Relationship between HLA-DP gene polymorphisms and clearance of chronic
hepatitis B virus infections: Case–control study and meta-analysis
Zehui Yan, Shun Tan, Yunjie Dan, Xiaowen Sun, Guohong Deng
⇑
, Yuming Wang
⇑
Institute of Infectious Diseases, Southwest Hospital, Third Military Medical University, 30 Gao Tan Yan Street, Sha Ping Ba District, Chongqing 400038, PR China
article info
Article history:
Received 18 January 2012
Received in revised form 28 March 2012
Accepted 29 March 2012
Available online 19 April 2012
Keywords:
Hepatitis B virus (HBV)
Human leukocyte antigens DP (HLA-DP)
Meta-analysis
Polymorphism
abstract
Hepatitis B virus (HBV) infection is a serious public health problem worldwide. Two common genetic
variants (rs3077 and rs9277535) of human leukocyte antigen DP (HLA-DP) have been reported to be asso-
ciated with persistent HBV infection in populations of Japan and Thailand. To confirm whether the asso-
ciation can be replicated in Chinese populations, an independent case–control study were conducted, and
two polymorphisms (rs3077 and rs9277535) were genotyped using the TaqMan SNP genotyping assay in
282 persistent chronic HBV carriers and 64 spontaneously HBV recovered carriers. To provide a more
definitive conclusion, a meta-analysis combining and summarizing five studies was performed by
random-effects model using the DerSimonian and Laird’s method. By using logistic regression analysis
with adjustment for covariates, including age, sex, and alcohol consumption, the results of our indepen-
dent case–control study showed that the minor allele’s homozygote (AA genotype) of rs3077 and
rs9277535 was significantly associated with decreasing risk/protection of HBV persistent chronic infec-
tion (for rs3077: P = 0.0017, OR = 0.29, 95% CI = 0.13–0.62; for rs9277535, P = 0.0004, OR = 0.26, 95% CI =
0.12–0.54). The results of meta-analysis pooling all eligible studies also showed that rs3077-A and
rs9277535-A alleles were associated with an increased clearance rate to HBV infection (rs3077:
OR = 0.57, 95% CI = 0.44–0.75; rs9277535: OR = 0.56, 95% CI = 0.47–0.63). These results further confirmed
the strong influence of HLA-DP gene variants on risk of spontaneous HBV clearance from persistent HBV
infection. Both A alleles of HLA-DP SNP rs3077 and rs9277535 showed strong protective effects for spon-
taneous HBV clearance from persistent HBV infection in the Han Chinese population.
Ó 2012 Elsevier B.V. All rights reserved.
1. Introduction
An estimated two billion people have been infected with the
hepatitis B virus (HBV), and more than 350 million have chronic
(long-term) liver infections. Although some HBV carriers spontane-
ously eliminate the virus, 2–10% of the individuals with chronic
hepatitis B (CHB) are estimated to develop liver cirrhosis every
year, and a subset of these individuals suffer from liver failure or
hepatocellular carcinoma (Lai et al., 2003). A very small proportion
of patients with persistent HBV infection can spontaneously clear
the virus without treatment and are termed spontaneously recov-
ered carriers (SRC). It has been reported that, in western countries,
1–2% of HBV carriers become HBsAg negative each year (Alward
et al., 1985), whereas in China, where HBV infection is endemic,
the rate of HBsAg clearance is much lower (0.05–0.1% per year)
(Yuen et al., 2004). However, the mechanism of spontaneous
recovery from chronic persistent HBV infection is not well clarified.
Persistent HBV infection or HBV clearance is influenced by com-
plex factors of viral factors, environmental factors, and genetic ma-
keup, for example, age at infection, gender, viral genotype,
ethnicity, host genetic variations and so on (Frodsham, 2005; Segal
and Hill, 2003). Candidate gene association studies have implicated
HBV clearance or persistence are associated with host gene poly-
morphisms, including human leukocyte antigen ( HLA) classes I
and II alleles (Singh et al., 2007) and non-HLA genes (e.g., ESR1)
(Deng et al., 2004). However, the results of these candidate gene
association studies are not universal, even conflicting for all inves-
tigated populations. Recently, Matsuda1 et al. conducted a two-
stage genome-wide association study (GWAS) and implicated
two single nucleotide polymorphisms (SNPs) (rs3077 and
rs9277535) in HLA-DP gene associated with risk of persistent
HBV infection in Japanese and Thai populations (Kamatani et al.,
2009). The same group also performed a second GWAS with an
increased sample size for the additional GWAS, and further con-
firmed that these two HLA-DP SNPs contributed to the risk of
1567-1348/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.meegid.2012.03.026
Abbreviations: HBV, hepatitis B virus; HLA, human leukocyte antigens; CHB,
chronic hepatitis B; SNP, single nucleotide polymorphism.
⇑
Corresponding authors. Tel.: +86 23 68754141; fax: +86 23 65334998 (G. Deng),
tel.: +86 23 68754858; fax: +86 23 65334998 (Y. Wang).
E-mail addresses: ghdengsnp@hotmail.com (G. Deng), wym417@163.com
(Y. Wang).
Infection, Genetics and Evolution 12 (2012) 1222–1228
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