|
- 现金
- 62111 元
- 精华
- 26
- 帖子
- 30437
- 注册时间
- 2009-10-5
- 最后登录
- 2022-12-28
|
Hepatitis B virus genotypes and genome characteristics in China
Hong-Mei Li, Jian-Qiong Wang, Rui Wang, Qian Zhao, Li Li, Jin-Ping Zhang and Tao Shen.
Hong-Mei Li, Rui Wang, College of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, Yunnan Province, China
Hong-Mei Li, Rui Wang, Qian Zhao, Li Li, Jin-Ping Zhang, Tao Shen, Basic and Clinical Medicine Institute of Yunnan Province, Provincial Key Laboratory for Birth Defects and Genetic Diseases, the First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
Jian-Qiong Wang, Clinical Laboratory, the First People’s Hospital of Yunnan Province, affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China
Qian Zhao, Kunming Medical College, Kunming 650500, Yunnan Province, China
Author contributions: Li HM, Li L and Zhang JP were in charge of information collection; Li HM, Wang R and Zhao Q participated in the statistical analysis; Li HM and Wang JQ designed the study and wrote the manuscript; Shen T provided advice and reviewed the manuscript; Li HM and Wang JQ contributed equally to this work.
Correspondence to: Dr. Tao Shen, Basic and Clinical Medicine Institute of Yunnan Province, Provincial Key Laboratory for Birth Defects and Genetic Diseases, the First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming 650032, Yunnan Province, China. [email protected]
Telephone: +86-871-63638453 Fax: +86-871-63648772
Received December 24, 2014; Revised March 3, 2015; Accepted April 3, 2015;
References
Abstract
AIM: To analyze the hepatitis B virus (HBV) characters in China, as well as the correlation between several HBV mutation and hepatitis symptoms.
METHODS: A total of 1148 HBV genome sequences from patients throughout China were collected via the National Center For Biotechnology Information database (information including: genotype, territory and clinical status). HBV genotypes were classified by a direct reference from the Genbank sequence annotation, phylogenetic tree and online software analysis (http://www.ncbi.nlm.nih.gov/projects/genotyping/formpage.cgi). The phylogenetic tree was constructed based on the neighbor-joining method by MEGA5.0 software. HBV sequences were grouped based on phylogenetic tree and the distance between the groups was calculated by using the computer between group mean distance methods. Seven hundred and twelve HBV sequences with clear annotation of clinical symptoms were selected to analyses the correlation of mutation and clinical symptoms. Characteristics of sequences were analyzed by using DNAStar and BioEdit software packages. The codon usage bias and RNA secondary structures analysis were performed by RNAdraw software. Recombination analysis was performed by using Simplot software.
RESULTS: In China, HBV genotype C was the predominant in Northeastern, genotype B was predominant in Central Southern areas, genotype B and C were both dominant in Southwestern areas, and the recombinant genotype C/D was predominant in Northwestern areas. C2 and B2 were identified as the two major sub-genotypes, FJ386674 might be a putative sub-genotype as B10. The basal core promoter double mutation and pre-C mutation showed various significant differences between hepatitis symptoms. In addition to ATG, many other HBV initiation codons also exist. HBV has codon usage bias; the termination codon of X, C and P open reading frames (ORF) were TAA, TAG, and TGA, respectively. The major stop codons of S-ORF were TAA (96.45%) and TGA (83.60%) in B2 and C2 subtype, respectively.
CONCLUSION: This study recapitulated the epidemiology of HBV in China, and the information might be meaningful critical for the future prevention and therapy of HBV infections.
Keywords: Hepatitis B virus, Genotype, Phylogenetic tree, Clinical symptoms, Mutation, Codon usage bias
Core tip: This study recapitulated the epidemiology of hepatitis B virus (HBV) in China. Genotype C was the predominant HBV genotype in Northeastern, genotype B was predominant in Central Southern areas, genotype B and C were both dominant in Southwestern areas, and the recombinant genotype C/D was predominant in Northwestern areas. C2 and B2 were identified as the two major subgenotypes, FJ386674 might be a putative sub-genotype as B10. Moreover, the termination codon usage bias of B2 (TAA) and C2 (TGA) subtype and the correlation between HBV sequence mutations and clinical symptoms were also determined.
............
Genotype distribution in the Chinese territory
HBV genotypes and sub-genotypes had obvious geographic features according to previous reports[34-36]. The current study also suggested a differential distribution of HBV genotypes in China. Within the northern areas of the Qinling Mountains-Huaihe River Line, genotype C (75.3%) was predominant, followed by a smaller percentage of type B (23.4%) and D (1.3%). While Sunbul[37] reported that genotype B was the major genotype in southern China, our results showed that the ratios of genotype B and C in the southern areas of China were 41% and 57%, respectively. This inconsistency may be due to differences in the selection of subjects and quantity of tested samples. Meanwhile, Northwestern China was dominated by recombinant genotype C/D and genotype D, with percentages of 49.3% and 24.6%, respectively. This result is consistent with a study by Yin et al[38]. Additionally, our investigation indicated that genotype I (originally reported as recombinant genotype A/C/G) was mainly located in the Guangxi[39], Shaanxi[40], Yunnan[41], and Sichuan Provinces[42], and I1 was the major sub-genotype in China.
From a geological perspective, many of the identified provinces were located on the Silk Route. For instance, the Guangdong Province was adjacent to Hong Kong and Macao; the Hainan and Taiwan regions were separated by the strait; Hong Kong, Macao, and Taiwan were once European colonies, where genotype A and D were dominant. Thus, we postulated that genotype I and recombinant genotype C/D was the result of a mixed genotype infection since it has already been discovered that recombination can occur in different genotypes of parental HBV strains[40,43]. Moreover, some studies proposed that genotype I may have existed for a long time in Shaanxi Province without being recognized, creating the question of how genotype I arose historically[40]. We hypothesized that a mixed genotype infection in patients from these areas may have occurred at first and subsequently resulted in recombinants. Furthermore, multiple factors, including extreme environmental effects[44] and special religious influences[42,45], may have helped preserved the resultant recombinant by natural selection.
Putative sub-genotype B10
To date, the definition of a new sub-genotype has been classified utilizing several major instructions. Firstly, a novel sub-genotype should be different from the known sub-genotype by 4% over the complete sequences. Secondly, a new sub-genotype should be an independent branch in the phylogenetic tree. Finally, a novel sub-genotype should have a bootstrap value over 75%[46].
In this study, Simplot results showed that FJ386674 represented a recombinant of genotypes B, C and H, with its two recombination breakpoints: one between nucleotides 500 and 960, and another from nucleotides 1700 to 1820 (Figure 3). Considering the results of phylogenetic tree and genetic distance, we designated FJ386674 as a putative sub-genotype B10.
However, despite the development of several new criteria for new sub-genotype classification, a number of controversial results still exist[32,33]. For instance, in this study, we found that 23 sequences had different genotyping and/or sub-genotyping due to different classification methods, and evolutionary distance among B3 and B5, B7-B9 (0.03 ± 0.00) was < 4%, a result consistent with a previous report indicating that B5, B7-B9 should be classified as a quasi-strain of B3[20,46]. Thus, the systematic approach of HBV putative sub-genotype classification needs to be further improved.
Correlation analysis of HBV BCP and pre-C to clinical symptoms
Many HBV mutations might be tightly associated with liver disease progression[47-49]. This study showed BCP double mutations were significantly different in ACLF and HCC. The results suggested that HCC had a lower mutation rate in the BCP region as compared with that of ACLF, which is consistent with a previous report[32]. However, other studies indicated that the BCP double mutation was associated with liver disease progression[47,48]. This inconsistency between current studies might be affected by many factors, like the genetic background of selected patients, the numbers of samples, and/or genotypes[49]. Some studies suggested a synergenistic action of the BCP double mutation and HBV genotype C in liver disease progression[50]. Although no statistically significant difference was observed between genotype B and C (P = 0.253) for all other hepatitis symptoms, the ratio of the BCP double mutation in genotype C has a tendency to be higher than that in genotype B (Figure 4), which is consistent with a previous study[51]. This might explain the intriguing relationship between genotype C and liver disease progression. Thus, the investigation of liver disease progression should not only look at the genotypes, but should also consider BCP mutations.
It has been suggested that the pre-C mutation is also tightly associated with liver disease progression[48,52]. In this study, we revealed that the pre-C mutation showed significant differences in HCC and LC, the mutation rate of the pre-C in ACLF, LC and HCC were higher than that of CHB (Figure 4), which is consistent with previous studies[48,52-55]. Thus, an HBV pre-C mutation might be tightly associated with liver disease progression.
In addition, some studies have reported the hepatitis B virus genotype C is associated with the process of liver disease[51,56]. This study also suggested no statistically significant difference in the HBV pre-C mutation between types B and C (P = 0.199). The detailed analysis indicated that only AHB was significantly different between types B and C (P = 0.038), while the mutation ratio in the same region was higher in type C without statistical significance for the other symptoms. This may explain why patients infected with genotype C HBV are more susceptible to the development of ACLF LC and HCC. We also found that the mutation rate of pre-C in ACLF was as high as 49.66% (Figure 4), which may be supported by a report that identified this mutation as a potential biomarker for ACLF onset[32]. Thus, the investigation of liver disease progression should always consider multiple factors, including the HBV genotype and associated mutations in order to achieve the most comprehensive understanding of the disease.
|
|
发表于 2015-6-17 17:48
