susceptibility to HBV infection and spontaneous clearance (p<0.001, OR=3.53, 95% CI 2.155; 5.908, and p<0.001, OR=7.75, 95% CI 4.646-13.114, respectively). Other important, albeit previously unknown, association was found between SUMO1 rs10185956T variant and spontaneous clearance of HCV infection (p=0.002, OR=2.71, 95% CI 1.332-5.869). Our observation, that deserves further confirmation with other SNPs and populations, underlines the involvement of selected immune polymorphisms, among which those in CD209, in the natural history of both chronic hepatitis B and C

Regulation by the RNA-binding protein Unkempt at its effector interface.

How RNA-binding proteins (RBPs) convey regulatory instructions to the core effectors of RNA processing is unclear. Here, we document the existence and functions of a multivalent RBP-effector interface. We show that the effector interface of a conserved RBP with an essential role in metazoan development, Unkempt, is mediated by a novel type of dual-purpose peptide motifs that can contact two different surfaces of interacting proteins. Unexpectedly, we find that the multivalent contacts do not merely serve effector recruitment but are required for the accuracy of RNA recognition by Unkempt. Systems analyses reveal that multivalent RBP-effector contacts can repurpose the principal activity of an effector for a different function, as we demonstrate for the reuse of the central eukaryotic mRNA decay factor CCR4-NOT in translational control. Our study establishes the molecular assembly and functional principles of an RBP-effector interface

TP53 R72P polymorphism modulates DNA methylation in hepatocellular carcinoma.

International audienceHepatocellular carcinoma (HCC) is characterized by widespread epidemiological and molecular heterogeneity. Previous work showed that in the western part of North Africa, a region of low incidence of HCC, mutations are scarce for this tumor type. As epigenetic changes are considered possible surrogates to mutations in human cancers, we decided, thus, to characterize DNA methylation in HCC from North-African patients. A set of 11 loci was investigated in a series of 45 tumor specimens using methylation-specific and combined-bisulfite restriction assay PCR. Results obtained on clinical samples were subsequently validated in liver cancer cell lines. DNA methylation at tumor suppressor loci is significantly higher in samples displaying chromosome instability. More importantly, DNA methylation was significantly higher in Arg/Arg when compared to Pro/Pro genotype carriers at codon 72 rs1042522 of TP53 (65% vs 20% methylated loci, p = 0.0006), a polymorphism already known to affect somatic mutation rate in human carcinomas. In vitro experiments in cell lines indicated that enzymes controlling DNA methylation were differentially regulated by codon 72 Arg or Pro isoforms of p53. Furthermore, the Arg72-carrying version of p53 was shown to re-methylate DNA more rapidly than the pro-harboring isoform. Finally, Pro-carrying cell lines were shown to be significantly more resistant to decitabine treatment (two-fold, p = 0.005). Our data suggest that Arg72Pro polymorphism in a WT p53 context may act as a primary driver of epigenetic changes in HCC. It suggests, in addition, that rs1042522 genotype may predict sensitivity to epigenetic-targeted therapy. This model of liver tumorigenesis that associates low penetrance genetic predisposition to epigenetic changes emerges from a region of low HCC incidence and it may, therefore, apply essentially to population living in similar areas. Surveys on populations submitted to highly mutagenic conditions as perinatally-acquired chronic hepatitis B or aflatoxin B1 exposure remained to be conducted to validate our observations as a general model

Oxidative Stress and Immune Responses During Hepatitis C Virus Infection in Tupaia belangeri

Abstract Hepatitis C virus (HCV) is a leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma. To address the molecular basis of HCV pathogenesis using tupaias (Tupaia belangeri), we characterized host responses upon HCV infection. Adult tupaias were infected with HCV genotypes 1a, 1b, 2a, or 4a. Viral RNA, alanine aminotransferase, anti-HCV core and anti-nonstructural protein NS3 antibody titres, reactive oxygen species (ROS), and anti-3β-hydroxysterol-Δ24reductase (DHCR24) antibody levels were measured at 2-week intervals from 0 to 41 weeks postinfection. All HCV genotypes established infections and showed intermittent HCV propagation. Moreover, all tupaias produced anti-core and anti-NS3 antibodies. ROS levels in sera and livers were significantly increased, resulting in induction of DHCR24 antibody production. Similarly, lymphocytic infiltration, disturbance of hepatic cords, and initiation of fibrosis were observed in livers from HCV-infected tupaias. Intrahepatic levels of Toll-like receptors 3, 7, and 8 were significantly increased in all HCV-infected tupaias. However, interferon-β was only significantly upregulated in HCV1a- and HCV2a-infected tupaias, accompanied by downregulation of sodium taurocholate cotransporting polypeptide. Thus, our findings showed that humoral and innate immune responses to HCV infection, ROS induction, and subsequent increases in DHCR24 auto-antibody production occurred in our tupaia model, providing novel insights into understanding HCV pathogenesis