The -94Ins/DelATTG polymorphism in NFκB1 promoter modulates chronic hepatitis C and liver disease progression

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.