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1 Department of Clinical Molecular Informative Medicine, Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya 467-8601, Japan
2 Department of Internal Medicine and Molecular Science, Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya 467-8601, Japan
3 Section of Gastroenterology, University of Santo Tomas, Manila, Philippines
Correspondence
Masashi Mizokami
mizokami{at}med.nagoya-cu.ac.jp
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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The DDBJ/EMBL/GenBank accession numbers of the complete genome sequences of HBV isolates PhCH24, PhLC03, PhLC14, PhHCC15, PhHCC13, PhHCC01, PhCH09, PhHCC03 and PhHCC05 are AB241109–AB241117, respectively.
A neighbour-joining phylogenetic tree showing the relationship of HBV/Aa strains from the Philippines with other HBV/Aa strains and representative strains from other genotypes is available as supplementary material in JGV Online.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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; Okamoto et al., 1988; Stuyver et al., 2000). A possible eighth genotype is proposed, with the tentative designation of H (Arauz-Ruiz et al., 2002), but it is closely related phylogenetically to genotype F.
The genotypes of HBV have distinct geographical distributions, which have been associated with anthropological history (Orito et al., 2001). HBV/A is prevalent in Europe, Africa and South-east Asia, including the Philippines (Sugauchi et al., 2004). HBV/B and HBV/C are predominant in Asia, HBV/D is common in the Mediterranean area, the Middle East and India, HBV/E is localized in sub-Saharan Africa and HBV/F (or H) is restricted to Central and South America. All these genotypes occur in the United States, with frequencies dependent on ethnicity (Chu et al., 2003). Moreover, HBV/G has been found in France, Germany and the United States (Chu et al., 2003; Stuyver et al., 2000; Vieth et al., 2002).
HBV strains even of the same genotype may differ both virologically and clinically. There are two subtypes (subgenotypes) of genotype B with distinct geographical distributions, provisionally designated Bj/B1 (‘j’ for Japan) and Ba/B2 (‘a’ standing for Asia) (Sugauchi et al., 2002), and clinical differences between patients infected with HBV/Bj (B1) and HBV/Ba (B2) are emerging (Akuta et al., 2003; Sugauchi et al., 2003). Additionally, there has been some evidence for virological and clinical differences between HBV/Aa (A1) in Africa/Asia and HBV/Ae (A2) in Europe/the United States (Kimbi et al., 2004; Sugauchi et al., 2004). Infection with HBV/Aa (A1) is associated with low serum levels of HBV DNA as well as a low prevalence of hepatitis B e antigen (HBeAg) in the serum, and is implicated in the high incidence of HBV-related HCC in Africa (Kew et al., 2005; Tanaka et al., 2004). More recently, HBV genotype C (HBV/C) has been classified into two geographically typical subtypes (subgenotypes), HBV/Cs (C1) in South-east Asia and HBV/Ce (C2) in East Asia, and there are virological differences between the two subtypes (subgenotypes) (Chan et al., 2004; Kramvis et al., 2005; Tanaka et al., 2005).
In Asia, HBV genotype B (HBV/B) and C predominate; however, HBV/Aa (A1) is also found in the Philippines. To date, there have been no large population studies on HBV genotypes in the Philippines. The aim of this study is to evaluate HBV genotypes among 100 HBV carriers in the Philippines by molecular evolutionary analysis and to determine the influences of HBV genotypes and viral mutations on clinical characteristics.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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-fetoprotein (AFP) level (
400 ng ml–1) (n=31). Patients who were co-infected with hepatitis C virus or human immunodeficiency virus were excluded. There were no patients who received antiviral treatment during the follow-up period. The study protocol was approved by the Ethics Committees of the participating institutions in accordance with the 1975 Declaration of Helsinki. Informed consent was obtained from each patient prior to any study-related procedures.
Serological markers of HBV infection.
Hepatitis B surface antigen (HBsAg) was determined by haemagglutination (MyCell; Institute of Immunology Co., Ltd, Tokyo, Japan) or ELISA (Axcysm; Abbott) and HBeAg was detected by chemiluminescent enzyme immunoassay (CLEIA) (Lumipulse f; FUJIREBIO Inc.).
Sequencing of HBV genome.
Nucleic acids were extracted from 100 µl serum using the QIAamp DNA Blood Mini kit (Qiagen). Nine complete genomes and 100 partial HBV genome regions bearing the core promoter and precore/core regions were amplified by PCR with several primer sets, as described previously (Sugauchi et al., 2001). Amplified HBV DNA fragments were sequenced directly using the ABI Prism Big Dye version 3.0 kit (Applied Biosystems) on an ABI 3100 DNA automated sequencer (Applied Biosystems). All sequences were analysed in both the forward and reverse directions. Complete and partial HBV genomes were assembled using GENETYX version 11.0 (Software Development Co.).
Molecular evolutionary analysis of HBV.
Reference sequences were retrieved from the DDBJ/EMBL/GenBank databases with their accession numbers for identification. Nucleotide sequences of HBV were aligned by the program CLUSTAL X and genetic distance was estimated with the 6-parameter method (Gojobori et al., 1982) in the Hepatitis Virus Database (Robertson et al., 1998). Based on these values, phylogenetic trees were constructed by the neighbour-joining method (Saitou & Nei, 1987) with the mid-point rooting option. To confirm the reliability of the phylogenetic trees, bootstrap resampling tests were performed 1000 times.
Statistical analyses.
Statistical differences were evaluated using the Mann–Whitney non-parametric test, Fisher's exact probability test and Student's t-test where appropriate. Multivariate analyses with logistic regression were used to determine independent factors for the progression to HCC. Differences were considered significant for a P value less than 0.05. The statistical analysis software used was Stata version 8.0 (StataCorp LP).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Phylogenetic relatedness among HBV/C and HBV/B in the Philippines
All 27 HBV/C strains found in the Philippines could be amplified and sequenced over the core promoter and precore/core regions spanning 398 bp. Together with 10 HBV/Cs (C1) strains, 10 HBV/Ce (C2) strains, two Vietnamese HBV/C strains (strains 3270 and 8290) that exhibit 4.5–5.7 % genetic difference from other HBV/C strains (Hannoun et al., 2000), two HBV/C strains from Polynesia (HBV/C3), two HBV/C strains from Australian aborigines (HBV/C4), seven HBV/Bj strains (B1), nine original HBV/Ba strains (B2), three HBV/B3 strains and three HBV/B4 strains retrieved from the database, the 27 HBV/C strains, 22 HBV/B strains and two of the 51 HBV/A strains sequenced in the present study were subjected to phylogenetic analyses along with HBV strains representative of HBV/Aa (A1), Ae (A2), D, E, F and G (Fig. 1). Note that 25 (93 %) of the 27 HBV/C strains in this study formed a novel cluster with the two atypical Vietnamese strains (Hannoun et al., 2000), separated from the other HBV/C strains (C1–4). Moreover, 21 (95 %) of the 22 HBV/B strains specifically clustered separately from previously reported HBV/B strains. On the other hand, all 51 HBV/A strains, which were just separated from the South African Aa (A1) strains, belonged to the same subtype (subgenotype) as these strains (see Supplementary Fig. S1 in JGV Online).
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, the complete genomes of nine strains (two HBV/A, two HBV/B and five HBV/C) were sequenced successfully (marked by asterisks in Fig. 1
). The lengths of the complete genomes corresponding to HBV/A, HBV/B and HBV/C were 3221, 3215 and 3215 nt, respectively. Two of the HBV/C strains had shorter lengths of 3060 nt due to preS2 and core deletions. One of the HBV/B strains had a shorter length of 3179 nt due to preS2 deletions. Phylogenetic analysis of the complete genome sequences revealed five distinct clusters within HBV/C supported by the bootstrap resampling test: HBV/Cs (C1), HBV/Ce (C2), HBV/C3, HBV/C4 and a fifth group consisting of the five HBV/C strains sequenced in the present study and two HBV/C strains from Vietnam (strains 3270 and 8290; Hannoun et al., 2000). Interestingly, 12 of 14 Vietnamese HBV/C strains (86 %) were classified into HBV/Cs (C1), the exceptions being the two strains reported by Hannoun et al. (2000), indicating that HBV/C is the predominant type in Vietnam. We named the fifth phylogenetic group HBV/C5.
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). A clear separation of HBV/C5 from the other four subtypes (subgenotypes) was found in the tree topology for all four regions. Phylogenetic trees constructed from the four regions revealed significant bootstrap values at the bifurcation of C5. The estimated intergroup nucleotide divergence over the complete genome sequences between C5 and the other subtypes (subgenotypes) was [mean±SD (range)] 6.4±0.5 % (5.0–7.4 %) versus Cs (C1), 5.7±0.5 % (4.5–6.5 %) versus Ce (C2), 6.5±0.6 % (5.6–7.5 %) versus C3 and 8.1±0.4 % (7.4–8.6 %) versus C4. In the HBV/C5 strains, the nucleotide divergence of the complete genomes between the five HBV/C5 strains determined in the present study and HBV/C5 strains 3270 and 8290 from Vietnam was 3.3±0.4 % (2.8–3.9 %), and the intragroup nucleotide divergence was 1.6±0.5 % (0.8–2.5 %) among the five HBV/C5 strains in the present study.
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. Note that 21 of the 22 HBV/B strains from the Philippines were classified into HBV/B5 and one to original HBV/Ba (B2) (Fig. 1). The B5 strains from the Philippines carried the recombination with HBV/C over the precore and core genes that is found in the original HBV/Ba (B2) strains. The estimated intergroup nucleotide divergence over the complete genome sequences between B5 and the other subtypes (subgenotypes) was [mean±SD (range)] 6.6±0.3 % (6.2–7.1 %) versus B1, 5.3±0.3 % (4.8–5.7 %) versus B2, 3.7±0.1 % (3.6–3.8 %) versus B3 and 5.0±0.08 % (4.9–5.1 %) versus B4. These complete sequence data mirrored serotyping: all subtype (subgenotype) C5 strains (PhCH24, PhLC03, PhLC14, PhHCC13 and PhHCC15) were adw2, the subtype (subgenotype) B5 strains (PhHCC03 and PhHCC05) were ayw1 and the subtype (subgenotype) Aa (A1) strains (PhCH09 and PhHCC01) were adw2.
Nucleotide and amino acid characteristics of the HBV/C5 strains
A comparison of substitutions between the seven HBV/C5 strains and the consensus sequence of HBV/C, retrieved from the DDBJ/EMBL/GenBank database, over the complete genome showed 22 genotype/subtype (subgenotype) -specific substitutions in the HBV/C5 strains, seven of which were specific for the five HBV/C5 strains from the Philippines (Table 1). As a result of these genotype/subtype (subgenotype) -specific substitutions, 11 amino acid changes were predicted in the HBV/C5 strains. Specific amino acid motifs in the HBV/C5 strains were predicted in the polymerase and preS1/preS2/S region, but not in the X or precore/core regions.
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). The prevalence of HBeAg was significantly higher in patients with CH than in those with LC or HCC (P<0.005). The proportion of HBV/A was higher in patients with CH than in those with LC or HCC (P<0.001), while HBV/C was significantly more prevalent in LC and HCC than in CH (P<0.05).
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); however, patients with HBV/A were significantly younger than those with HBV/B or HBV/C (P<0.01). The reason behind this observation is that there were more CH patients with HBV/A than with HBV/B or HBV/C (49, 18 and 11 %, respectively; P<0.01). Although no significant differences in HBV genotypes were found between patients with LC and HCC, HBV/B and HBV/C were significantly more prevalent in LC and HCC patients than HBV/A (P<0.02).
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; Ito et al., 2006). The frequency of mutations in the core promoter region (T1653 and T1762/A1764) was compared among HBV/A, B and C (Table 3). The T1653 mutation was detected in HBV/A and HBV/C (18 and 22 %), but was not detected in HBV/B. The double mutation in the core promoter region (T1762/A1764) was found to be significantly less frequent in carriers of HBV/A than in HBV/B or HBV/C. We also compared the frequency of mutations in the precore region and in Kozak sequences preceding the ATG initiator codon of the precore region among HBV/A, B and C (Table 3). Substitutions in the Kozak sequences (T1809 and T1812) and the mutation in the encapsidation signal of the precore region [T1862 and H1888 (where H means not G)] were identified only in HBV/A. No significant difference in the frequency of the precore stop mutation A1896 was found among HBV/A, HBV/B and HBV/C (0, 9 and 4 %, respectively). All HBV/C5 strains had the C1856 and T1858 mutations, as well as HBV/Ce.
Characteristics of HBV genotypes among HCC patients
To clarify the virological and clinical characteristics of HCC patients, we compared several factors, such as age, HBeAg positivity and the frequency of mutations among HCC patients with each of the three genotypes (Table 4). There were no significant differences in age, HBeAg positivity or the frequency of the precore stop mutation A1896 in the three genotypes. The prevalence of the T1653 mutation was significantly higher in HCC patients with HBV/C than in those with HBV/B (P<0.05) (Table 4). Logistic regression analysis was performed on age, sex, HBeAg, HBV genotype and the mutations T1653, T1762/A1764 and A1896 to identify factors that might contribute to the progression to HCC. Age [odds ratio (OR) 3.43; 95 % confidence interval (CI) 1.04–11.36; P=0.044] and the presence of the T1762/A1764 mutation (OR 14.08; 95 % CI, 3.62–4.74; P<0.001) were significant risks for progression to HCC.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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), which are distinct from previous HBV/C strains (C1–4) (Norder et al., 2004). As reported by Hannoun et al. (2000), these strains were relatively divergent from previously reported strains, with an overall nucleotide difference of 4–8 % justifying the classification of HBV/C5 as a distinct subtype (subgenotype) according to recent proposals on HBV nomenclature. Phylogenetic analyses of the four ORFs (PreS1/PreS2/S, X, P and precore/core) supported the conclusion that the HBV/C5 strains, including the two Vietnamese strains and five strains from this study, formed a specific cluster without recombination. In general, genotypic classification of HBV is likely to correlate with the geographical origin of strains. Interestingly, phylogenetic analyses on the core promoter and precore/core regions showed that most HBV/C strains (n=25) from the Philippines belonged to the novel subtype (subgenotype) HBV/C5, whereas only two strains from Vietnam were included in this group; most HBV/C strains from Vietnam have been classified into HBV/Cs (C1). Hence, the origin of HBV/C5 might be the Philippines.
Twenty-two genotype/subtype (subgenotype) -specific substitutions were found in the HBV/C5 strains; seven of them were specific for the five HBV/C5 strains from the Philippines. We have already reported a new PCR-RFLP method to distinguish between HBV/C1 and HBV/C2. Using an RFLP with these five specific sites for HBV/C5, it would be possible to discriminate HBV/C5 conveniently among HBV/C. Investigating the mutation pattern of HBV/C5 for distinctive mutations between HBV/C1 and HBV/C2 reported previously (Tanaka et al., 2005), the mutation pattern of HBV/C5 in the encapsidation signal is close to that of HBV/C2; all HBV/C5 strains had C1856 and T1858 mutations, which are also found in HBV/C2. Generally, the precore stop mutation A1896 is accompanied by a C-to-T substitution at nt 1858, forming a base pair with it on the secondary structure of the encapsidation signal, and these mutations can stabilize the 
-loop structure. Although T1858 is frequently found in HBV/C5, only one of 25 HBV/C5 strains possessed the A1896 mutation.
There were also 22 HBV/B strains found in the Philippines, and most of them (21/22, 95 %) formed a specific cluster distinct from previously reported HBV/B strains. It has been reported that genotype B can be classified into two subgroups: HBV/Ba (B2), which is prevalent in Asia, and HBV/Bj (B1), which is restricted to Japan (Sugauchi et al., 2002). Furthermore Norder et al. (2004) reported that HBV/B strains could be divided into four subtypes (subgenotypes) confirmed by significant bootstrap support when comparing 72 HBV/B complete genomes from around the world. In our phylogenetic analysis of complete genome sequences, HBV/B strains from the Philippines were newly classified into a fifth group, carrying a recombination with HBV/C over the precore and core genes that is also found in the original HBV/Ba (B2). However, because we could only determine the complete genomes of two HBV/B strains from the Philippines, the clinical and virological differences between HBV/B from the Philippines and other strains were not able to be clarified.
In the Philippines, HBV/Aa (A1) is one of the major genotypes, as it is in South Africa (Bowyer et al., 1997; Kramvis et al., 2002; Sugauchi et al., 2004). HBV/Aa (A1) in South Africa is suggested to be associated with HCC in younger carriers (Kew et al., 2005); however, in the present study, the proportion of HBV/Aa (A1) was higher in patients with CH than in those with LC or HCC. HBV/C or HBV/B in the Philippines was associated with HCC development, suggesting that HBV/Aa (A1) in the Philippines might be different from HBV/Aa (A1) in South Africa. To elucidate the virological differences between HBV/Aa (A1) strains in the Philippines and South Africa, complete genome sequences were compared. Most HBV/Aa (A1) from the Philippines had specific mutations in the encapsidation signal of the precore region (T1862 and H1888) and specific substitutions in the Kozak sequences (T1809 and T1812), as did South African strains (Tanaka et al., 2004; Kimbi et al., 2004). We could not find virological characteristics to distinguish the HBV/Aa (A1) from the Philippines from that in South Africa because only two complete sequences were obtained from HBV/Aa (A1) strains in the Philippines. Further functional studies of HBV/Aa (A1) strains in the Philippines and South Africa will be required in order to establish the difference between these strains.
Finally, we compared other mutations among the three genotypes to find clinical manifestations. Ito et al. (2006) reported that the prevalence of T1653 was found to be significantly higher in HCC patients than in CH patients with HBV/C, indicating that T1653 was a predictive factor for HCC in HBV/C. In this study, the prevalence of the T1653 mutation was significantly higher in HCC patients with HBV/C only. These findings indicate that T1653 mutation is one of the critical risk factors for HCC with HBV/C. It was also reported that HBV carriers with the core promoter double mutation T1762/A1764 were at increased risk of HCC and that this mutant may contribute to the pathogenesis of HBV infection. In agreement with previous reports, our data indicate that a high prevalence of the core promoter double mutation was found in HCC patients with HBV/B or HBV/C. HBV/B strains from the Philippines carried the recombination with HBV/C over the core promoter, precore and core genes that is found in original HBV/Ba (B2) strains. Multiple logistic regression analysis showed that age and the presence of the core promoter double mutation were independent risk factors for progression to HCC. However, HBV genotype (HBV/B and C) was not a significant factor for progression to HCC, since both HBV/B and HBV/C were also prevalent in LC patients in this study.
In conclusion, HBV genotypes A, B and C are prevalent in the Philippines. We found novel subtypes (subgenotypes) of HBV/C and HBV/B among chronic liver disease patients in the Philippines. However, few clinical differences among these subtypes (subgenotypes) have been reported. Further clinical studies would be required in a case–control study with large-scale cohorts to evaluate the clinical manifestations of HBV/C5 and HBV/B5.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Received 25 November 2005;
accepted 8 February 2006.
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