angiotensinogen and Hepatitis-C--Chronic

Hepatic stellate cells express all components of the renin-angiotensinogen (AGT) system and secrete active angiotensin II. Animal studies provided evidence that angiotensin II stimulates the accumulation of extracellular matrix by enhancing transforming growth factor beta1 production. A functional genetic alteration in the human AGT promoter (c.1-44G>A) has been linked to accelerated progression of fibrosis in hepatitis C virus infection.. We enrolled 2154 patients with chronic liver disease of various etiologies, including 1286 individuals with chronic hepatitis C virus infection as well as 207 healthy volunteers. We performed genotyping for two AGT variants, c.1-44G>A and c.803T>C (p.M268T), by melting curve analysis using fluorescence resonance energy transfer probes.. Allele frequencies and genotype distributions of both variants did not differ between patients and controls. Genotype frequencies of the c.1-44G>A variant were GG 31.0%, GA 45.6%, and AA 23.4% in patients and GG 30.0%, GA 47.8%, and AA 22.2% in controls. The genotype frequencies of p.M268T, which is in strong linkage disequilibrium with c.1-44G>A, were MM 30.8%, MT 45.5%, and TT 23.4% in patients and MM 29.0%, MT 48.8%, and TT 22.2% in controls. Both variants were associated with neither higher stages of fibrosis nor requirement for liver transplantation in any of the diagnosis subgroups. Particularly, these genetic alterations were not associated with progressive fibrosis in chronic HCV infection.. In contrast to previous reports, both AGT variants do not predispose to the progression of fibrosis in chronic liver disease.

Topics: Adult; Aged; Aged, 80 and over; Alleles; Angiotensinogen; Case-Control Studies; Disease Progression; Female; Fibrosis; Gene Frequency; Genetic Variation; Genotype; Hepatic Stellate Cells; Hepatitis C, Chronic; Humans; Linkage Disequilibrium; Liver Diseases; Liver Diseases, Alcoholic; Male; Middle Aged; Risk Factors; Young Adult

Progressive hepatic fibrosis and cirrhosis develops in 20% to 30% of patients with chronic hepatitis C virus (HCV). We propose that host genetic factors influencing fibrogenesis may account for some of the variability in progression of this disease. In progressive fibrosis of other organs, particularly heart and kidney, production of the profibrogenic cytokine, transforming growth factor beta1 (TGF-beta1), may be enhanced by angiotensin II, the principal effector molecule of the renin-angiotensin system. The inheritance of polymorphisms in TGF-beta1, interleukin 10 (IL-10), tumor necrosis factor alpha (TNF-alpha), and genes of the renin-angiotensin system was examined in 128 patients with chronic HCV. The influence of genotypes on the stage of hepatic fibrosis was tested after adjustment for potential confounders (age, gender, alcohol consumption, portal inflammation, and steatosis), which may have independent effects on histological severity. The stage of fibrosis was 0 in 30 (23.4%), 1 in 44 (34.4%), 2 in 27 (21.1%), and 3 or 4 in 27 (21.1%). A statistically significant relationship was seen between inheritance of high TGF-beta1- and angiotensinogen (AT)-producing genotypes and the development of progressive hepatic fibrosis. This association persisted after correcting for potential confounders. Patients who inherited neither of the profibrogenic genotypes had no or only minimal fibrosis. Knowledge of these polymorphisms may have prognostic significance in patients with chronic HCV and may direct more aggressive therapy towards those patients with an increased risk of disease progression. The documentation of a significant relationship between AT genotype and fibrosis raises the novel suggestion that angiotensin II may be another mediator of extracellular matrix production in the liver.

Topics: Adult; Aged; Angiotensinogen; Female; Genes, ras; Hepatitis C, Chronic; Humans; Interleukin-10; Liver Cirrhosis; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha