The epidermal growth factor (EGF) rs4444903 A>G polymorphism is associated with the occurrence of several types of cancer including hepatocellular carcinoma. Since the up-regulation of EGF is characteristic of the cirrhotic liver, it might be hypothesized that the EGF rs4444903 A>G polymorphism could be associated with a worse liver disease in patients chronically infected by hepatitis B virus (HBV). This study aimed to ascertain the relationship between the carriage of EGF rs4444903 A>G polymorphism and more advanced stages of chronic HBV related liver disease. In a cross-sectional study, 170 consecutive HBV positive, hepatitis Delta (HDV) and hepatitis C (HCV) negative patients (125 males, median age 52 years) were included. These patients were classified, according to the current clinical guidelines, in the following 3 groups: a) Hepatitis B s antigen (HBsAg) inactive carriers (N. = 30), b) active carriers (N. = 96) and c) HBV-related end-stage liver disease (N. = 44), referring to patients evaluated for liver transplantation. The longitudinal study included 62 HBV positive (31 hepatitis B e antigen positive) HDV and HCV negative patients (42 males, median age 30 years). All these patients had a biopsy proven chronic hepatitis at presentation. All patients underwent periodic clinical and laboratory monitoring for a median time of 21 (range 0.6-33) years. Twenty four patients received antiviral treatment: 15 with interferon (IFN) or pegylated IFN and 9 with nucleoside analogues. A group of 209 healthy blood donors, age and gender matched, served as controls. Seventy nine of controls had evidence of resolved HBV infection (being anti-HBs and anti-core seropositive). In the cross-sectional study, a significant linear trend was detected in descending the G allele frequencies from 53.4% observed in HBsAg+ liver transplant candidates to 40.6% in active carriers and 39.4% in HBsAg+ inactive carriers plus Anti-HBc+ control subjects (p=0.048). In the longitudinal study, EGF rs4444903 A>G polymorphism was found to be an independent predictor of cirrhosis development (O.R: 7.73, 95% C.I: 1.21-49.5, p=0.007). Three groups of patients were identified: A/A female homozygotes (N.=9), A/A male homozygotes (N.=13) and carriers of the G allele of either gender (N.=40). Cirrhosis did not occur among A/A females (N.=0/9), occurred seldom among A/A males (N.=2/13) and reached the highest frequency among G/* patients (N=13/40, p=0.026). In conclusion, EGF rs4444903 A>G polymorphism appears to be associated with a worse evolution of chronic HBV infection and with cirrhosis development. The effect might be at least in part modulated by the female gender.
Carriage of the EGF RS4444903 A>G functional polimorphism associates with disease progression in chronic HBV infection.
FATTOVICH, Giovanna;PASINO, Michela;
2011-01-01
Abstract
The epidermal growth factor (EGF) rs4444903 A>G polymorphism is associated with the occurrence of several types of cancer including hepatocellular carcinoma. Since the up-regulation of EGF is characteristic of the cirrhotic liver, it might be hypothesized that the EGF rs4444903 A>G polymorphism could be associated with a worse liver disease in patients chronically infected by hepatitis B virus (HBV). This study aimed to ascertain the relationship between the carriage of EGF rs4444903 A>G polymorphism and more advanced stages of chronic HBV related liver disease. In a cross-sectional study, 170 consecutive HBV positive, hepatitis Delta (HDV) and hepatitis C (HCV) negative patients (125 males, median age 52 years) were included. These patients were classified, according to the current clinical guidelines, in the following 3 groups: a) Hepatitis B s antigen (HBsAg) inactive carriers (N. = 30), b) active carriers (N. = 96) and c) HBV-related end-stage liver disease (N. = 44), referring to patients evaluated for liver transplantation. The longitudinal study included 62 HBV positive (31 hepatitis B e antigen positive) HDV and HCV negative patients (42 males, median age 30 years). All these patients had a biopsy proven chronic hepatitis at presentation. All patients underwent periodic clinical and laboratory monitoring for a median time of 21 (range 0.6-33) years. Twenty four patients received antiviral treatment: 15 with interferon (IFN) or pegylated IFN and 9 with nucleoside analogues. A group of 209 healthy blood donors, age and gender matched, served as controls. Seventy nine of controls had evidence of resolved HBV infection (being anti-HBs and anti-core seropositive). In the cross-sectional study, a significant linear trend was detected in descending the G allele frequencies from 53.4% observed in HBsAg+ liver transplant candidates to 40.6% in active carriers and 39.4% in HBsAg+ inactive carriers plus Anti-HBc+ control subjects (p=0.048). In the longitudinal study, EGF rs4444903 A>G polymorphism was found to be an independent predictor of cirrhosis development (O.R: 7.73, 95% C.I: 1.21-49.5, p=0.007). Three groups of patients were identified: A/A female homozygotes (N.=9), A/A male homozygotes (N.=13) and carriers of the G allele of either gender (N.=40). Cirrhosis did not occur among A/A females (N.=0/9), occurred seldom among A/A males (N.=2/13) and reached the highest frequency among G/* patients (N=13/40, p=0.026). In conclusion, EGF rs4444903 A>G polymorphism appears to be associated with a worse evolution of chronic HBV infection and with cirrhosis development. The effect might be at least in part modulated by the female gender.
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