title: The -94Ins/DelATTG polymorphism in NFκB1 promoter modulates chronic hepatitis C and liver disease progression.
abstract: Infection with Hepatitis C Virus (HCV) is one of the most important risk factor of hepatocellular carcinoma (HCC). HCV is suspected to induce HCC primarily through chronic inflammation and promotion of cirrhosis, a well-known pre-neoplastic condition. The NF-κB pathway is a key regulator of immune and inflammatory processes and plays a pivotal role in oncogenesis. Genetic variations affecting the pathway may alter NF-κB activity in response to HCV infection and contribute to liver tumorigenesis. The present study aims to evaluate the association between -94Ins/DelATTG (rs28362491) polymorphism in NF-κB1 gene promoter region and 2758G>A (rs696) single nucleotide polymorphism in the 3'UTR region of NFκBIA and the outcomes of HCV infection. In this case-control study, 559 subjects (343 patients with HCV infection including 237 mild chronic hepatitis patients and 106 patients with Advanced Liver Disease (AdLD), 78 individuals who naturally cleared HCV and 138 healthy subjects) were genotyped for the NFκB1 and NFκBIA SNPs using PCR-RFLP. Logistic regression was used to assess the association between polymorphisms and the outcome and progression of the infection. Variation at rs696 was not associated with HCV resolution or progression (P>0.05). By contrast, the Ins/Ins genotype was associated with a 4-fold increase of AdLD risk when compared to mild chronic hepatitis C (OR=4.69; 95% CI, 2.15-10.19; P=0.0001) and the risk was more pronounced when compared to healthy controls (OR=5.02; 95% CI, 2.30-10.98; P=0.00005). Furthermore, carriage of Ins allele at rs28362491 was significantly associated with higher viral loads (P=0.003). Our results suggest that variation in NFκB1 gene promoter modulates the progression of chronic hepatitis C toward advanced liver disease.
authors.affiliation: Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco; Faculté des Sciences d'El Jadida, Université Chouaib Doukkali, El Jadida, Morocco.
authors.forename: Fatima-Zohra
authors.initials: FZ
authors.lastname: Fakhir
authors.affiliation: Faculté des Sciences et Techniques de Mohammedia, Mohammedia, Morocco.
authors.forename: Mustapha
authors.initials: M
authors.lastname: Lkhider
authors.affiliation: Service de Medicine B, CHU Ibn Rochd, Casablanca, Morocco.
authors.forename: Wafaa
authors.initials: W
authors.lastname: Badre
authors.affiliation: Service de Medicine B, CHU Ibn Rochd, Casablanca, Morocco.
authors.forename: Rhimou
authors.initials: R
authors.lastname: Alaoui
authors.affiliation: Unité Organisation Nucléaire et Oncogenèse, INSERM U993, Institut Pasteur, Paris, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Pineau
authors.affiliation: Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco. Electronic address: sayeh.ezzikouri@pasteur.ma.
authors.forename: Sayeh
authors.initials: S
authors.lastname: Ezzikouri
authors.affiliation: Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco. Electronic address: soumaya.benjelloun@pasteur.ma.
authors.forename: Soumaya
authors.initials: S
authors.lastname: Benjelloun
mesh_terms: D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000209:etiology; D016022:Case-Control Studies; D018450:Disease Progression; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D019698:Hepatitis C, Chronic / Q000235:genetics* / Q000821:virology; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics; D054643:INDEL Mutation; D008103:Liver Cirrhosis / Q000209:etiology; D008113:Liver Neoplasms / Q000209:etiology; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D000072000:NF-KappaB Inhibitor alpha; D052002:NF-kappa B p50 Subunit / Q000235:genetics*; D011401:Promoter Regions, Genetic
chemical_list: D020672:I-kappa B Proteins; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha
keywords: Hepatitis C Virus; Hepatocellular carcinoma; Inflammation; IκB; NF-κB