Host genetic factors influence disease progression in chronic hepatitis C

Abstract

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 β1 (TGF‐β1), may be enhanced by angiotensin II, the principal effector molecule of the renin‐angiotensin system. The inheritance of polymorphisms in TGF‐β1, interleukin 10 (IL‐10), tumor necrosis factor α (TNF‐α), 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‐β1– 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.

Single nucleotide polymorphisms and haplotypes in the IL10 region associated with HCV clearance

“…Several recent studies suggested that IL10 polymorphisms may influence HCV outcome in the host [38][39][40][41]49 while others have not found associations. 42,43 Generally, these are concentrated on the proximal IL10 promoter polymorphisms that have been associated with the differential IL-10 expression, 46,50 while other polymorphisms, particularly those in the distal part of the promoter, have also been implicated.…”

Is there a future for TNF promoter polymorphisms?

“…Most studies that have looked at outcome of disease have found no association with TNF SNPs. 104,[111][112][113][114][115] However, two studies have appeared that did find an association of TNF SNPs with HCV. 116,117 The latter study 117 is curious not because of the reported higher occurrence of the À238A allele among chronic HCV patients, but because the reported frequency in a healthy control group (n ¼ 99) drops from 7 117 to 3.5% in an article published concurrently by the same group.…”

Bi-allelic presence of the interleukin-10 receptor 1 G330R allele is associated with cirrhosis in chronic HCV-1 infection

“…Some evidence for the involvement of host genetic factors in the outcome of HCV infection exists. [13][14][15] Antiviral therapy of CHC with pegylated interferon alfa-2a or -2b and ribavirin yields HCV eradication rates from 54 to 56% 16,17 and sustained response might diminish fibrosis. 18 However, antiviral therapy carries substantial morbidity at high costs.…”