Effect of cytokine gene polymorphism on histological activity index, viral load and response to treatment in patients with chronic hepatitis C genotype 3.
OBJECTIVE
To investigate the association between cytokine gene polymorphism and disease status in chronic hepatitis C genotype 3 by liver biopsy, ALT, HCV RNA levels and response to treatment.


METHODS
Patients with chronic hepatitis C genotype 3 were analyzed for single nucleotide polymorphisms of interleukin (IL)-10, IL-1 beta, interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta) by polymerase chain reaction using sequence-specific oligonucleotide primers. Liver biopsies were assessed by modified histological activity index (HAI) scoring system using a scale of 0-18 for grading the necro-inflammatory activity and 0-6 for staging the fibrosis. HCV RNA levels were determined by bDNA assay. The patients were treated with interferon alpha and ribavirin for 6 mo. Sustained virological response was assessed 6 mo after the completion of the treatment.


RESULTS
Out of the 40 patients analyzed, 26 were males. Mean age was 40.5+/-12.5 years (range 18-65 years). The frequencies of different dimorphic polymorphisms based on single nucleotide substitution were as follows: IL-10-1082 G/A 85%, A/A 12.5%, G/G 2.5%; IL-10-819 A/C 87.5%, C/C 10%, A/A 2.5%; IL-10-592 C/A 72.5%, C/C 27.5%; IL-1 C 90%, U 10%; IFN-874 T/A 50%, T/T 27.5%, A/A 22.5%; TNF-308 A/G 95%, G/G 5%; TGF-10 T/C 52.5%, C/C 35%, T/T 12.5%. The mean grades of necro-inflammatory activity of different genotypes of IL-10 at promoter site -1082 were A/A = 3.6, A/G = 5.0, and G/G = 10.0 and the difference was significant (P = 0.029). The difference in the stage of disease at a scale of 0-6 was A/A 0.8, A/G 2.3, and G/G 4.0 (P = 0.079). The difference in the HAI seemed to be related to the presence of allele -1082G. For IL-10 -819 genotypes, mean scores of fibrosis were A/A = 6.0, A/C = 2.2, and C/C = 1.0 (P = 0.020) though the inflammatory activity was not much different. No significant differences in HAI were noted among polymorphisms of other cytokines. Moreover, ALT and HCV RNA levels were not significantly different among different cytokine polymorphisms. There was a significant correlation of HAI and HCV RNA levels with the duration of disease. TGFbeta -10 genotype CC patients had a better end of treatment response than those with other genotypes (P = 0.020). Sustained virological response to the treatment was not influenced by the cytokine polymorphism. No effect of other factors like viral load, degree of fibrosis, gender, steatosis, was observed on sustained virological response in this population infected with genotype 3.


CONCLUSIONS
There is no significant correlation between cytokine polymorphisms and HAI except for the polymorphisms of anti-inflammatory cytokine IL-10, which may influence hepatic inflammatory activity and fibrosis in patients with chronic hepatitis C genotype 3. Sustained virological response in this genotype does not seem to be influenced by cytokine gene polymorphisms.
Abbas
Zaigham
Z
Department of Medicine, The Aga Khan University Hospital, Karachi, Pakistan. zaigham@akunet.org
Moatter
Tariq
T
Hussainy
Akber
A
Jafri
Wasim
W
D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use; D016207:Cytokines / Q000097:blood / Q000235:genetics*; D016174:Hepacivirus / Q000235:genetics* / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012254:Ribavirin / Q000627:therapeutic use; D016896:Treatment Outcome; D019562:Viral Load
D000998:Antiviral Agents; D016207:Cytokines; D016898:Interferon-alpha; D012254:Ribavirin