Host genetic factors influence disease progression in chronic hepatitis C

Progressive hepatic fibrosis and cirrhosis develops in 20% to 30% of patien ts with chronic hepatitis C virus (HCV). We propose Chat host genetic facto rs influencing fibrogenesis may account far some of the variability in prog ression of this disease. In progressive fibrosis of other organs, particula rly heart and kidney, production of the profibrogenic cytokine, transformin g growth factor beta 1 (TGF-beta 1), may be enhanced by angiotensin II, the principal effector molecule of the renin-angiotensin system. The inheritan ce of polymorphisms in TGF-beta 1, interleukin 10 (IL-10), tumor necrosis f actor alpha (TNF-alpha), and genes of the renin-angiotensin system was exam ined in 128 patients with chronic HCV. The influence of genotypes on the st age of hepatic fibrosis was tested after adjustment for potential confounde rs (age, gender, alcohol consumption, portal inflammation, and steatosis), which may have independent effects on histological severity. The stage of f ibrosis was 0 in 30 (23.4%), 1 in 44 (34.4%), 2 in 21 (21.1%), and 3 or 4 i n 21 (21.1%), A statistically significant relationship was seen between inh eritance of high TGF-beta 1- and angiotensinogen (AT)-producing genotypes a nd the development of progressive hepatic fibrosis. This association persis ted after correcting for potential confounders. Patients who inherited neit her of the profibrogenic genotypes had no or only minimal fibrosis. Knowled ge 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 signi ficant relationship between AT genotype and fibrosis raises the novel sugge stion that angiotensin II may be another mediator of extracellular matrix p roduction in the liver.