A genotypic association implicates myeloperoxidase in the progression of hepatic fibrosis in chronic hepatitis C virus infection.
The hepatitis C virus (HCV) is a major cause of liver disease and the complications of cirrhosis. Liver biopsies, performed prior to the development of liver cirrhosis, characteristically show an inflammatory cell infiltrate with varying degrees of fibrosis. Precisely how HCV infection induces hepatic fibrogenesis is unknown. Recent studies suggest the release of oxidants, cytokines and proteases from the host immune system are key to the development of fibrosis. Macrophages and neutrophils, cells heavily represented in the inflammatory cell response, contain the oxidant generating enzyme myeloperoxidase (MPO). Cellular levels of MPO can be influenced by a functional promotor polymorphism, -463G/A, which precedes the MPO gene. We examined the relationship between this MPO promotor genotype and the degree of fibrosis in 166 patients with chronic HCV infection. All patients had previously participated in clinical drug trials for the treatment of chronic HCV infection. The MPO genotype was determined from cryo-preserved lymphocytes obtained from patients prior to treatment. The degree of fibrosis was estimated from liver biopsy specimens obtained prior to treatment. We found that patients with the MPO GA/AA genotype were more likely to have advanced fibrosis scores compared with those with the GG genotype: Of the patients with GG genotype, 78% (79 of 102 cases) had lower Knodell Fibrosis scores of 0 or 1, compared to 56% (37 of 64 cases) of patients with GA/AA genotype (P < 0.05). The mechanism(s) by which MPO contributes to fibrosis progression remains to be determined.
Reynolds
W F
WF
Sidney Kimmel Cancer Center, San Diego, CA 92121, USA. wreynolds@skcc.org
Patel
K
K
Pianko
S
S
Blatt
L M
LM
Nicholas
J J
JJ
McHutchison
J G
JG
D005260:Female; D019698:Hepatitis C, Chronic / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009195:Peroxidase / Q000235:genetics*
D009195:Peroxidase