Interleukin-10 promoter polymorphism predicts initial response of chronic hepatitis B to interferon alfa
Virology Journal
Interleukin-10 promoter polymorphism predicts initial response of chronic hepatitis B to interferon alfa
Shaoyang Wang 0
Dedong Huang 0
Shunlai Sun 0
Weimin Ma 0
Qin Zhen 0
0 Department of infectious diseases, the Fuzhou General Hospital , Fu Zhou, Fujian Province 350003 , China
In order to examine whether variation in interleukin-10 promoter polymorphism would predict the likelihood of sustain response of chronic hepatitis B to treatment with interferon alfa (IFN-a), the inheritance of 3 biallelic polymorphisms in the IL-10 gene promoter in patients with 52 chronic hepatitis B were determined by polymerase chain reaction (PCR)-bared techniques, restriction enzyme digestion or direct sequencing. The relationship to the outcome of antiviral therapy for chronic HBV infection was studied in 24 patients who had a virologically sustained response(SR) and in 28 non-responder(NR) to interferon alfa-2b and several IL-10 variants were more frequent among SR compared with NR. Carriage of the -592A allele, -592A/A genotype and -1082/-1819/-592 ATA haplotype was associated with SR. Our findings indicate that heterogeneity in the promoter region of the IL-10 gene has a role in determining the initial response of chronic hepatitis B to IFN-a therapy.
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Introduction
Hepatitis B is a worldwide disease and remains a
significant etiology of chronic hepatitis, cirrhosis and
hepatocellular carcinoma, especially in several areas of Asia
and Africa[1]. It is estimated to affect over 350 million
people worldwide, with a mortality of over 1.2 million
deaths per year because of acute or chronic hepatitis B
infection[2,3]. For active hepatitis B patients with
detectable hepatitis B virus e antigen (HBeAg) or hepatitis B
virus (HBV) DNA and elevated alanine aminotransferase
(ALT) serum levels, treatment is often recommended.
Six-month course of interferon alfa (IFN-a) therapy has
been shown to induce a long-term sustained remission
in 25% to 40% of chronic hepatitis B patients[1,4,5].
However, the question remains unresolved as to why
only a certain percentage of patients respond to therapy.
Hence, predictive factors determining therapeutic
responses are focused by many investigations.
Multivariate analyses have shown that the most
important predictors of good response to
IFN-atreatment include high ALT levels, low serum HBV DNA,
female gender, and histological activity on liver biopsy
in chronic HBV patients[6-8]. However, despite these
studies of viral factors and clinical markers affecting
treatment response, the role of the host genetic
background was less well studied[9].
The role of cytokines and the cellular immune
response in the pathogenesis and eradication of chronic
HBV has been investigated. Several proinflammatory
cytokines such as Th1 cytokines (including IL-2 and
IFN-g) and TNF-a are believed to participate in
elimination of HBV [8,10,11]. In contrast, IL-10 and IL-4, Th2
cytokine, act as potent inhibitors of Th1 effectors
mechanisms[8,12-14]. There are some evidences that the
capacity for cytokine production in individuals has a
major genetic component [15]. This has been ascribed
to polymorphisms within the regulatory regions or
signal sequences of cytokine. Several polymorphic sites
within the IL-10 gene promoter region have been
described, including three bi-allelic polymorphisms at
positions1082, 819, and 592 from the transcription
start site. The IL-10819 T and C alleles were
completely in linkage disequilibrium with the IL-10592A and
C alleles, respectively. The592A allele was exclusively
associated with the1082A allele. These result in three
different haplotypes: GCC, ACC, and ATA[16]. It was
reported that allelic variation in these polymorphisms
may be associated with the disease progression of
chronic HBV infection[17]. Heterogeneity in the
promoter region of the IL-10 gene has been reported to have a
role in determining the initial and sustained response of
chronic hepatitis C to IFN-atherapy[18]. However, there
are differences in the immunopathogenesis of HBV and
HCV infection[19], it is necessary to investigate whether
IL-10 gene promoter polymorphisms could serve as a
candidate prediction of response to IFN-atherapy in
chronic HBV infection. To prove this hypothesis, we
examined the inheritance of the 3 biallelic
polymorphisms in patients with chronic HBV and the association
of these polymorphisms with response to IFN-a. For
HBV patients, it is very important to predict the
response to antiviral therapy, especially for IFN-a
therapy, given the many displeasing side effects associated
with this medical regimen and the high cost of therapy.
Patients and methods
Patients
We retrospectively enrolled 52 Chinese Han patients
with chronic hepatitis B from our outpatients clinics at
Fuzhou general hospital, between February 2007 and
December 2008. There were 28 non-responders (NR) to
IFN treatment with a mean age of 32 years and 24
sustained responders (SR) with a mean age of 35 years.
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