Mestrado em Medicina e Oncologia Molecular / Master Degree Course in Molecular and Oncology Medicine / Chronic hepatitis C (HC) is a major public health problem because of the number of infected
persons (3% of the world population and about 150000 Portuguese individuals) and the
potencial to cause cirrhosis, end-stage liver disease, and hepatocelular carcinoma in many of
those infected. The most effective treatment (pegylated interferon and ribavirin) has variable
response rates, between 45 e 80%, and major side effects. Treatment duration depends on viral
genotype and virological response after the first 12 weeks on therapy. Genotype and viral load
are independent factors of response. However, the question is why hosts infected with same genotype
and similar viral loads have different treatment response rates. Genotype 1, high viral
load, higher quasispecies diversity, NS5A interferon determining sensitivity domain variations
was associated with lower responses. Others identified host factors for therapy response such
as race, gene expression, HLA-DRB and class I alleles and cytokine gene polymorphisms as interferon-
, TNF- , interferon response genes. Gene expression analysis by microarrays found 8
genes as response discriminants. Pre-treatment cytokine and supressors of cytokine levels may
also correlate with treatment response.
Our aim was to analyse if host genetic polymorphisms related to Th1 immune response polarization,
hepatic lesion mechanisms and signaling after TCR activation or IFN signaling - OPN,
TNF- , ACP1 respectivelly could explain different treatment responses. We also analysed
healthy individuals and correlated OPN plasma levels and OPN genotypes. Patients with HCV genotype
1 and 4 were included.
Matherial: 95 patients treated with pegylated interferon and ribavirin were selected.
Control group included healthy blood donors. HC group was classified according to treatment response
type: non responders (NR); end of treatment response and relapse (RR); Sustained response
(SR). Absence of SR (NSR) = NR+RR. Methods: Blood was collected for DNA and plasma
extraction. Genetic polymorphisms were performed by PCR-RFLP: 8090 OPN (C/T), -308 TNF-
(A/G), ACP1 (A/B/C). Plasma OPN concentrations measured by ELISA commercial Kit. Statistical
analysis: SPSS vs13.
Results: OPN and ACP1 genotype distribution was signifficantly different in subjects
with HC in comparison with those of control group. OPN TT genotype, TNF- GG, ACP1 AA and
AB are more frequent in HC group. OR for HC was : 2,22 if OPN TT genotype, 1,57 if TNF-
AA or AG, and 9,99 if ACP1 with lower phosphatasic activity. 87 CHC patients were infected by
genotype 1 virus and 8 by genotype 4. According to treatment response HC subgroups are: 43
NR, 16 RR, 36 SR and 59 NSR. No significant differences were observed between those groups
concerning age, sex, viral load, histological activity and fibrosis stages. OPN TT allele carriers
predominate in NSR and CC predominate in SR. OR for SR versus NSR is 3,32 if one T allele is
present and 0,29 if one C allele is present. TNF- and ACP1 genotypes were not significantly different
is those treatment response subgroups.
NSR has lower median plasma OPN levels. Also TT genotypes had lower levels. RR patients
had the lowest levels plasma OPN levels.
Conclusions: our results suggest that both OPN and ACP1 genotypes are related to HC
susceptibility. OPN genotype is a host factor related to treatment response and that there is a
trend toward higher median plasma OPN levels in responders.
| Identifer | oai:union.ndltd.org:up.pt/oai:repositorio-aberto.up.pt:10216/22133 |
| Date | 21 December 2007 |
| Creators | Costa, Cilénia Baldaia Enes da |
| Publisher | Faculdade de Medicina da Universidade do Porto, FMUP |
| Source Sets | Universidade do Porto |
| Language | Portuguese |
| Detected Language | English |
| Type | Dissertação |
| Format | application/pdf, application/pdf, application/pdf |
| Rights | openAccess |
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