江苏省海门市肝癌高发地区人群乙型肝炎病毒进化分析
摘要
江苏省海门市地处长江三角洲地区,是原发性肝细胞癌的高发市。HBV感染是海门市肝癌高发的最重要危险因素,应在肝癌防治决策时予以充分重视。在同一生存环境条件下,HBV感染可促使肝癌发病年龄提前。
乙型肝炎病毒是一种DNA病毒,有四个重叠的开放读码框架(S、C、P和X)。S基因的变异可改变HBsAg的空间结构和免疫原性,导致其抗原性和蛋白表达水平下降。C基因变异将影响HBV病毒载量及HCC进程,其主要突变是nt 1896 G→A,使HBeAg合成终止。HBV基本核心启动子中最重要、最常见的基因突变是nt 1762 A→T、nt 1764 G→A双突变,既增强HBV复制力,又降低HBeAg合成,还增加肝细胞凋亡,从而加重患者病情。P基因变异以YMDD基序的变异(aa M552V或aa M552I,生成YVDD或YIDD)最为重要,YMDD变异伴“a”决定簇内变异时可使HBV的复制能力明显增强。
目前发现的HBV已有A-J共10种基因型,我国主要流行的是B和C基因型。HBV基因型与感染的预后有关,与B基因型相比,C基因型HBV与肝癌的发病更加密切,也会导致更严重的肝纤维化结局。而不同基因型混合感染可引起携带者肝炎复燃。
本研究采用多阶段随机抽样,在充分考虑抽样可行性和科学性的基础上对海门市一般人群进行乙肝血清学调查,包括一般情况,肝炎患病史,乙肝病毒暴露史,乙肝疫苗免疫接种史等。采用ELISA检测方法定性检测HBsAg及半定量检测抗-HBs,对HBsAg阳性血清抽提DNA,并用巢氏PCR扩增HBV S基因及LA-PCR扩增HBV DNA,从而掌握当地HBV的流行规律、变异及主要基因型。
本项目调查对象共计5,624人,HBsAg阳性率为6.035%。不同性别人群间的HBsAg阳性率不存在统计学差异。<30岁人群HBsAg阳性率明显低于≥30岁人群HBsAg阳性率,10岁以下儿童HBsAg阳性率为0%。文化程度越高,HBsAg阳性率越低。医护人员的HBsAg阳性率最低,农民的HBsAg阳性率最高。长期一起生活的直系血亲中有乙肝患者人群的HBsAg阳性率远高于直系血亲中没有乙肝患者人群的HBsAg阳性率。做过手术和做过内窥镜人群的HBsAg阳性率分别高于没有做过的人群的HBsAg阳性率。献血人群的HBsAg阳性率低于没有献血人群的HBsAg阳性率。不同出生地点调查对象的HBsAg阳性率存在统计学差异,表现为：出生于县级以上医院者<出生于乡镇级医院者<出生于家中者。Logistic回归分析显示,乙肝感染相关因素中,长期一起生活的亲人中患有乙肝、做过内窥镜是调查对象乙肝感染的危险因素,而献血是调查对象乙肝感染的保护因素。后者可能是健康工人偏倚所致。
抗-HBs滴度＜10IU/ml者占43.334%；抗-HBs滴度＞10IU/ml人群中,抗-HBs滴度越高所占构成比越高。HBsAg阴性人群与一般人群的抗-HBs滴度分布比例相似；HBsAg阳性人群中,抗-HBs滴度＜10 IU/ml者所占比例为90.845%,抗-HBs滴度位于(10,160]IU/ml者所占比例均低于1.5%,但是抗-HBs滴度>160IU/ml者所占比例为5.282%。不同性别人群间抗-HBs滴度的分布比例基本相同。年龄越低,抗-HBs滴度＜10IU/ml者占该年龄段人群比例越低。抗-HBs滴度＞10IU/ml人群中,小于10岁人群里位于(40,80]IU/ml者所占比例最低；[10,60)岁人群抗-HBs滴度分布与一般人群抗-HBs滴度分布相似；60岁以上人群各个抗-HBs滴度人群所占比例基本相同。不同文化程度和职业人群的抗-HBs滴度分布近似于该年龄段人群的抗-HBs滴度分布。是否做过内窥镜(做过内窥镜者的抗-HBs滴度较低)和不同的出生地点(出生于县级以上医院>乡镇级医院>在家出生者的抗-HBs滴度)对人群的抗-HBs滴度分布比例有影响。Logistic回归分析显示,乙肝感染相关因素中,是否做过内窥镜是抗-HBs是否具有保护作用的危险因素。
乙肝疫苗计划免疫前出生人群的HBsAg阳性率远高于乙肝疫苗计划免疫后出生人群的HBsAg阳性率,抗-HBs平均滴度则表现相反。曾经在村医或个体诊所做过牙科诊疗、与家人共用牙刷和在乡镇及乡镇级以上医院出生的人群中,乙肝疫苗计划免疫前出生人群HBsAg阳性率分别高于乙肝疫苗计划免疫后出生人群的HBsAg阳性率,抗-HBs平均滴度则表现相反。
巢式PCR扩增HBV S基因检测阳性率为45.8%。B基因型占10.8%,C基因型占86.9%,B/C混合型占2.3%。C基因型HBV S基因(特别在亲水区(nt245-nt391))的变异度普遍高于B基因型。相同基因型的不同患病类型乙肝患者的HBVS基因之间并无明显分隔,而B基因型HBV S基因之间同源性更高。所有可能导致HBV的抗原性和免疫应答发生改变的样本均为C基因型,占5.38%,平均年龄为46.71±1.17岁,抗-HBs均小于10 IU/ml。海门市乙肝HBsAg主要为adrq+血清型(82.3%),其次为adw2血清型(16.2%)。
LA-PCR扩增HBV DNA检测阳性率为15.4%,DNA在1814 nt-2452 nt区域相对比较保守。4例样本pre-C基因发生nt 1896 G→A单个碱基替换。B基因型HBV BCP并未发生双重突变(nt 1762 A→T和nt 1764 G→A); C基因型HBVBCP中,发生双重突变(nt 1762 A→T和nt 1764 G→A)的占全部C基因型的47.06%，仅发生nt 1762 A→T突变者占5.88%,仅发生nt 1764 G→A突变者占11.76%。海门市与黑龙江和上海的HBV平均进化距离差距最小,其次为北京、安徽、启东、台湾和西藏。海门市HBV平均进化距离与中国其他地区HBV平均进化距离的差距主要出于基因型分布的差异所致。
就C基因型HBV DNA而言,海门株之间的进化距离比较大,也大于某些地区株与海门株之间的进化距离。海门株与本地区及其他各个地区株之间的pre-C/C基因、C基因和X基因进化距离普遍小于同样地区之间的HBV DNA进化距离,而P基因的进化距离则普遍大于同样地区之间的HBV DNA进化距离。与其他地区相比,海门株之间的pre-S1/pre-S2区域序列变异程度较大,同源性较低。尽管海门市为HCC高发区,但是从海门市一般人群中筛选出的HBV DNA与其他地区的HCC患者的HBV DNA之间的同源性并不高,反而与北京等地区的慢性HBV患者的HBV DNA之间的同源性较高。
经过近二十年的乙肝疫苗计划免疫工作,海门市HBV的预防工作卓有成效,HBV感染情况已经得到明显好转。青少年的HBV感染率并未随着年龄的增长而有所上升；而随着当地成年人年龄的增长,乙肝患者体内HBV可能会被清除,或是由于HBV S基因变异所致的HBsAg假阴性。
海门市HBV存在家庭内或家族聚集感染,可能是垂直传播,遗传因素,水平传播综合作用的结果；从病毒学方面看,HBV家族聚集性感染和非家族聚集感染临床类型差异不大。海门市HBV也通过内窥镜检查进行传播。仅出生地点的不同对HBV感染有影响,说明出生时所接受到的医疗水平程度对HBV感染有影响。乙肝疫苗计划免疫对于中低教育程度和中低收入家庭来说,是预防HBV感染的主要途径。乡镇及乡镇以下级别医院的牙科诊疗可能是海门市HBV社会传播的途径之一,家庭内共用牙刷可能也是海门市HBV家庭内传播的途径之一
综上所述,海门市一般人群HBV感染的主要影响因素为：年龄、受教育程度、直系血亲中是否有人患有乙肝、是否做过内窥镜、出生地点和乙肝疫苗计划免疫。年龄、受教育程度和出生地点主要影响乙肝疫苗的免疫接种,而海门市HBV感染主要来源于垂直传播途径和通过内窥镜、牙科诊疗和家庭内共用牙刷等水平传播途径。乙肝疫苗的及时接种是阻止海门市HBV传播的最有效的方法。
海门市HBV S基因已经出现了能改变HBV抗原性和免疫原性的变异,应当密切关注以防止乙肝疫苗失效。海门市作为HCC高发区,当地HBV DNA与其他非HCC高发区HBV DNA(无论是否来源于HCC患者)的差异并不显著,X基因的差异甚至更小,提示尽管血清HBV病毒水平是HCC发生独立的预期因素,且慢性乙型肝炎炎症应答过程中逐渐累积的基因改变是HCC发生的最重要因素,但HBV的变异程度并不是海门市HCC高发的直接原因,而可能是HCC其它直接危险因素的促进因素。
本研究受实验条件所限制,并未测量HBsAg阳性标本血清中的HBV DNA水平,可以在后续研究中进行近一步分析及探讨。
Haimen City, Jiangsu Province, located in the Yangtze River Delta, is the high incidence city of primary hepatocellular carcinoma (HCC). HBV infection, the most important risk factors and promotion condition in younger while living in the same environmental, should be full attention to decision-making in the HCC control.
As a DNA virus, there are four overlapping open reading frames (S, C, P and X) in Hepatitis B virus. S gene mutation changes the HBsAg spatial structure and immunogenicity, leading to low levels of antigenicity and protein. C gene mutation, mainly nt 1896 G→A for termination of HBeAg synthesis, will affect viral load and the process of HCC. The most important and common mutation in Basic core promoter is nt 1762 A→T, nt 1764 G→A double mutation,which not only enhanced HBV replication ability, but also reduce HBeAg synthesis as well as increased hepatocyte apoptosis, thereby increasing the patient condition. YMDD mutation (aa M552V or aa M552Ⅰ, generate YVDD or YIDD) is the most important mutation in P gene. HBV replication is obviously enhanced due to YMDD mutation with "a" determinant.
Currently there are 10 HBV genotypes in the world. The popular genotypes in China are B and C. HBV genotype is connected with prognosis of HBV infection. Compared with genotype B, genotype C is more closely with HCC, and will lead to more severe liver fibrosis. The mixed infection of different genotypes of HBV can cause resurgence.
We carried out the hepatitis B serological surveys in the general population of Haimen City with multi-stage random sampling, including general conditions, history of liver diseases, exposure history of hepatitis B virus, and vaccination history for hepatitis B. After HBsAg qualitative detection and semi-quantitative detection of anti-HBs by ELISA, extraction of HBV DNA, Nested PCR amplification of HBV S gene and the LA-PCR amplification of HBV DNA, we grasp the prevalence, the variation and the major genotype of HBV in Haimen.
HBsAg positive rate was 6.035% in the totally investigatory population of 5,624. The HBsAg-positive rate between two gender is not statistics different.<30 HBsAg-positive rate in population at aged<30 years was significantly lower than aged≥30 years of age, and HBsAg-positive rate of children under the age of 10 was 0. The higher educational level, HBsAg-positive rate is lower. The lowest rate of HBsAg-positive was in health care workers, but the highest was in peasants. The HBsAg-positive rate in the groups of consanguinities who were hepatitis B patients was significantly higher than the groups of consanguinities without hepatitis B virus. The HBsAg-positive rate in surgery and endoscopy groups was significantly higher than the groups without surgery and endoscopy. The HBsAg positive rate among blood donors is lower than the non-blood donors. The HBsAg-positive rate among the different place of birth was significantly different, as follows: who was born in hospitals above county level< who was born in the township-level hospitals Whose Anti-HBs titers< 10 IU/ml were accounted for 43.334% in totally investigatory population; in anti-HBs titer of> 1OIU/ml population, however, the groups with higher anti-HBs titers is larger than the groups with lower anti-HBs titers. The distribution of anti-HBs titer in HBsAg negative population was same as the general population. In HBsAg-positive population, whose anti-HBs titers<10 IU/ml were accounted for 90.845%; whose anti-HBs titers in (10,160] IU/ml is lower than 1.5%; but whose anti-HBs titers> 160IU/mlwere accounted for 5.282%. The distribution of anti-HBs titer between two genders was similar. In anti-HBs titer<10 IU/ml population, the percentage of younger is gradully lower than elder. In anti-HBs titer> 10 IU/ml population, children below age of 10 whose located in (40,80] IU/ml was accounted for the lowest percentage; the distribution of anti-HBs titer in [10,60) years population was same as the general population; the percentage of different anti-HBs titer in people over the age of 60 was similar. The anti-HBs titer distribution in differently educational and occupational groups was similar to the age groups. Endoscopy done groups had lower anti-HBs titers. The distribution of anti-HBs titer can be impacted by different place of birth (born in or above the county level hospitals> born in township-level hospitals> born at home). Logistic regression analysis showed that endoscopy was the risk factors of anti-HBs protective effects.
HBsAg-positive rate of population, especially in those who having done dental in the village doctor or individual clinics, sharing a toothbrush with family members and born in and above township level hospitals, who were born before the era of planned immunization was much higher than after the era of planned immunization, but the average anti-HBs titer was performance of the contrary.
Amplified by nested PCR, test positive percentage for HBV S gene was 45.8%. B genotype was accounted for 10.8%, C genotype was accounted for 86.9%, and B/ C mixed genotype was accounted for 2.3%. The variability of genotype C HBV S gene, particularly in the hydrophilic region (nt 245-nt 391), was generally higher than genotype B. HBV S gene among different disease patients with the same genotype was no significant separation, and genotype B HBV S gene was higher homology. All that may lead to HBV antigens and immune response changes, accounting for 5.38%, were genotype C, which average age was 46.71±1.17 years and anti-HBs titer was less than 10 Ul/1. All Haimen's HBV samples were mainly adrq+ HBsAg serotypes (accounted for 82.3%), followed by adw2 serotypes (accounted for 16.2%).
Amplified by LA-PCR, test positive percentage for HBV DNA was 15.4%, and the nt 1814-nt 2452 region is relatively conservative.4 cases of pre-C gene occurred nt 1896 G→A single base substitutions. BCP double mutations did not occur (nt1762A→T and nt1764G→A) in genotype B; in genotype C, however, BCP double mutations (ntl762A→T and ntl764G→A) was accounted for 47.06%, where as only ntl762A→T mutation and only nt1764G→A mutation was accounted for 5.88% and 11.76%, respectively. The average evolutionary distance of HBV DNA among Haimen, Shanghai and Heilongjiang was the smallest gap, followed by Beijing, Anhui, Qidong, Taiwan and Tibet, which is mainly due to different genotype distribution.
On the genotype C HBV DNA, the evolutionary distance among Haimen strains was relatively large, even much greater than the distance between Haimen and some areas'strains. The distance on the pre-C/C gene, C gene and X gene, in the opposite of P gene, in Haimen strains and between Haimen and other areas' strains were lower than the HBV DNA among the same areas' strains. Compared with other regions, the pre-S1/pre-S2 gene in Haimen strains had grester variation. Despite of the high HCC incidence in Haimen, the evolutionary distance on HBV DNA between Haimen strains from the general population and other areas' strains from HCC patients is larger than those between Haimen and Beijing strains from HB patiants.
After nearly two decades of hepatitis B vaccine program immunization, HBV prevention in Haimen City is effective and HBV infection has been significantly decreased. HBV infection rate of young people is increased with growing up; and in the local adult, HBV hepatitis B patients is likely to be removed with aging, or false negative HBsAg caused by HBV S gene mutation.
There is HBV infection within the family or family gathering in Haimen, which may be the combined result of vertical transmission, genetic factors and horizontal transmission. But there is non-significant difference of clinical types between familial and non-familial aggregation in virology. Places of birth can influence on HBV infection, indicating that the level of medical received at birth can imapct on HBV infection. For the low education and income families, Hepatitis B vaccine immunization is the main way to prevent HBV infection. HBV is spread through not only some ways of social transmission, such as the endoscope and dental in and below township-level hospitals, but the ways of family transmission by sharing a toothbrush as well. In summary, the main factors of HBV infection in the general Haimen population include:age, educational level, consanguinities who were hepatitis B patients, endoscopy, place of birth and hepatitis B vaccine immunization. Age, educational level and place of birth mainly effect hepatitis B vaccine immunization, and Haimen HBV infection is mainly from vertical transmission and horizontal transmission by endoscopy, dental and sharing a toothbrush in family. Hepatitis B vaccine in the right time is the best way to prevent the spread of HBV in Haimen.
The variation of HBV S gene in Haimen, which can changes in antigenicity and immunogenicity, should be closely watched to prevent hepatitis B vaccine failure. As the high-incidence HCC area, the distance of HBV DNA, as well as X gene, was not significant between Haimen and other low-incidence HCC areas, regardless whether from HCC patients, which suggesting that variation of HBV is not the direct cause of high-incidence HCC, but maybe the simulating factor to other direct factors in Haimen, although the viral load of serum HBV is independent expected factors and genetic changes during chronic hepatitis B inflammatory response is the most important factor in HCC occurred.
Limited by the experimental conditions, this study did not measure HBV load in HBsAg positive samples, which need to be carried out taking a step forward in follow-up studies.
乙型肝炎病毒是一种DNA病毒,有四个重叠的开放读码框架(S、C、P和X)。S基因的变异可改变HBsAg的空间结构和免疫原性,导致其抗原性和蛋白表达水平下降。C基因变异将影响HBV病毒载量及HCC进程,其主要突变是nt 1896 G→A,使HBeAg合成终止。HBV基本核心启动子中最重要、最常见的基因突变是nt 1762 A→T、nt 1764 G→A双突变,既增强HBV复制力,又降低HBeAg合成,还增加肝细胞凋亡,从而加重患者病情。P基因变异以YMDD基序的变异(aa M552V或aa M552I,生成YVDD或YIDD)最为重要,YMDD变异伴“a”决定簇内变异时可使HBV的复制能力明显增强。
目前发现的HBV已有A-J共10种基因型,我国主要流行的是B和C基因型。HBV基因型与感染的预后有关,与B基因型相比,C基因型HBV与肝癌的发病更加密切,也会导致更严重的肝纤维化结局。而不同基因型混合感染可引起携带者肝炎复燃。
本研究采用多阶段随机抽样,在充分考虑抽样可行性和科学性的基础上对海门市一般人群进行乙肝血清学调查,包括一般情况,肝炎患病史,乙肝病毒暴露史,乙肝疫苗免疫接种史等。采用ELISA检测方法定性检测HBsAg及半定量检测抗-HBs,对HBsAg阳性血清抽提DNA,并用巢氏PCR扩增HBV S基因及LA-PCR扩增HBV DNA,从而掌握当地HBV的流行规律、变异及主要基因型。
本项目调查对象共计5,624人,HBsAg阳性率为6.035%。不同性别人群间的HBsAg阳性率不存在统计学差异。<30岁人群HBsAg阳性率明显低于≥30岁人群HBsAg阳性率,10岁以下儿童HBsAg阳性率为0%。文化程度越高,HBsAg阳性率越低。医护人员的HBsAg阳性率最低,农民的HBsAg阳性率最高。长期一起生活的直系血亲中有乙肝患者人群的HBsAg阳性率远高于直系血亲中没有乙肝患者人群的HBsAg阳性率。做过手术和做过内窥镜人群的HBsAg阳性率分别高于没有做过的人群的HBsAg阳性率。献血人群的HBsAg阳性率低于没有献血人群的HBsAg阳性率。不同出生地点调查对象的HBsAg阳性率存在统计学差异,表现为：出生于县级以上医院者<出生于乡镇级医院者<出生于家中者。Logistic回归分析显示,乙肝感染相关因素中,长期一起生活的亲人中患有乙肝、做过内窥镜是调查对象乙肝感染的危险因素,而献血是调查对象乙肝感染的保护因素。后者可能是健康工人偏倚所致。
抗-HBs滴度＜10IU/ml者占43.334%；抗-HBs滴度＞10IU/ml人群中,抗-HBs滴度越高所占构成比越高。HBsAg阴性人群与一般人群的抗-HBs滴度分布比例相似；HBsAg阳性人群中,抗-HBs滴度＜10 IU/ml者所占比例为90.845%,抗-HBs滴度位于(10,160]IU/ml者所占比例均低于1.5%,但是抗-HBs滴度>160IU/ml者所占比例为5.282%。不同性别人群间抗-HBs滴度的分布比例基本相同。年龄越低,抗-HBs滴度＜10IU/ml者占该年龄段人群比例越低。抗-HBs滴度＞10IU/ml人群中,小于10岁人群里位于(40,80]IU/ml者所占比例最低；[10,60)岁人群抗-HBs滴度分布与一般人群抗-HBs滴度分布相似；60岁以上人群各个抗-HBs滴度人群所占比例基本相同。不同文化程度和职业人群的抗-HBs滴度分布近似于该年龄段人群的抗-HBs滴度分布。是否做过内窥镜(做过内窥镜者的抗-HBs滴度较低)和不同的出生地点(出生于县级以上医院>乡镇级医院>在家出生者的抗-HBs滴度)对人群的抗-HBs滴度分布比例有影响。Logistic回归分析显示,乙肝感染相关因素中,是否做过内窥镜是抗-HBs是否具有保护作用的危险因素。
乙肝疫苗计划免疫前出生人群的HBsAg阳性率远高于乙肝疫苗计划免疫后出生人群的HBsAg阳性率,抗-HBs平均滴度则表现相反。曾经在村医或个体诊所做过牙科诊疗、与家人共用牙刷和在乡镇及乡镇级以上医院出生的人群中,乙肝疫苗计划免疫前出生人群HBsAg阳性率分别高于乙肝疫苗计划免疫后出生人群的HBsAg阳性率,抗-HBs平均滴度则表现相反。
巢式PCR扩增HBV S基因检测阳性率为45.8%。B基因型占10.8%,C基因型占86.9%,B/C混合型占2.3%。C基因型HBV S基因(特别在亲水区(nt245-nt391))的变异度普遍高于B基因型。相同基因型的不同患病类型乙肝患者的HBVS基因之间并无明显分隔,而B基因型HBV S基因之间同源性更高。所有可能导致HBV的抗原性和免疫应答发生改变的样本均为C基因型,占5.38%,平均年龄为46.71±1.17岁,抗-HBs均小于10 IU/ml。海门市乙肝HBsAg主要为adrq+血清型(82.3%),其次为adw2血清型(16.2%)。
LA-PCR扩增HBV DNA检测阳性率为15.4%,DNA在1814 nt-2452 nt区域相对比较保守。4例样本pre-C基因发生nt 1896 G→A单个碱基替换。B基因型HBV BCP并未发生双重突变(nt 1762 A→T和nt 1764 G→A); C基因型HBVBCP中,发生双重突变(nt 1762 A→T和nt 1764 G→A)的占全部C基因型的47.06%，仅发生nt 1762 A→T突变者占5.88%,仅发生nt 1764 G→A突变者占11.76%。海门市与黑龙江和上海的HBV平均进化距离差距最小,其次为北京、安徽、启东、台湾和西藏。海门市HBV平均进化距离与中国其他地区HBV平均进化距离的差距主要出于基因型分布的差异所致。
就C基因型HBV DNA而言,海门株之间的进化距离比较大,也大于某些地区株与海门株之间的进化距离。海门株与本地区及其他各个地区株之间的pre-C/C基因、C基因和X基因进化距离普遍小于同样地区之间的HBV DNA进化距离,而P基因的进化距离则普遍大于同样地区之间的HBV DNA进化距离。与其他地区相比,海门株之间的pre-S1/pre-S2区域序列变异程度较大,同源性较低。尽管海门市为HCC高发区,但是从海门市一般人群中筛选出的HBV DNA与其他地区的HCC患者的HBV DNA之间的同源性并不高,反而与北京等地区的慢性HBV患者的HBV DNA之间的同源性较高。
经过近二十年的乙肝疫苗计划免疫工作,海门市HBV的预防工作卓有成效,HBV感染情况已经得到明显好转。青少年的HBV感染率并未随着年龄的增长而有所上升；而随着当地成年人年龄的增长,乙肝患者体内HBV可能会被清除,或是由于HBV S基因变异所致的HBsAg假阴性。
海门市HBV存在家庭内或家族聚集感染,可能是垂直传播,遗传因素,水平传播综合作用的结果；从病毒学方面看,HBV家族聚集性感染和非家族聚集感染临床类型差异不大。海门市HBV也通过内窥镜检查进行传播。仅出生地点的不同对HBV感染有影响,说明出生时所接受到的医疗水平程度对HBV感染有影响。乙肝疫苗计划免疫对于中低教育程度和中低收入家庭来说,是预防HBV感染的主要途径。乡镇及乡镇以下级别医院的牙科诊疗可能是海门市HBV社会传播的途径之一,家庭内共用牙刷可能也是海门市HBV家庭内传播的途径之一
综上所述,海门市一般人群HBV感染的主要影响因素为：年龄、受教育程度、直系血亲中是否有人患有乙肝、是否做过内窥镜、出生地点和乙肝疫苗计划免疫。年龄、受教育程度和出生地点主要影响乙肝疫苗的免疫接种,而海门市HBV感染主要来源于垂直传播途径和通过内窥镜、牙科诊疗和家庭内共用牙刷等水平传播途径。乙肝疫苗的及时接种是阻止海门市HBV传播的最有效的方法。
海门市HBV S基因已经出现了能改变HBV抗原性和免疫原性的变异,应当密切关注以防止乙肝疫苗失效。海门市作为HCC高发区,当地HBV DNA与其他非HCC高发区HBV DNA(无论是否来源于HCC患者)的差异并不显著,X基因的差异甚至更小,提示尽管血清HBV病毒水平是HCC发生独立的预期因素,且慢性乙型肝炎炎症应答过程中逐渐累积的基因改变是HCC发生的最重要因素,但HBV的变异程度并不是海门市HCC高发的直接原因,而可能是HCC其它直接危险因素的促进因素。
本研究受实验条件所限制,并未测量HBsAg阳性标本血清中的HBV DNA水平,可以在后续研究中进行近一步分析及探讨。
Haimen City, Jiangsu Province, located in the Yangtze River Delta, is the high incidence city of primary hepatocellular carcinoma (HCC). HBV infection, the most important risk factors and promotion condition in younger while living in the same environmental, should be full attention to decision-making in the HCC control.
As a DNA virus, there are four overlapping open reading frames (S, C, P and X) in Hepatitis B virus. S gene mutation changes the HBsAg spatial structure and immunogenicity, leading to low levels of antigenicity and protein. C gene mutation, mainly nt 1896 G→A for termination of HBeAg synthesis, will affect viral load and the process of HCC. The most important and common mutation in Basic core promoter is nt 1762 A→T, nt 1764 G→A double mutation,which not only enhanced HBV replication ability, but also reduce HBeAg synthesis as well as increased hepatocyte apoptosis, thereby increasing the patient condition. YMDD mutation (aa M552V or aa M552Ⅰ, generate YVDD or YIDD) is the most important mutation in P gene. HBV replication is obviously enhanced due to YMDD mutation with "a" determinant.
Currently there are 10 HBV genotypes in the world. The popular genotypes in China are B and C. HBV genotype is connected with prognosis of HBV infection. Compared with genotype B, genotype C is more closely with HCC, and will lead to more severe liver fibrosis. The mixed infection of different genotypes of HBV can cause resurgence.
We carried out the hepatitis B serological surveys in the general population of Haimen City with multi-stage random sampling, including general conditions, history of liver diseases, exposure history of hepatitis B virus, and vaccination history for hepatitis B. After HBsAg qualitative detection and semi-quantitative detection of anti-HBs by ELISA, extraction of HBV DNA, Nested PCR amplification of HBV S gene and the LA-PCR amplification of HBV DNA, we grasp the prevalence, the variation and the major genotype of HBV in Haimen.
HBsAg positive rate was 6.035% in the totally investigatory population of 5,624. The HBsAg-positive rate between two gender is not statistics different.<30 HBsAg-positive rate in population at aged<30 years was significantly lower than aged≥30 years of age, and HBsAg-positive rate of children under the age of 10 was 0. The higher educational level, HBsAg-positive rate is lower. The lowest rate of HBsAg-positive was in health care workers, but the highest was in peasants. The HBsAg-positive rate in the groups of consanguinities who were hepatitis B patients was significantly higher than the groups of consanguinities without hepatitis B virus. The HBsAg-positive rate in surgery and endoscopy groups was significantly higher than the groups without surgery and endoscopy. The HBsAg positive rate among blood donors is lower than the non-blood donors. The HBsAg-positive rate among the different place of birth was significantly different, as follows: who was born in hospitals above county level< who was born in the township-level hospitals
HBsAg-positive rate of population, especially in those who having done dental in the village doctor or individual clinics, sharing a toothbrush with family members and born in and above township level hospitals, who were born before the era of planned immunization was much higher than after the era of planned immunization, but the average anti-HBs titer was performance of the contrary.
Amplified by nested PCR, test positive percentage for HBV S gene was 45.8%. B genotype was accounted for 10.8%, C genotype was accounted for 86.9%, and B/ C mixed genotype was accounted for 2.3%. The variability of genotype C HBV S gene, particularly in the hydrophilic region (nt 245-nt 391), was generally higher than genotype B. HBV S gene among different disease patients with the same genotype was no significant separation, and genotype B HBV S gene was higher homology. All that may lead to HBV antigens and immune response changes, accounting for 5.38%, were genotype C, which average age was 46.71±1.17 years and anti-HBs titer was less than 10 Ul/1. All Haimen's HBV samples were mainly adrq+ HBsAg serotypes (accounted for 82.3%), followed by adw2 serotypes (accounted for 16.2%).
Amplified by LA-PCR, test positive percentage for HBV DNA was 15.4%, and the nt 1814-nt 2452 region is relatively conservative.4 cases of pre-C gene occurred nt 1896 G→A single base substitutions. BCP double mutations did not occur (nt1762A→T and nt1764G→A) in genotype B; in genotype C, however, BCP double mutations (ntl762A→T and ntl764G→A) was accounted for 47.06%, where as only ntl762A→T mutation and only nt1764G→A mutation was accounted for 5.88% and 11.76%, respectively. The average evolutionary distance of HBV DNA among Haimen, Shanghai and Heilongjiang was the smallest gap, followed by Beijing, Anhui, Qidong, Taiwan and Tibet, which is mainly due to different genotype distribution.
On the genotype C HBV DNA, the evolutionary distance among Haimen strains was relatively large, even much greater than the distance between Haimen and some areas'strains. The distance on the pre-C/C gene, C gene and X gene, in the opposite of P gene, in Haimen strains and between Haimen and other areas' strains were lower than the HBV DNA among the same areas' strains. Compared with other regions, the pre-S1/pre-S2 gene in Haimen strains had grester variation. Despite of the high HCC incidence in Haimen, the evolutionary distance on HBV DNA between Haimen strains from the general population and other areas' strains from HCC patients is larger than those between Haimen and Beijing strains from HB patiants.
After nearly two decades of hepatitis B vaccine program immunization, HBV prevention in Haimen City is effective and HBV infection has been significantly decreased. HBV infection rate of young people is increased with growing up; and in the local adult, HBV hepatitis B patients is likely to be removed with aging, or false negative HBsAg caused by HBV S gene mutation.
There is HBV infection within the family or family gathering in Haimen, which may be the combined result of vertical transmission, genetic factors and horizontal transmission. But there is non-significant difference of clinical types between familial and non-familial aggregation in virology. Places of birth can influence on HBV infection, indicating that the level of medical received at birth can imapct on HBV infection. For the low education and income families, Hepatitis B vaccine immunization is the main way to prevent HBV infection. HBV is spread through not only some ways of social transmission, such as the endoscope and dental in and below township-level hospitals, but the ways of family transmission by sharing a toothbrush as well. In summary, the main factors of HBV infection in the general Haimen population include:age, educational level, consanguinities who were hepatitis B patients, endoscopy, place of birth and hepatitis B vaccine immunization. Age, educational level and place of birth mainly effect hepatitis B vaccine immunization, and Haimen HBV infection is mainly from vertical transmission and horizontal transmission by endoscopy, dental and sharing a toothbrush in family. Hepatitis B vaccine in the right time is the best way to prevent the spread of HBV in Haimen.
The variation of HBV S gene in Haimen, which can changes in antigenicity and immunogenicity, should be closely watched to prevent hepatitis B vaccine failure. As the high-incidence HCC area, the distance of HBV DNA, as well as X gene, was not significant between Haimen and other low-incidence HCC areas, regardless whether from HCC patients, which suggesting that variation of HBV is not the direct cause of high-incidence HCC, but maybe the simulating factor to other direct factors in Haimen, although the viral load of serum HBV is independent expected factors and genetic changes during chronic hepatitis B inflammatory response is the most important factor in HCC occurred.
Limited by the experimental conditions, this study did not measure HBV load in HBsAg positive samples, which need to be carried out taking a step forward in follow-up studies.
引文
[1]海门市统计局.海门统计年鉴——2005[M].2006：15-60.
[2]林文尧,钱雪峰,张维芳,等.海门市原发性肝细胞癌死亡率时间趋势分析[J].江苏预防医学.2003,14(1)：4-6.
[3]王寒松,黄培新,唐锦高,等.海门市2001-2007年恶性肿瘤发病状况与趋势分析[J].中国肿瘤.2010,19(2)：100-104.
[4]全国肿瘤防治研究办公室,全国肿瘤登记中心,卫生部疾病预防控制局.中国部分市、县恶性肿瘤的发病与死亡,第3卷(1998-2002)[M].北京：人民卫生出版社,2007：25-376.
[5]王兰萍,唐锦高,钱雪峰,等.乙肝病毒感染与原发性肝细胞癌的队列研究[J].南通大学学报(医学版).2005,25(5)：332-334.
[6]H. Vildozola Gonzales,J. L. Salinas. Natural history of chronic hepatitis B virus infection[J]. Rev Gastroenterol Peru.2009,29(2):147-157.
[7]Y. F. Liaw,C. M. Chu. Hepatitis B virus infection[J]. Lancet.2009,373(9663): 582-592.
[8]H. X. Yan, J. C. Ma, T. Bian, et al. [The analysis of "alpha" dominant mutation of hepatitis B virus in community-based Zhengding area, Hebei province][J]. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi.2009,23(1):11-13.
[9]Y. Zhang, F. Wang,J. C. Ma. Evaluations of 5 kinds of China-made enzyme immunoassay kits for hepatitis B virus surface antigen detection[J]. Zhongguo Ji Hua Mian Yi.2009,15(5):388-391.
[10]X. L. Zhou, P. N. Sun, T. H. Huang, et al. Effects of hepatitis B virus S protein on human sperm function[J]. Hum Reprod.2009,24(7):1575-1583.
[11]C. H. Chen, C. S. Changchien, C. M. Lee, et al. A study on sequence variations in pre-S/surface, X and enhancer Ⅱ/core promoter/precore regions of occult hepatitis B virus in non-B, non-C hepatocellular carcinoma patients in Taiwan[J]. Int J Cancer. 2009,125(3):621-629.
[12]F. Y. Sung, C. M. Jung, C. F. Wu, et al. Hepatitis B virus core variants modify natural course of viral infection and hepatocellular carcinoma progression[J]. Gastroenterology.2009,137(5):1687-1697.
[13]T. F. Baumert, C. Yang, P. Schurmann, et al. Hepatitis B virus mutations associated with fulminant hepatitis induce apoptosis in primary Tupaia hepatocytes[J]. Hepatology.2005,41(2):247-256.
[14]K. Shiraki, M. Hamada, K. Sugimoto, et al. Detection of precore-mutant hepatitis B virus genome in patients with acute and fulminant hepatitis using mutation site-specific assay (MSSA)[J]. Hepatogastroenterology.2002,49(47):1352-1356.
[15]Y. H. Shih, S. H. Yeh, P. J. Chen, et al. Hepatitis B virus quantification and detection of YMDD mutants in a single reaction by real-time PCR and annealing curve analysis[J]. Antivir Ther.2008,13(4):469-480.
[16]D. Li, H. X. Gu, S. Y. Zhang, et al. YMDD mutations and genotypes of hepatitis B virus in northern China[J]. Jpn J Infect Dis.2006,59(1):42-45.
[17]C. T. Bock, H. L. Tillmann, J. Torresi, et al. Selection of hepatitis B virus polymerase mutants with enhanced replication by lamivudine treatment after liver transplantation[J]. Gastroenterology.2002,122(2):264-273.
[18]S. K. Ono, N. Kato, Y. Shiratori, et al. The polymerase L528M mutation cooperates with nucleotide binding-site mutations, increasing hepatitis B virus replication and drug resistance[J]. J Clin Invest.2001,107(4):449-455.
[19]K. Koike. Hepatitis B virus X gene is implicated in liver carcinogenesis[J]. Cancer Lett.2009,286(1):60-68.
[20]L. Ye, N. Dong, Q. Wang, et al. Progressive changes in hepatoma cells stably transfected with hepatitis B virus X gene[J]. Intervirology.2008,51(1):50-58.
[21]P. Zhu, D. Tan, Z. Peng, et al. Polymorphism analyses of hepatitis B virus X gene in hepatocellular carcinoma patients from southern China[J]. Acta Biochim Biophys Sin (Shanghai).2007,39(4):265-272.
[22]T. Guettouche,H. J. Hnatyszyn. Chronic hepatitis B and viral genotype:the clinical significance of determining HBV genotypes[J]. Antivir Ther.2005,10(5): 593-604.
[23]S. Schaefer. Hepatitis B virus taxonomy and hepatitis B virus genotypes[J]. World J Gastroenterol.2007,13(1):14-21.
[24]T. T. Tran, T. N. Trinh,K. Abe. New complex recombinant genotype of hepatitis B virus identified in Vietnam[J]. J Virol.2008,82(11):5657-5663.
[25]C. M. Olinger, P. Jutavijittum, J. M. Hubschen, et al. Possible new hepatitis B virus genotype, southeast Asia[J]. Emerg Infect Dis.2008,14(11):1777-1780.
[26]K. Tatematsu, Y. Tanaka, F. Kurbanov, et al. A genetic variant of hepatitis B virus divergent from known human and ape genotypes isolated from a Japanese patient and provisionally assigned to new genotype J[J]. J Virol.2009,83(20):10538-10547.
[27]F. Sugauchi, E. Orito, T. Ichida, et al. Epidemiologic and virologic characteristics of hepatitis B virus genotype B having the recombination with genotype C[J]. Gastroenterology.2003,124(4):925-932.
[28]G W. Cao. Clinical relevance and public health significance of hepatitis B virus genomic variations[J]. World J Gastroenterol.2009,15(46):5761-5769.
[29]C. T. Wai, C. J. Chu, M. Hussain, et al. HBV genotype B is associated with better response to interferon therapy in HBeAg(+) chronic hepatitis than genotype C[J]. Hepatology.2002,36(6):1425-1430.
[30]H. L. Chan, G L. Wong, C. H. Tse, et al. Hepatitis B virus genotype C is associated with more severe liver fibrosis than genotype B[J]. Clin Gastroenterol Hepatol.2009,7(12):1361-1366.
[31]N. L. Toan, H. Song le, P. G Kremsner, et al. Impact of the hepatitis B virus genotype and genotype mixtures on the course of liver disease in Vietnam[J]. Hepatology.2006,43(6):1375-1384.
[32]周红星,周亮.海门市2006年一般人群病毒性肝炎监测结果[J].职业与健康.2007,23(13)：1120-1121.
[33]陈长荣,袁权,葛胜祥,等.无偿献血者中隐匿性乙型肝炎病毒感染及表面抗原突变分析[J].病毒学报.2009,25(3)：178-184.
[34]L. O. Magnius,H. Norder. Subtypes, genotypes and molecular epidemiology of the hepatitis B virus as reflected by sequence variability of the S-gene[J]. Intervirology.1995,38(1-2):24-34.
[35]任来峰,张烜榕,申元英,等.大理白族自治州乙型肝炎病毒基因型分布研究[J].中国热带医学.2009,9(3)：428-429,458.
[36]江建华.海门市10年恶性肿瘤死亡分析[J].江苏预防医学.2001,12(3)：71-72.
[37]X. Liang, S. Bi, W. Yang, et al. Epidemiological serosurvey of hepatitis B in China--declining HBV prevalence due to hepatitis B vaccination[J]. Vaccine.2009, 27(47):6550-6557.
[38]朱荣,曹文英,李显,等.江苏省病毒性肝炎感染率研究[J].江苏预防医学.1996，3：3-5.
[39]G. T. Kumar, S. N. Kazim, M. Kumar, et al. Hepatitis B virus genotypes and hepatitis B surface antigen mutations in family contacts of hepatitis B virus infected patients with occult hepatitis B virus infection[J]. J Gastroenterol Hepatol.2009, 24(4):588-598.
[40]陈明春,郑有限,叶培英,等.泉州地区乙型肝炎病毒基因型调查及其流行病学研究[J].中国卫生检验杂志.2010,20(1)：174-176.
[41]李永勤,薛卫宁,付建军,等.不良结局家族聚集性乙肝感染者HBV基因分型[J].齐齐哈尔医学院学报.2008,29(10)：1155-1157.
[42]M. Thursz. Pros and cons of genetic association studies in hepatitis B[J]. Hepatology.2004,40(2):284-286.
[43]E. L. Wynder, I. T. Higgins,R. E. Harris. The wish bias[J]. J Clin Epidemiol. 1990,43(6):619-621.
[44]S. G Lim, R. Mohammed, M. F. Yuen, et al. Prevention of hepatocellular carcinoma in hepatitis B virus infection[J]. J Gastroenterol Hepatol.2009,24(8): 1352-1357.
[45]N. Y. Rots, A. J. Wijmenga-Monsuur, W. Luytjes, et al. Hepatitis B vaccination strategies tailored to different endemicity levels:some considerations [J]. Vaccine. 2010,28(4):893-900.
[46]S. Awerkiew, M. Daumer, M. Reiser, et al. Reactivation of an occult hepatitis B virus escape mutant in an anti-HBs positive, anti-HBc negative lymphoma patient[J]. J Clin Virol.2007,38(1):83-86.
[47]W. H. Gerlich. Breakthrough of hepatitis B virus escape mutants after vaccination and virus reactivation[J]. J Clin Virol.2006,36 Suppl 1:S18-22.
[48]X. Huang, D. Lu, G Ji, et al. Hepatitis B virus (HBV) vaccine-induced escape mutants of HBV S gene among children from Qidong area, China[J]. Virus Res.2004, 99(1):63-68.
[49]T. Shizuma, K. Hasegawa, K. Ishikawa, et al. Molecular analysis of antigenicity and immunogenicity of a vaccine-induced escape mutant of hepatitis B virus[J]. J Gastroenterol.2003,38(3):244-253.
[50]T. Kalinina, A. Iwanski, H. Will, et al. Deficiency in virion secretion and decreased stability of the hepatitis B virus immune escape mutant G145R[J]. Hepatology.2003,38(5):1274-1281.
[51]H. L. Chan, C. H. Tse, F. Mo, et al. High viral load and hepatitis B virus subgenotype ce are associated with increased risk of hepatocellular carcinoma[J]. J Clin Oncol.2008,26(2):177-182.
[52]C. T. Zhu,C. L. Dong. Characteristics of general distribution of hepatitis B virus genotypes in China[J]. Hepatobiliary Pancreat Dis Int.2009,8(4):397-401.
[53]经继生,黄培,阮成荣,等.江苏省乙型肝炎病毒基因型分布与临床相关性[J].肝脏.2006,11(5)：335-336.
[54]J. F. Perz, G. L. Armstrong, L. A. Farrington, et al. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide[J]. J Hepatol.2006,45(4):529-538.
[55]U. H. Iloeje, H. I. Yang, J. Su, et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load[J]. Gastroenterology.2006,130(3):678-686.
[56]S. Mahmood, G. Niiyama, A. Kamei, et al. Influence of viral load and genotype in the progression of Hepatitis B-associated liver cirrhosis to hepatocellular carcinoma[J]. Liver Int.2005,25(2):220-225.
[57]K. Hagymasi, Z. Tulassay. Epidemiology, risk factors and molecular pathogenesis of primary liver cancer[J]. Orv Hetil.2008,149(12):541-548.
[58]R. H. Luo, Z. X. Zhao, X. Y. Zhou, et al. Risk factors for primary liver carcinoma in Chinese population[J]. World J Gastroenterol.2005,11(28):4431-4434.
[59]S. Z. Yu, W. Chen,J. Li. The prospective research of risk factors of primary liver cancer in Nanhui County, Shanghai[J]. Zhonghua Liu Xing Bing Xue Za Zhi.1995, 16(1):22-24.
[60]周晓明,俞顺章,陈启明,等.主成分法分析肝癌危险因素[J].中国卫生统计.2001,18(2)：88-89.
[61]孟炜,唐锦高,沈福民,等.原发性肝癌危险因素的巢式病例对照研究[J].复旦学报(医学版).2002,29(5)：368-371.
[62]W. L. Tsai, G. H. Lo, P. I. Hsu, et al. Role of genotype and precore/basal core promoter mutations of hepatitis B virus in patients with chronic hepatitis B with acute exacerbation[J]. Scand J Gastroenterol.2008,43(2):196-201.
[63]C. J. Liu,J. H. Kao. Core promoter mutations of hepatitis B virus and hepatocellular carcinoma: story beyond A1762T/G1764A mutations[J]. J Gastroenterol Hepatol.2008,23(3):347-350.
[64]J. H. Kao, P. J. Chen, M. Y. Lai, et al. Basal core promoter mutations of hepatitis B virus increase the risk of hepatocellular carcinoma in hepatitis B carriers[J]. Gastroenterology.2003,124(2):327-334.
[65]G. Chen, W. Lin, F. Shen, et al. Past HBV viral load as predictor of mortality and morbidity from HCC and chronic liver disease in a prospective study[J]. Am J Gastroenterol.2006,101(8):1797-1803.
[1]T. Guettouche,H. J. Hnatyszyn. Chronic hepatitis B and viral genotype: the clinical significance of determining HBV genotypes[J]. Antivir Ther.2005,10(5):593-604.
[2]S. Schaefer. Hepatitis B virus taxonomy and hepatitis B virus genotypes[J]. World J Gastroenterol.2007,13(1):14-21.
[3]T. T. Tran, T. N. Trinh,K. Abe. New complex recombinant genotype of hepatitis B virus identified in Vietnam[J]. J Virol.2008,82(11):5657-5663.
[4]C. M. Olinger, P. Jutavijittum, J. M. Hubschen, et al. Possible new hepatitis B virus genotype, southeast Asia[J]. Emerg Infect Dis.2008,14(11):1777-1780.
[5]K. Tatematsu, Y. Tanaka, F. Kurbanov, et al. A genetic variant of hepatitis B virus divergent from known human and ape genotypes isolated from a Japanese patient and provisionally assigned to new genotype J[J]. J Virol.2009,83(20):10538-10547.
[6]C. T. Zhu,C. L. Dong. Characteristics of general distribution of hepatitis B virus genotypes in China[J]. Hepatobiliary Pancreat Dis Int.2009,8(4):397-401.
[7]C. T. Wai, C. J. Chu, M. Hussain, et al. HBV genotype B is associated with better response to interferon therapy in HBeAg(+) chronic hepatitis than genotype C[J]. Hepatology.2002,36(6):1425-1430.
[8]H. L. Chan, G. L. Wong, C. H. Tse, et al. Hepatitis B virus genotype C is associated with more severe liver fibrosis than genotype B[J]. Clin Gastroenterol Hepatol.2009, 7(12):1361-1366.
[9]N. L. Toan, H. Song le, P. G. Kremsner, et al. Impact of the hepatitis B virus genotype and genotype mixtures on the course of liver disease in Vietnam[J]. Hepatology.2006, 43(6):1375-1384.
[10]R. Jardi, M. Buti, F. Rodriguez-Frias, et al. Rapid detection of lamivudine-resistant hepatitis B virus polymerase gene variants[J]. J Virol Methods.1999,83(1-2):181-187.
[11]M. A. Aslam, F. R. Awan, I. Tauseef, et al. Identification of hepatitis B virus core mutants by PCR-RFLP in chronic hepatitis B patients from Punjab, Pakistan[J]. Arch Virol.2008,153(1):163-170.
[12]J. Yuan, B. Zhou, Y. Tanaka, et al. Hepatitis B virus (HBV) genotypes/subgenotypes in China: mutations in core promoter and precore/core and their clinical implications[J]. J Clin Virol.2007,39(2):87-93.
[13]殷继明,李卓,郝娃,等.慢性无症状乙型肝炎病毒携带者的基因型研究[J].天津医药.2005(12)：745-747.
[14]宋淑静,何忠平,庄辉,等.中国北方5城市慢性乙型肝炎患者的基因分型[J].中国公共卫生.2004,20(2)：166-167.
[15]郭拥军,文江平,周学红,等.北京地区乙型肝炎病毒基因型的分布[J].医学理论与实践.2007,20(9)：1104-1105.
[16]周莉,于岩岩,王勤环,等.乙肝病毒基因型与患者临床预后关系的研究[J].临床肝胆病杂志.2005,21(6)：324-326.
[17]王继荣,周莉,赵洪斌,等.北京地区乙肝病毒S基因序列多态性及其分布[J].世界华人消化杂志.2007,15(23)：2496-2502.
[18]严艳,李卓,殷继明,等.北京地区乙型肝炎病毒基因型及基因亚型的分布和临床意义[J].中国误诊学杂志.2008,8(15)：3537-3539.
[19]孔洪彬,李友生,刘丽红.邯郸市慢性乙型肝炎病毒基因型和亚型分布状况分析[J].中国医疗前沿.2008,3(4)：111.
[20]孔洪彬,李友生,李兴丰,等.慢性乙型肝炎病毒基因型和亚型分布及与临床关系的探讨[J].中国实用内科杂志.2007,27(22)：1779-1781.
[21]邓健,马艳霞,郭娜娜,等.邯郸市乙型肝炎基因分型及其临床意义研究[J].中国实验诊断学.2010,14(1)：59-61.
[22]苏义.衡水地区慢性乙肝患者乙肝病毒基因型分布调查[J].中国误诊学杂志.2010,10(1)：247.
[23]王玉华,孙谢文,韩忠厚,等.秦皇岛市乙型肝炎病毒基因分型及分析[J].中华传染病杂志.2005,23(3)：174-175.
[24]张薇薇,梁景青,赵嘉惠.太原地区慢性乙型肝炎患者基因型分布的研究[J].山西医科大学学报.2005,36(2)：183-184.
[25]李淑珍,王素萍,史晓红,等.太原地区HBV宫内传播的基因型分布及传播特征[J].山西医科大学学报.2004,35(6)：566-568.
[26]牛春红,田新强,米亚英.山西地区家族聚集性慢性乙型肝炎病毒感染者病毒载量及组织病变与基因型的关系[J].中国现代医药杂志.2009,11(7)：23-25.
[27]郭瑜,刘晓燕,胡惠梅,等.山西省乙型肝炎病毒基因型别的初步研究[J].中华实验和临床病毒学杂志.2006,20(4)：361-363.
[28]郭瑜,刘晓燕,陈斯勇,等.我国常见乙型肝炎病毒基因型与基本核心启动子 及前C区突变关系的初步研究[J].病毒学报.2006,22(6)：436-439.
[29]高慧,张缭云,薛瑞霞.家族性乙型肝炎病毒基因型分布与临床转归关系的研究[J].中华医院感染学杂志.2009,19(18)：2394-2396.
[30]鲁仁杰,王慧玲,李光晨,等.132例急性乙型肝炎患者HBV基因型分析[J].内蒙古民族大学学报(自然科学版).2006,21(1)：85-86.
[31]张健,何恩静,陈艳,等.本溪地区乙肝患者病毒基因型分析[J].中华微生物学和免疫学杂志.2003,23(9)：706.
[32]范金水,庄辉,李远贵,等.我国8城市HBsAg阳性和阴性乙肝患者的病毒血清型和基因型分析[J].中华微生物学和免疫学杂志.1998,18(2)：7-10.
[33]吴云海.沈阳地区乙肝病毒基因型分布与疾病谱的临床意义[J].临床和实验医学杂志.2008,7(5)：103-104.
[34]赵文瑾,何群,赵雨杰.乙肝病毒基因分型检测芯片的构建及初步应用[J].中国医科大学学报.2007,36(4)：395-397.
[35]曹彬,张晓棠,吴星.沈阳地区乙型肝炎病毒基因型与临床特征相关性的分析[J].沈阳医学院学报.2009,11(1)：56-57.
[36]黄海燕,孟祥伟,张玲玲.长春地区乙型肝炎病毒基因分型与肝病发病关系的研究[J].中华流行病学杂志.2006,27(12)：1057-1060.
[37]冯相伟,孟繁平,汪杨,等.慢性乙型肝炎患者血清HBV基因分型[J].微生物学杂志.2007,27(3)：27-29.
[38]许强,周剑惠,王兆南,等.吉林省乙型肝炎病毒基因型分型及临床研究[J].中国计划免疫.2006,12(3)：223-225.
[39]刘桂艳,周剑惠,许强,等.乙型肝炎病毒基因型与临床流行病学相关性研究[J].中国实验诊断学.2007,11(9)：1201-1203.
[40]韩学吉,许顺姬,偰光华,等.延边地区朝鲜族乙型肝炎病毒感染者病毒基因型的检测与分析[J].世界华人消化杂志.2008,16(22)：2529-2532.
[41]许军,王齐欣,范春蕾,等.中国南北两城市乙型肝炎病毒基因型与血清型的构成差异[J].中华实验和临床病毒学杂志.2003,17(4)：29-31.
[42]李迪,张淑云,谷鸿喜,等.黑龙江地区乙型肝炎病毒耐药变异与基因型[J].世界华人消化杂志.2005,13(14)：58-61.
[43]佟松,李玉军,苏辉,等.哈尔滨地区肝炎患者血清中HBV DNA基因型分析[J].哈尔滨医科大学学报.2008,42(1)：25-27.
[44]欧强,陈良,唐徐英.上海地区部分乙型肝炎患者乙型肝炎病毒基因型分析[J].检验医学.2007,14(1)：31-33.
[45]肖春海,顾宾峰,顾应嘉,等.上海市金山地区乙型肝炎病毒基因型分布及其 与临床的关系[J].检验医学.2008,15(6)：590-593.
[46]吉强,高春芳,赵云鹏,等.乙型肝炎病毒前C区1896点突变、基因分型及其实验室特征分析[J].第二军医大学学报.2007,28(12)：1302-1305.
[47]闵志军,徐培君,张力超,等.常州地区乙型肝炎病毒基因分型及HBV DNA定量的临床研究[J].现代实用医学.2009,21(2)：99-100,116.
[48]濮翔科,王永忠,陈敏,等.乙型肝炎病毒基因分型荧光PCR检测及临床应用[J].放射免疫学杂志.2007,20(6)：593-594.
[49]徐天敏,王永忠,濮翔科,等.肝癌患者血清中乙型肝炎病毒基因分型及临床意义[J].中西医结合肝病杂志.2008,18(5)：269-270.
[50]刘纯成,李桂珍.江苏地区乙型肝炎患者HBV基因分型与血清HBV DNA水平研究[J].江西医学检验.2007,25(1)：5-7.
[51]朱崇尧,曹海燕,李红生,等.连云港地区慢性乙型肝炎患者HBV基因型的研究[J].预防医学论坛.2008,14(1)：37-39.
[52]赵绍林,陈乃玲,韦玉芳,等.苏北地区乙型肝炎病毒基因型分布及临床[J].中国实验诊断学.2008,12(10)：1281-1283.
[53]曾文权,赵巍.南京地区HBV基因型分布及其前C区1896变异的特点[J].中国全科医学.2005,8(20)：1671-1672.
[54]张勇扬,王爱平,唐勤.乙肝病毒基因变异和基因型(亚型)与肝细胞癌的关系[J].实用医学杂志.2007,23(21)：3323-3325.
[55]隋云华,徐静,孟运运,等.乙型肝炎病毒基因分型的临床探讨[J].临床医学.2007,27(10)：76-77.
[56]曹利,孙梅,刘新钰.肝炎肝硬化患者血清乙型肝炎病毒基因型分析[J].江苏医药.2008,34(3)：295-296.
[57]周光耀,金玲湘,蒋道荣.江苏省南通地区乙型肝炎病毒基因分型与临床相关性[J].中国临床保健杂志.2008,11(6)：600-601,681.
[58]周明先,徐晓凤,薛祖洪,等.江苏省泰州地区乙肝病毒基因型与基因变异的研究[J].实用临床医药杂志.2004,8(4)：59-61,64.
[59]周明先,徐晓凤,朱亚平,等.泰州地区乙肝病毒基因型分布及临床意义[J].临床检验杂志.2004,22(4)：298,312.
[60]刘成永,侯远沛,钱秀梅,等.徐州地区乙型肝炎病毒基因型分布及其意义[J].临床肝胆病杂志.2005,21(3)：151-152.
[61]王春颖,杨友国,王骥,等.徐州地区乙型肝炎病毒基因型与肝组织学改变的关系[J].江苏医药.2008,34(2)：139-141.
[62]侯远沛,刘成永,高玉金.乙型肝炎病毒前C区和BCP区突变及基因型对 HBeAg表达的影响[J].临床肝胆病杂志.2007,23(4)：251-253.
[63]黄惠臣.张家港地区乙型肝炎病毒基因分型及其意义[J].中国热带医学.2006,6(11)：1935-1936,1939.
[64]郭晓凤,张永乐,梁伟峰.杭州地区部分乙型肝炎患者HBV基因型分析[J].医学研究杂志.2007,36(11)：78-79.
[65]潘克女,张永乐,刘艳萍,等.实时荧光PCR法分析浙江省乙型肝炎病毒基因型的分布[J].医学研究杂志.2008,37(1)：51-52.
[66]郭晓凤,梁伟峰,张永乐.杭州地区112例乙型肝炎病毒基因型分布调查及意义[J].现代实用医学.2010,22(1)：9-11.
[67]裘春宁,童文娟,吴盛海,等.杭州地区乙型肝炎病毒基因型分析[J].中国卫生检验杂志.2010,20(2)：385-386,418.
[68]钱福初,秦基取,杨水新,等.湖州地区乙型肝炎病毒基因型分布研究[J].浙江预防医学.2009,21(11)：6-7,14.
[69]崔华复,陈建英,张智勤,等.仙居地区HBV基因型分布与若干相关问题的研究[J].中西医结合肝病杂志.2005,15(5)：288-289.
[70]俞松山.三门地区乙肝病毒基因型分布及临床意义[J].当代医学(学术版).2007,122(8)：32-33.
[71]肖扬,周岳进,王开鉴,等.浙江温州地区1020例乙型肝炎患者HBV基因分型研究[J].中西医结合肝病杂志.2005,15(1)：41-42.
[72]陈红,郑晓群,江明华,等.温州地区乙型肝炎病毒基因型分布调查及意义[J].江西医学检验.2007,25(3)：216-218.
[73]陈劲华,翁正军.浙江省义乌地区病毒性乙型肝炎病毒基因型分布[J].疾病监测.2009,24(10)：774-776.
[74]王世意,王忠发,王虹玲,等.舟山海岛中学生HBV基因型分布调查[J].海峡预防医学杂志.2006,12(2)：34-35.
[75]唐克明,高伏圣,张春林,等.中国安徽地区肝癌组织中HBV基因型的分布研究[J].中国现代医学杂志.2008(12).
[76]周丽鸿,李筱青,宣柳,等.皖江地区自然人群HBV M及HBV基因型的检测分析[J].实用预防医学.2008,15(6)：1706-1709.
[77]纪惠玲,郑能雄,姚栩,等.两种乙肝病毒基因分型方法的比较[J].海峡预防医学杂志.2007,13(5)：14-16.
[78]姚栩,纪惠玲,郭燕,等.福州市健康人群中乙肝病毒感染的检测分析[J].实用预防医学.2007,14(5)：1387-1389.
[79]郑能雄,王镜泉,纪惠玲,等.福州市人群乙型肝炎分子流行病学研究[J].海峡 预防医学杂志.2007,13(4)：4-6.
[80]郭燕,郑能雄,姚栩,等.福州市乙肝病毒基因型和基因亚型的分布及其与前C、C基因启动子变异的关系[J].中国病原生物学杂志.2008,3(10)：731-734.
[81]胡盈莹,江家骥,欧文湖,等.福建省部分地区乙型肝炎病毒基因型分布及其临床意义[J].中华流行病学杂志.2004,25(3)：73-77.
[82]张启华,杨红,许正锯,等.乙型肝炎病毒基因型与血清HBV DNA水平的关系[J].胃肠病学和肝病学杂志.2004,13(5)：525-527.
[83]陈明春,郑有限,叶培英,等.泉州地区乙型肝炎病毒基因型调查及其流行病学研究[J].中国卫生检验杂志.2010,20(1)：174-176.
[84]董菁,任建林,王琳,等.厦门市乙型肝炎患者病毒基因型的分析[J].世界华人消化杂志.2007,15(12)：1376-1381.
[85]徐龙,车达平,吕定英,等.江西地区乙型肝炎病毒基因型分布与临床的相关性[J].中华肝脏病杂志.2006,14(2)：147-148.
[86]张华,温志立,叶倩,等.江西乙型肝炎病毒基因型分布及其与临床的相关性[J].实用肝脏病杂志.2009,12(3)：184-186,200.
[87]王宏碧,刘云华,崔江龙,等.50例乙肝病毒感染者病毒基因型检测的分析[J].实验与检验医学.2008,26(4)：381-382.
[88]周培静,王磊,耿大影,等.山东地区乙型肝炎病毒感染者乙肝病毒基因型和亚型的分布[J].山东大学学报(医学版).2006,44(12)：1261-1264.
[89]张纵,范文博,于进红,等.山东省乙型肝炎病毒基因型分布及临床研究[J].预防医学论坛.2009,15(12)：1216-1218,1221.
[90]江新泉,刘洪爱,宋其双,等.泰安地区HBV基因型分布及临床意义[J].泰山医学院学报.2009,30(12)：900-901.
[91]石建凤.乙肝病毒基因分型与HBV-DNA水平及HBeAg之间关系的探讨[J].实用医技杂志.2007,14(34)：4688-4689.
[92]董菲,王憬惺,杨通汉,等.昆明、洛阳两地献血者人群HBV携带者的HBV基因型分布[J].中国输血杂志.2009,22(7)：552-555.
[93]蔡晓静,付玉军,朱本元,等.平顶山地区乙肝病毒基因分型检测报告[J].现代预防医学.2009,12(22)：4401.
[94]邹祺,张善锋,毛红丽.河南省乙型肝炎病毒基因型的分布[J].郑州大学学报(医学版).2006,41(5)：941-942.
[95]马金春,王鲁文,廖勇峰,等.黄石地区慢性无症状乙型肝炎病毒携带者的基因型分布[J].中西医结合肝病杂志.2006,16(5)：287-289.
[96]王昌艳,陈悦,龚作炯.十堰地区乙肝病毒基因型分布及其临床意义[J].中西医 结合肝病杂志.2007,17(4)：230-233.
[97]童巧霞,吴艳艳,罗端德.湖北省地区乙型肝炎病毒基因分型及其临床意义[J].临床内科杂志.2006,23(2)：126-128.
[98]王平,田德英,张东绅,等.乙肝病毒基因型与干扰素近期疗效探讨[J].中西医结合肝病杂志.2008,18(3)：151-152.
[99]刘映霞,胡国龄,谭德明.湖南省乙肝病毒基因型分布及临床意义[J].湖南医科大学学报.2002,27(1)：29-31.
[100]代国知,陈亚光,林应标,等.药物治疗后乙型肝炎病毒基因类型转化分析[J].实用预防医学.2009,16(1)：253-254.
[101]代国知,林应标,陈亚光,等.郴州市198例乙肝患者的病毒基因类型分析[J].南华大学学报·医学版.2006,34(2)：275-276.
[102]焦荣华.湖南衡阳地区乙型肝炎患者HBV基因分型与血清HBVDNA水平研究[J].湖南环境生物职业技术学院学报.2009,15(3)：24-27.
[103]廖可育,彭志高,侯宏锦,等.乙型肝炎病毒基因型的研究[J].实用预防医学.2004,11(5)：909-910.
[104]于红缨,邵凌云,符政远,等.湖南省怀化市少数民族及汉族慢性乙型肝炎患者病毒基因分型及临床分析[J].中华实验和临床感染病杂志(电子版).2008,2(1)：44-49.
[105]任瑞庆,陈寿云,叶锦俊,等.东莞地区乙型肝炎患者HBV基因分型研究[J].检验医学与临床.2006,3(6)：249-250.
[106]张丽华,任瑞庆,黎景宜.乙型肝炎病毒基因型与病毒复制的关系[J].检验医学与临床.2008,5(2)：84-85.
[107]司建华,崔金环,钟锐兴.乙型肝炎病毒基因型的分布及临床意义[J].实用医学杂志.2007,23(15)：2372-2373.
[108]朱冰,仇瑞珍,苏燕莉,等.广州地区小儿无症状乙肝病毒携带者的基因型研究[J].现代临床医学生物工程学杂志.2002,8(1)：26-28.
[109]区映研,杨海红,曾文铤,等.乙肝病毒基因分型与HBV-DNA水平及临床表现的研究[J].中国热带医学.2006,6(5)：750-751,808.
[110]陈金军,马世武,王战会,等.乙型肝炎病毒基因型B/C型患者血清和肝细胞内HBsAg表达水平的差异[J].中华医学杂志.2006,86(28)：1947-1951.
[111]陈伟烈,蔡晓莉,魏绍静,等.基因芯片技术在乙肝病毒基因型及YMDD变异检测中的应用[J].中国实验诊断学.2007,11(2)：207-212.
[112]祝玲玲,朱平安,谭萍,等HBsAg阳性少见血清学模式HBV感染者基因型分析[J].实用预防医学.2008,15(2)：320-322.
[113]黄重敏,覃亚勤,覃后继,等.广西百色地区壮族人群乙型肝炎病毒基因型分布初步调查[J].中华流行病学杂志.2003,24(11)：1063.
[114]卢平宣.百色地区乙型肝炎患者血清中病毒基因分型检测与分析[J].华北煤炭医学院学报.2005,7(6)：715-716.
[115]黄重敏,覃亚勤,覃后继,等.桂西壮族人群乙肝病毒基因型研究[J].中国病毒学.2004,19(2)：82-83.
[116]葛宪民,江世强,蒋东方,等.广西北部乙型肝炎病毒基因型流行分布的研究[J].医学文选.2003,22(1)：4-7.
[117]苏明华,江建宁,周元平,等.乙型肝炎病毒基因型、BCP及PC区变异与拉米夫定治疗后HBV DNA反弹的关系[J].世界华人消化杂志.2007,15(33)：3507-3513.
[118]邱平,肖芙蓉,贾杰,等.海南地区HBV基因分型与YMDD变异[J].肝脏.2007,12(4)：319-320.
[119]H. M. Xu, H. Ren, Y. L. Qing, et al. Establishment of consensus sequence of PreS/S of hepatitis B virus with genotype B/serotype adw2 or genotype C/serotype adrq+ prevailing in Chongqing of China[J]. Zhonghua Liu Xing Bing Xue Za Zhi.2003,24(10): 913-916.
[120]谭文婷,邓国宏,王宇明,等.重庆地区乙肝病毒基因型分布及其临床意义[J].第三军医大学学报.2008,30(24)：2321-2323.
[121]曾爱中,黄爱龙,郭进军,等.型特异引物PCR法分析238株乙肝病毒基因型[J].重庆医科大学学报.2008,33(1)：53-56.
[122]邓少丽,黄恒柳,陈伟,等.乙型肝炎病毒耐药变异与基因型检测在临床上的应用[J].重庆医学.2008,37(3)：249-251.
[123]熊杰,邹东花,白生华.成都地区乙型肝炎病毒基因型分布特点及其意义[J].四川医学.2009,30(4)：578-579.
[124]邹立新,杜琼,黄桂香,等.四川部分地区乙型肝炎病毒基因分型分析[J].实用医院临床杂志.2008,5(6)：63-64.
[125]童文彬,孙莉,何吉兰,等.四川省两县区乙型肝炎病毒基因型、血清亚型分析[J].现代预防医学.2009,36(4)：763-765.
[126]赖辉,陈涛,候莉,等.川南地区乙型肝炎病毒基因型的分布及临床意义[J].西南国防医药.2009,19(6)：581-584.
[127]丁静娟,张权,彭亮,等.贵州乙型肝炎病毒基因型分布及意义分析[J].中华实验和临床病毒学杂志.2006,20(3)：241-243.
[128]李威,张烜榕,申元英,等.云南大理白族人群乙型肝炎病毒基因型和亚型的分布[J].中国病原生物学杂志.2008,3(3)：166-169.
[129]任来峰,张烜榕,申元英,等.大理白族自治州乙型肝炎病毒基因型分布研究[J].中国热带医学.2009,9(3)：428-429,458.
[130]庄林,游晶,陈红英,等.云南地区乙型肝炎病毒基因型分布与临床的相关性[J].世界华人消化杂志.2007,15(19)：2120-2127.
[131]曹占良,高英堂,王玮,等.某地区乙型肝炎病毒基因型分布及特点[J].武警医学院学报.2009,18(7)：608-611.
[132]曹占良,阿西,苏旭,等.拉萨地区乙型肝炎病毒携带者感染基因型的实验研究[J].武警医学院学报.2007,16(2)：130-132.
[133]谢本维,汪中涛,郑必海,等.世居藏族患者乙肝病毒基因型及其临床特点分析[J].临床肝胆病杂志.2008,24(6)：410-412.
[134]张岩,白雪帆,李新红,等.陕西地区乙型肝炎患者血清中病毒的基因分型[J].第四军医大学学报.2002,23(8)：746-748.
[135]薛红安,王媛,杨倩.乙型肝炎病毒相关性原发性肝癌患者前-X基因的分子流行病学意义[J].第四军医大学学报.2007,28(10)：935-937.
[136]李永勤,田亚丽,李建元,等.陕西地区不同类型乙型肝炎感染者HBV基因的分型研究[J].齐齐哈尔医学院学报.2008,29(8)：917-918.
[137]刘娜,徐光华,冯继红,等.延安市乙型肝炎病毒基因型分子流行病学研究[J].延安大学学报(医学科学版).2009,7(2)：1-4.
[138]李天一,陈青锋,肖萍,等.兰州地区乙肝病毒基因亚型的感染情况[J].临床消化病杂志.2002,15(3)：99-100.
[139]李天一,陈青锋,吴国琳.乙肝病毒基因分型的临床意义[J].临床肝胆病杂志.2007,23(2)：119-120.
[140]姜双应,易虎,邵锡如,等.青海省同德地区藏族人群乙型肝炎病毒基因型的探讨[J].病毒学报.2006,22(5)：400-402.
[141]杨少奇,王战会,杨力,等.回族乙型肝炎病毒基因型分布及其临床意义[J].中华肝脏病杂志.2006,14(6)：466-467.
[142]王复元,吴秀娟,张大军,等.克拉玛依地区HBV基因分型及进化分析[J].中国卫生检验杂志.2007,17(3)：479-480.
[143]周晓明,俞顺章,陈启明,等.主成分法分析肝癌危险因素[J].中国卫生统计.2001,18(2)：88-89.
[144]叶小华,郜艳晖,张敏,等.HBV感染与肝癌关系的Meta分析[J].数理医药学杂志.2007,20(6)：810-813.
[2]林文尧,钱雪峰,张维芳,等.海门市原发性肝细胞癌死亡率时间趋势分析[J].江苏预防医学.2003,14(1)：4-6.
[3]王寒松,黄培新,唐锦高,等.海门市2001-2007年恶性肿瘤发病状况与趋势分析[J].中国肿瘤.2010,19(2)：100-104.
[4]全国肿瘤防治研究办公室,全国肿瘤登记中心,卫生部疾病预防控制局.中国部分市、县恶性肿瘤的发病与死亡,第3卷(1998-2002)[M].北京：人民卫生出版社,2007：25-376.
[5]王兰萍,唐锦高,钱雪峰,等.乙肝病毒感染与原发性肝细胞癌的队列研究[J].南通大学学报(医学版).2005,25(5)：332-334.
[6]H. Vildozola Gonzales,J. L. Salinas. Natural history of chronic hepatitis B virus infection[J]. Rev Gastroenterol Peru.2009,29(2):147-157.
[7]Y. F. Liaw,C. M. Chu. Hepatitis B virus infection[J]. Lancet.2009,373(9663): 582-592.
[8]H. X. Yan, J. C. Ma, T. Bian, et al. [The analysis of "alpha" dominant mutation of hepatitis B virus in community-based Zhengding area, Hebei province][J]. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi.2009,23(1):11-13.
[9]Y. Zhang, F. Wang,J. C. Ma. Evaluations of 5 kinds of China-made enzyme immunoassay kits for hepatitis B virus surface antigen detection[J]. Zhongguo Ji Hua Mian Yi.2009,15(5):388-391.
[10]X. L. Zhou, P. N. Sun, T. H. Huang, et al. Effects of hepatitis B virus S protein on human sperm function[J]. Hum Reprod.2009,24(7):1575-1583.
[11]C. H. Chen, C. S. Changchien, C. M. Lee, et al. A study on sequence variations in pre-S/surface, X and enhancer Ⅱ/core promoter/precore regions of occult hepatitis B virus in non-B, non-C hepatocellular carcinoma patients in Taiwan[J]. Int J Cancer. 2009,125(3):621-629.
[12]F. Y. Sung, C. M. Jung, C. F. Wu, et al. Hepatitis B virus core variants modify natural course of viral infection and hepatocellular carcinoma progression[J]. Gastroenterology.2009,137(5):1687-1697.
[13]T. F. Baumert, C. Yang, P. Schurmann, et al. Hepatitis B virus mutations associated with fulminant hepatitis induce apoptosis in primary Tupaia hepatocytes[J]. Hepatology.2005,41(2):247-256.
[14]K. Shiraki, M. Hamada, K. Sugimoto, et al. Detection of precore-mutant hepatitis B virus genome in patients with acute and fulminant hepatitis using mutation site-specific assay (MSSA)[J]. Hepatogastroenterology.2002,49(47):1352-1356.
[15]Y. H. Shih, S. H. Yeh, P. J. Chen, et al. Hepatitis B virus quantification and detection of YMDD mutants in a single reaction by real-time PCR and annealing curve analysis[J]. Antivir Ther.2008,13(4):469-480.
[16]D. Li, H. X. Gu, S. Y. Zhang, et al. YMDD mutations and genotypes of hepatitis B virus in northern China[J]. Jpn J Infect Dis.2006,59(1):42-45.
[17]C. T. Bock, H. L. Tillmann, J. Torresi, et al. Selection of hepatitis B virus polymerase mutants with enhanced replication by lamivudine treatment after liver transplantation[J]. Gastroenterology.2002,122(2):264-273.
[18]S. K. Ono, N. Kato, Y. Shiratori, et al. The polymerase L528M mutation cooperates with nucleotide binding-site mutations, increasing hepatitis B virus replication and drug resistance[J]. J Clin Invest.2001,107(4):449-455.
[19]K. Koike. Hepatitis B virus X gene is implicated in liver carcinogenesis[J]. Cancer Lett.2009,286(1):60-68.
[20]L. Ye, N. Dong, Q. Wang, et al. Progressive changes in hepatoma cells stably transfected with hepatitis B virus X gene[J]. Intervirology.2008,51(1):50-58.
[21]P. Zhu, D. Tan, Z. Peng, et al. Polymorphism analyses of hepatitis B virus X gene in hepatocellular carcinoma patients from southern China[J]. Acta Biochim Biophys Sin (Shanghai).2007,39(4):265-272.
[22]T. Guettouche,H. J. Hnatyszyn. Chronic hepatitis B and viral genotype:the clinical significance of determining HBV genotypes[J]. Antivir Ther.2005,10(5): 593-604.
[23]S. Schaefer. Hepatitis B virus taxonomy and hepatitis B virus genotypes[J]. World J Gastroenterol.2007,13(1):14-21.
[24]T. T. Tran, T. N. Trinh,K. Abe. New complex recombinant genotype of hepatitis B virus identified in Vietnam[J]. J Virol.2008,82(11):5657-5663.
[25]C. M. Olinger, P. Jutavijittum, J. M. Hubschen, et al. Possible new hepatitis B virus genotype, southeast Asia[J]. Emerg Infect Dis.2008,14(11):1777-1780.
[26]K. Tatematsu, Y. Tanaka, F. Kurbanov, et al. A genetic variant of hepatitis B virus divergent from known human and ape genotypes isolated from a Japanese patient and provisionally assigned to new genotype J[J]. J Virol.2009,83(20):10538-10547.
[27]F. Sugauchi, E. Orito, T. Ichida, et al. Epidemiologic and virologic characteristics of hepatitis B virus genotype B having the recombination with genotype C[J]. Gastroenterology.2003,124(4):925-932.
[28]G W. Cao. Clinical relevance and public health significance of hepatitis B virus genomic variations[J]. World J Gastroenterol.2009,15(46):5761-5769.
[29]C. T. Wai, C. J. Chu, M. Hussain, et al. HBV genotype B is associated with better response to interferon therapy in HBeAg(+) chronic hepatitis than genotype C[J]. Hepatology.2002,36(6):1425-1430.
[30]H. L. Chan, G L. Wong, C. H. Tse, et al. Hepatitis B virus genotype C is associated with more severe liver fibrosis than genotype B[J]. Clin Gastroenterol Hepatol.2009,7(12):1361-1366.
[31]N. L. Toan, H. Song le, P. G Kremsner, et al. Impact of the hepatitis B virus genotype and genotype mixtures on the course of liver disease in Vietnam[J]. Hepatology.2006,43(6):1375-1384.
[32]周红星,周亮.海门市2006年一般人群病毒性肝炎监测结果[J].职业与健康.2007,23(13)：1120-1121.
[33]陈长荣,袁权,葛胜祥,等.无偿献血者中隐匿性乙型肝炎病毒感染及表面抗原突变分析[J].病毒学报.2009,25(3)：178-184.
[34]L. O. Magnius,H. Norder. Subtypes, genotypes and molecular epidemiology of the hepatitis B virus as reflected by sequence variability of the S-gene[J]. Intervirology.1995,38(1-2):24-34.
[35]任来峰,张烜榕,申元英,等.大理白族自治州乙型肝炎病毒基因型分布研究[J].中国热带医学.2009,9(3)：428-429,458.
[36]江建华.海门市10年恶性肿瘤死亡分析[J].江苏预防医学.2001,12(3)：71-72.
[37]X. Liang, S. Bi, W. Yang, et al. Epidemiological serosurvey of hepatitis B in China--declining HBV prevalence due to hepatitis B vaccination[J]. Vaccine.2009, 27(47):6550-6557.
[38]朱荣,曹文英,李显,等.江苏省病毒性肝炎感染率研究[J].江苏预防医学.1996，3：3-5.
[39]G. T. Kumar, S. N. Kazim, M. Kumar, et al. Hepatitis B virus genotypes and hepatitis B surface antigen mutations in family contacts of hepatitis B virus infected patients with occult hepatitis B virus infection[J]. J Gastroenterol Hepatol.2009, 24(4):588-598.
[40]陈明春,郑有限,叶培英,等.泉州地区乙型肝炎病毒基因型调查及其流行病学研究[J].中国卫生检验杂志.2010,20(1)：174-176.
[41]李永勤,薛卫宁,付建军,等.不良结局家族聚集性乙肝感染者HBV基因分型[J].齐齐哈尔医学院学报.2008,29(10)：1155-1157.
[42]M. Thursz. Pros and cons of genetic association studies in hepatitis B[J]. Hepatology.2004,40(2):284-286.
[43]E. L. Wynder, I. T. Higgins,R. E. Harris. The wish bias[J]. J Clin Epidemiol. 1990,43(6):619-621.
[44]S. G Lim, R. Mohammed, M. F. Yuen, et al. Prevention of hepatocellular carcinoma in hepatitis B virus infection[J]. J Gastroenterol Hepatol.2009,24(8): 1352-1357.
[45]N. Y. Rots, A. J. Wijmenga-Monsuur, W. Luytjes, et al. Hepatitis B vaccination strategies tailored to different endemicity levels:some considerations [J]. Vaccine. 2010,28(4):893-900.
[46]S. Awerkiew, M. Daumer, M. Reiser, et al. Reactivation of an occult hepatitis B virus escape mutant in an anti-HBs positive, anti-HBc negative lymphoma patient[J]. J Clin Virol.2007,38(1):83-86.
[47]W. H. Gerlich. Breakthrough of hepatitis B virus escape mutants after vaccination and virus reactivation[J]. J Clin Virol.2006,36 Suppl 1:S18-22.
[48]X. Huang, D. Lu, G Ji, et al. Hepatitis B virus (HBV) vaccine-induced escape mutants of HBV S gene among children from Qidong area, China[J]. Virus Res.2004, 99(1):63-68.
[49]T. Shizuma, K. Hasegawa, K. Ishikawa, et al. Molecular analysis of antigenicity and immunogenicity of a vaccine-induced escape mutant of hepatitis B virus[J]. J Gastroenterol.2003,38(3):244-253.
[50]T. Kalinina, A. Iwanski, H. Will, et al. Deficiency in virion secretion and decreased stability of the hepatitis B virus immune escape mutant G145R[J]. Hepatology.2003,38(5):1274-1281.
[51]H. L. Chan, C. H. Tse, F. Mo, et al. High viral load and hepatitis B virus subgenotype ce are associated with increased risk of hepatocellular carcinoma[J]. J Clin Oncol.2008,26(2):177-182.
[52]C. T. Zhu,C. L. Dong. Characteristics of general distribution of hepatitis B virus genotypes in China[J]. Hepatobiliary Pancreat Dis Int.2009,8(4):397-401.
[53]经继生,黄培,阮成荣,等.江苏省乙型肝炎病毒基因型分布与临床相关性[J].肝脏.2006,11(5)：335-336.
[54]J. F. Perz, G. L. Armstrong, L. A. Farrington, et al. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide[J]. J Hepatol.2006,45(4):529-538.
[55]U. H. Iloeje, H. I. Yang, J. Su, et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load[J]. Gastroenterology.2006,130(3):678-686.
[56]S. Mahmood, G. Niiyama, A. Kamei, et al. Influence of viral load and genotype in the progression of Hepatitis B-associated liver cirrhosis to hepatocellular carcinoma[J]. Liver Int.2005,25(2):220-225.
[57]K. Hagymasi, Z. Tulassay. Epidemiology, risk factors and molecular pathogenesis of primary liver cancer[J]. Orv Hetil.2008,149(12):541-548.
[58]R. H. Luo, Z. X. Zhao, X. Y. Zhou, et al. Risk factors for primary liver carcinoma in Chinese population[J]. World J Gastroenterol.2005,11(28):4431-4434.
[59]S. Z. Yu, W. Chen,J. Li. The prospective research of risk factors of primary liver cancer in Nanhui County, Shanghai[J]. Zhonghua Liu Xing Bing Xue Za Zhi.1995, 16(1):22-24.
[60]周晓明,俞顺章,陈启明,等.主成分法分析肝癌危险因素[J].中国卫生统计.2001,18(2)：88-89.
[61]孟炜,唐锦高,沈福民,等.原发性肝癌危险因素的巢式病例对照研究[J].复旦学报(医学版).2002,29(5)：368-371.
[62]W. L. Tsai, G. H. Lo, P. I. Hsu, et al. Role of genotype and precore/basal core promoter mutations of hepatitis B virus in patients with chronic hepatitis B with acute exacerbation[J]. Scand J Gastroenterol.2008,43(2):196-201.
[63]C. J. Liu,J. H. Kao. Core promoter mutations of hepatitis B virus and hepatocellular carcinoma: story beyond A1762T/G1764A mutations[J]. J Gastroenterol Hepatol.2008,23(3):347-350.
[64]J. H. Kao, P. J. Chen, M. Y. Lai, et al. Basal core promoter mutations of hepatitis B virus increase the risk of hepatocellular carcinoma in hepatitis B carriers[J]. Gastroenterology.2003,124(2):327-334.
[65]G. Chen, W. Lin, F. Shen, et al. Past HBV viral load as predictor of mortality and morbidity from HCC and chronic liver disease in a prospective study[J]. Am J Gastroenterol.2006,101(8):1797-1803.
[1]T. Guettouche,H. J. Hnatyszyn. Chronic hepatitis B and viral genotype: the clinical significance of determining HBV genotypes[J]. Antivir Ther.2005,10(5):593-604.
[2]S. Schaefer. Hepatitis B virus taxonomy and hepatitis B virus genotypes[J]. World J Gastroenterol.2007,13(1):14-21.
[3]T. T. Tran, T. N. Trinh,K. Abe. New complex recombinant genotype of hepatitis B virus identified in Vietnam[J]. J Virol.2008,82(11):5657-5663.
[4]C. M. Olinger, P. Jutavijittum, J. M. Hubschen, et al. Possible new hepatitis B virus genotype, southeast Asia[J]. Emerg Infect Dis.2008,14(11):1777-1780.
[5]K. Tatematsu, Y. Tanaka, F. Kurbanov, et al. A genetic variant of hepatitis B virus divergent from known human and ape genotypes isolated from a Japanese patient and provisionally assigned to new genotype J[J]. J Virol.2009,83(20):10538-10547.
[6]C. T. Zhu,C. L. Dong. Characteristics of general distribution of hepatitis B virus genotypes in China[J]. Hepatobiliary Pancreat Dis Int.2009,8(4):397-401.
[7]C. T. Wai, C. J. Chu, M. Hussain, et al. HBV genotype B is associated with better response to interferon therapy in HBeAg(+) chronic hepatitis than genotype C[J]. Hepatology.2002,36(6):1425-1430.
[8]H. L. Chan, G. L. Wong, C. H. Tse, et al. Hepatitis B virus genotype C is associated with more severe liver fibrosis than genotype B[J]. Clin Gastroenterol Hepatol.2009, 7(12):1361-1366.
[9]N. L. Toan, H. Song le, P. G. Kremsner, et al. Impact of the hepatitis B virus genotype and genotype mixtures on the course of liver disease in Vietnam[J]. Hepatology.2006, 43(6):1375-1384.
[10]R. Jardi, M. Buti, F. Rodriguez-Frias, et al. Rapid detection of lamivudine-resistant hepatitis B virus polymerase gene variants[J]. J Virol Methods.1999,83(1-2):181-187.
[11]M. A. Aslam, F. R. Awan, I. Tauseef, et al. Identification of hepatitis B virus core mutants by PCR-RFLP in chronic hepatitis B patients from Punjab, Pakistan[J]. Arch Virol.2008,153(1):163-170.
[12]J. Yuan, B. Zhou, Y. Tanaka, et al. Hepatitis B virus (HBV) genotypes/subgenotypes in China: mutations in core promoter and precore/core and their clinical implications[J]. J Clin Virol.2007,39(2):87-93.
[13]殷继明,李卓,郝娃,等.慢性无症状乙型肝炎病毒携带者的基因型研究[J].天津医药.2005(12)：745-747.
[14]宋淑静,何忠平,庄辉,等.中国北方5城市慢性乙型肝炎患者的基因分型[J].中国公共卫生.2004,20(2)：166-167.
[15]郭拥军,文江平,周学红,等.北京地区乙型肝炎病毒基因型的分布[J].医学理论与实践.2007,20(9)：1104-1105.
[16]周莉,于岩岩,王勤环,等.乙肝病毒基因型与患者临床预后关系的研究[J].临床肝胆病杂志.2005,21(6)：324-326.
[17]王继荣,周莉,赵洪斌,等.北京地区乙肝病毒S基因序列多态性及其分布[J].世界华人消化杂志.2007,15(23)：2496-2502.
[18]严艳,李卓,殷继明,等.北京地区乙型肝炎病毒基因型及基因亚型的分布和临床意义[J].中国误诊学杂志.2008,8(15)：3537-3539.
[19]孔洪彬,李友生,刘丽红.邯郸市慢性乙型肝炎病毒基因型和亚型分布状况分析[J].中国医疗前沿.2008,3(4)：111.
[20]孔洪彬,李友生,李兴丰,等.慢性乙型肝炎病毒基因型和亚型分布及与临床关系的探讨[J].中国实用内科杂志.2007,27(22)：1779-1781.
[21]邓健,马艳霞,郭娜娜,等.邯郸市乙型肝炎基因分型及其临床意义研究[J].中国实验诊断学.2010,14(1)：59-61.
[22]苏义.衡水地区慢性乙肝患者乙肝病毒基因型分布调查[J].中国误诊学杂志.2010,10(1)：247.
[23]王玉华,孙谢文,韩忠厚,等.秦皇岛市乙型肝炎病毒基因分型及分析[J].中华传染病杂志.2005,23(3)：174-175.
[24]张薇薇,梁景青,赵嘉惠.太原地区慢性乙型肝炎患者基因型分布的研究[J].山西医科大学学报.2005,36(2)：183-184.
[25]李淑珍,王素萍,史晓红,等.太原地区HBV宫内传播的基因型分布及传播特征[J].山西医科大学学报.2004,35(6)：566-568.
[26]牛春红,田新强,米亚英.山西地区家族聚集性慢性乙型肝炎病毒感染者病毒载量及组织病变与基因型的关系[J].中国现代医药杂志.2009,11(7)：23-25.
[27]郭瑜,刘晓燕,胡惠梅,等.山西省乙型肝炎病毒基因型别的初步研究[J].中华实验和临床病毒学杂志.2006,20(4)：361-363.
[28]郭瑜,刘晓燕,陈斯勇,等.我国常见乙型肝炎病毒基因型与基本核心启动子 及前C区突变关系的初步研究[J].病毒学报.2006,22(6)：436-439.
[29]高慧,张缭云,薛瑞霞.家族性乙型肝炎病毒基因型分布与临床转归关系的研究[J].中华医院感染学杂志.2009,19(18)：2394-2396.
[30]鲁仁杰,王慧玲,李光晨,等.132例急性乙型肝炎患者HBV基因型分析[J].内蒙古民族大学学报(自然科学版).2006,21(1)：85-86.
[31]张健,何恩静,陈艳,等.本溪地区乙肝患者病毒基因型分析[J].中华微生物学和免疫学杂志.2003,23(9)：706.
[32]范金水,庄辉,李远贵,等.我国8城市HBsAg阳性和阴性乙肝患者的病毒血清型和基因型分析[J].中华微生物学和免疫学杂志.1998,18(2)：7-10.
[33]吴云海.沈阳地区乙肝病毒基因型分布与疾病谱的临床意义[J].临床和实验医学杂志.2008,7(5)：103-104.
[34]赵文瑾,何群,赵雨杰.乙肝病毒基因分型检测芯片的构建及初步应用[J].中国医科大学学报.2007,36(4)：395-397.
[35]曹彬,张晓棠,吴星.沈阳地区乙型肝炎病毒基因型与临床特征相关性的分析[J].沈阳医学院学报.2009,11(1)：56-57.
[36]黄海燕,孟祥伟,张玲玲.长春地区乙型肝炎病毒基因分型与肝病发病关系的研究[J].中华流行病学杂志.2006,27(12)：1057-1060.
[37]冯相伟,孟繁平,汪杨,等.慢性乙型肝炎患者血清HBV基因分型[J].微生物学杂志.2007,27(3)：27-29.
[38]许强,周剑惠,王兆南,等.吉林省乙型肝炎病毒基因型分型及临床研究[J].中国计划免疫.2006,12(3)：223-225.
[39]刘桂艳,周剑惠,许强,等.乙型肝炎病毒基因型与临床流行病学相关性研究[J].中国实验诊断学.2007,11(9)：1201-1203.
[40]韩学吉,许顺姬,偰光华,等.延边地区朝鲜族乙型肝炎病毒感染者病毒基因型的检测与分析[J].世界华人消化杂志.2008,16(22)：2529-2532.
[41]许军,王齐欣,范春蕾,等.中国南北两城市乙型肝炎病毒基因型与血清型的构成差异[J].中华实验和临床病毒学杂志.2003,17(4)：29-31.
[42]李迪,张淑云,谷鸿喜,等.黑龙江地区乙型肝炎病毒耐药变异与基因型[J].世界华人消化杂志.2005,13(14)：58-61.
[43]佟松,李玉军,苏辉,等.哈尔滨地区肝炎患者血清中HBV DNA基因型分析[J].哈尔滨医科大学学报.2008,42(1)：25-27.
[44]欧强,陈良,唐徐英.上海地区部分乙型肝炎患者乙型肝炎病毒基因型分析[J].检验医学.2007,14(1)：31-33.
[45]肖春海,顾宾峰,顾应嘉,等.上海市金山地区乙型肝炎病毒基因型分布及其 与临床的关系[J].检验医学.2008,15(6)：590-593.
[46]吉强,高春芳,赵云鹏,等.乙型肝炎病毒前C区1896点突变、基因分型及其实验室特征分析[J].第二军医大学学报.2007,28(12)：1302-1305.
[47]闵志军,徐培君,张力超,等.常州地区乙型肝炎病毒基因分型及HBV DNA定量的临床研究[J].现代实用医学.2009,21(2)：99-100,116.
[48]濮翔科,王永忠,陈敏,等.乙型肝炎病毒基因分型荧光PCR检测及临床应用[J].放射免疫学杂志.2007,20(6)：593-594.
[49]徐天敏,王永忠,濮翔科,等.肝癌患者血清中乙型肝炎病毒基因分型及临床意义[J].中西医结合肝病杂志.2008,18(5)：269-270.
[50]刘纯成,李桂珍.江苏地区乙型肝炎患者HBV基因分型与血清HBV DNA水平研究[J].江西医学检验.2007,25(1)：5-7.
[51]朱崇尧,曹海燕,李红生,等.连云港地区慢性乙型肝炎患者HBV基因型的研究[J].预防医学论坛.2008,14(1)：37-39.
[52]赵绍林,陈乃玲,韦玉芳,等.苏北地区乙型肝炎病毒基因型分布及临床[J].中国实验诊断学.2008,12(10)：1281-1283.
[53]曾文权,赵巍.南京地区HBV基因型分布及其前C区1896变异的特点[J].中国全科医学.2005,8(20)：1671-1672.
[54]张勇扬,王爱平,唐勤.乙肝病毒基因变异和基因型(亚型)与肝细胞癌的关系[J].实用医学杂志.2007,23(21)：3323-3325.
[55]隋云华,徐静,孟运运,等.乙型肝炎病毒基因分型的临床探讨[J].临床医学.2007,27(10)：76-77.
[56]曹利,孙梅,刘新钰.肝炎肝硬化患者血清乙型肝炎病毒基因型分析[J].江苏医药.2008,34(3)：295-296.
[57]周光耀,金玲湘,蒋道荣.江苏省南通地区乙型肝炎病毒基因分型与临床相关性[J].中国临床保健杂志.2008,11(6)：600-601,681.
[58]周明先,徐晓凤,薛祖洪,等.江苏省泰州地区乙肝病毒基因型与基因变异的研究[J].实用临床医药杂志.2004,8(4)：59-61,64.
[59]周明先,徐晓凤,朱亚平,等.泰州地区乙肝病毒基因型分布及临床意义[J].临床检验杂志.2004,22(4)：298,312.
[60]刘成永,侯远沛,钱秀梅,等.徐州地区乙型肝炎病毒基因型分布及其意义[J].临床肝胆病杂志.2005,21(3)：151-152.
[61]王春颖,杨友国,王骥,等.徐州地区乙型肝炎病毒基因型与肝组织学改变的关系[J].江苏医药.2008,34(2)：139-141.
[62]侯远沛,刘成永,高玉金.乙型肝炎病毒前C区和BCP区突变及基因型对 HBeAg表达的影响[J].临床肝胆病杂志.2007,23(4)：251-253.
[63]黄惠臣.张家港地区乙型肝炎病毒基因分型及其意义[J].中国热带医学.2006,6(11)：1935-1936,1939.
[64]郭晓凤,张永乐,梁伟峰.杭州地区部分乙型肝炎患者HBV基因型分析[J].医学研究杂志.2007,36(11)：78-79.
[65]潘克女,张永乐,刘艳萍,等.实时荧光PCR法分析浙江省乙型肝炎病毒基因型的分布[J].医学研究杂志.2008,37(1)：51-52.
[66]郭晓凤,梁伟峰,张永乐.杭州地区112例乙型肝炎病毒基因型分布调查及意义[J].现代实用医学.2010,22(1)：9-11.
[67]裘春宁,童文娟,吴盛海,等.杭州地区乙型肝炎病毒基因型分析[J].中国卫生检验杂志.2010,20(2)：385-386,418.
[68]钱福初,秦基取,杨水新,等.湖州地区乙型肝炎病毒基因型分布研究[J].浙江预防医学.2009,21(11)：6-7,14.
[69]崔华复,陈建英,张智勤,等.仙居地区HBV基因型分布与若干相关问题的研究[J].中西医结合肝病杂志.2005,15(5)：288-289.
[70]俞松山.三门地区乙肝病毒基因型分布及临床意义[J].当代医学(学术版).2007,122(8)：32-33.
[71]肖扬,周岳进,王开鉴,等.浙江温州地区1020例乙型肝炎患者HBV基因分型研究[J].中西医结合肝病杂志.2005,15(1)：41-42.
[72]陈红,郑晓群,江明华,等.温州地区乙型肝炎病毒基因型分布调查及意义[J].江西医学检验.2007,25(3)：216-218.
[73]陈劲华,翁正军.浙江省义乌地区病毒性乙型肝炎病毒基因型分布[J].疾病监测.2009,24(10)：774-776.
[74]王世意,王忠发,王虹玲,等.舟山海岛中学生HBV基因型分布调查[J].海峡预防医学杂志.2006,12(2)：34-35.
[75]唐克明,高伏圣,张春林,等.中国安徽地区肝癌组织中HBV基因型的分布研究[J].中国现代医学杂志.2008(12).
[76]周丽鸿,李筱青,宣柳,等.皖江地区自然人群HBV M及HBV基因型的检测分析[J].实用预防医学.2008,15(6)：1706-1709.
[77]纪惠玲,郑能雄,姚栩,等.两种乙肝病毒基因分型方法的比较[J].海峡预防医学杂志.2007,13(5)：14-16.
[78]姚栩,纪惠玲,郭燕,等.福州市健康人群中乙肝病毒感染的检测分析[J].实用预防医学.2007,14(5)：1387-1389.
[79]郑能雄,王镜泉,纪惠玲,等.福州市人群乙型肝炎分子流行病学研究[J].海峡 预防医学杂志.2007,13(4)：4-6.
[80]郭燕,郑能雄,姚栩,等.福州市乙肝病毒基因型和基因亚型的分布及其与前C、C基因启动子变异的关系[J].中国病原生物学杂志.2008,3(10)：731-734.
[81]胡盈莹,江家骥,欧文湖,等.福建省部分地区乙型肝炎病毒基因型分布及其临床意义[J].中华流行病学杂志.2004,25(3)：73-77.
[82]张启华,杨红,许正锯,等.乙型肝炎病毒基因型与血清HBV DNA水平的关系[J].胃肠病学和肝病学杂志.2004,13(5)：525-527.
[83]陈明春,郑有限,叶培英,等.泉州地区乙型肝炎病毒基因型调查及其流行病学研究[J].中国卫生检验杂志.2010,20(1)：174-176.
[84]董菁,任建林,王琳,等.厦门市乙型肝炎患者病毒基因型的分析[J].世界华人消化杂志.2007,15(12)：1376-1381.
[85]徐龙,车达平,吕定英,等.江西地区乙型肝炎病毒基因型分布与临床的相关性[J].中华肝脏病杂志.2006,14(2)：147-148.
[86]张华,温志立,叶倩,等.江西乙型肝炎病毒基因型分布及其与临床的相关性[J].实用肝脏病杂志.2009,12(3)：184-186,200.
[87]王宏碧,刘云华,崔江龙,等.50例乙肝病毒感染者病毒基因型检测的分析[J].实验与检验医学.2008,26(4)：381-382.
[88]周培静,王磊,耿大影,等.山东地区乙型肝炎病毒感染者乙肝病毒基因型和亚型的分布[J].山东大学学报(医学版).2006,44(12)：1261-1264.
[89]张纵,范文博,于进红,等.山东省乙型肝炎病毒基因型分布及临床研究[J].预防医学论坛.2009,15(12)：1216-1218,1221.
[90]江新泉,刘洪爱,宋其双,等.泰安地区HBV基因型分布及临床意义[J].泰山医学院学报.2009,30(12)：900-901.
[91]石建凤.乙肝病毒基因分型与HBV-DNA水平及HBeAg之间关系的探讨[J].实用医技杂志.2007,14(34)：4688-4689.
[92]董菲,王憬惺,杨通汉,等.昆明、洛阳两地献血者人群HBV携带者的HBV基因型分布[J].中国输血杂志.2009,22(7)：552-555.
[93]蔡晓静,付玉军,朱本元,等.平顶山地区乙肝病毒基因分型检测报告[J].现代预防医学.2009,12(22)：4401.
[94]邹祺,张善锋,毛红丽.河南省乙型肝炎病毒基因型的分布[J].郑州大学学报(医学版).2006,41(5)：941-942.
[95]马金春,王鲁文,廖勇峰,等.黄石地区慢性无症状乙型肝炎病毒携带者的基因型分布[J].中西医结合肝病杂志.2006,16(5)：287-289.
[96]王昌艳,陈悦,龚作炯.十堰地区乙肝病毒基因型分布及其临床意义[J].中西医 结合肝病杂志.2007,17(4)：230-233.
[97]童巧霞,吴艳艳,罗端德.湖北省地区乙型肝炎病毒基因分型及其临床意义[J].临床内科杂志.2006,23(2)：126-128.
[98]王平,田德英,张东绅,等.乙肝病毒基因型与干扰素近期疗效探讨[J].中西医结合肝病杂志.2008,18(3)：151-152.
[99]刘映霞,胡国龄,谭德明.湖南省乙肝病毒基因型分布及临床意义[J].湖南医科大学学报.2002,27(1)：29-31.
[100]代国知,陈亚光,林应标,等.药物治疗后乙型肝炎病毒基因类型转化分析[J].实用预防医学.2009,16(1)：253-254.
[101]代国知,林应标,陈亚光,等.郴州市198例乙肝患者的病毒基因类型分析[J].南华大学学报·医学版.2006,34(2)：275-276.
[102]焦荣华.湖南衡阳地区乙型肝炎患者HBV基因分型与血清HBVDNA水平研究[J].湖南环境生物职业技术学院学报.2009,15(3)：24-27.
[103]廖可育,彭志高,侯宏锦,等.乙型肝炎病毒基因型的研究[J].实用预防医学.2004,11(5)：909-910.
[104]于红缨,邵凌云,符政远,等.湖南省怀化市少数民族及汉族慢性乙型肝炎患者病毒基因分型及临床分析[J].中华实验和临床感染病杂志(电子版).2008,2(1)：44-49.
[105]任瑞庆,陈寿云,叶锦俊,等.东莞地区乙型肝炎患者HBV基因分型研究[J].检验医学与临床.2006,3(6)：249-250.
[106]张丽华,任瑞庆,黎景宜.乙型肝炎病毒基因型与病毒复制的关系[J].检验医学与临床.2008,5(2)：84-85.
[107]司建华,崔金环,钟锐兴.乙型肝炎病毒基因型的分布及临床意义[J].实用医学杂志.2007,23(15)：2372-2373.
[108]朱冰,仇瑞珍,苏燕莉,等.广州地区小儿无症状乙肝病毒携带者的基因型研究[J].现代临床医学生物工程学杂志.2002,8(1)：26-28.
[109]区映研,杨海红,曾文铤,等.乙肝病毒基因分型与HBV-DNA水平及临床表现的研究[J].中国热带医学.2006,6(5)：750-751,808.
[110]陈金军,马世武,王战会,等.乙型肝炎病毒基因型B/C型患者血清和肝细胞内HBsAg表达水平的差异[J].中华医学杂志.2006,86(28)：1947-1951.
[111]陈伟烈,蔡晓莉,魏绍静,等.基因芯片技术在乙肝病毒基因型及YMDD变异检测中的应用[J].中国实验诊断学.2007,11(2)：207-212.
[112]祝玲玲,朱平安,谭萍,等HBsAg阳性少见血清学模式HBV感染者基因型分析[J].实用预防医学.2008,15(2)：320-322.
[113]黄重敏,覃亚勤,覃后继,等.广西百色地区壮族人群乙型肝炎病毒基因型分布初步调查[J].中华流行病学杂志.2003,24(11)：1063.
[114]卢平宣.百色地区乙型肝炎患者血清中病毒基因分型检测与分析[J].华北煤炭医学院学报.2005,7(6)：715-716.
[115]黄重敏,覃亚勤,覃后继,等.桂西壮族人群乙肝病毒基因型研究[J].中国病毒学.2004,19(2)：82-83.
[116]葛宪民,江世强,蒋东方,等.广西北部乙型肝炎病毒基因型流行分布的研究[J].医学文选.2003,22(1)：4-7.
[117]苏明华,江建宁,周元平,等.乙型肝炎病毒基因型、BCP及PC区变异与拉米夫定治疗后HBV DNA反弹的关系[J].世界华人消化杂志.2007,15(33)：3507-3513.
[118]邱平,肖芙蓉,贾杰,等.海南地区HBV基因分型与YMDD变异[J].肝脏.2007,12(4)：319-320.
[119]H. M. Xu, H. Ren, Y. L. Qing, et al. Establishment of consensus sequence of PreS/S of hepatitis B virus with genotype B/serotype adw2 or genotype C/serotype adrq+ prevailing in Chongqing of China[J]. Zhonghua Liu Xing Bing Xue Za Zhi.2003,24(10): 913-916.
[120]谭文婷,邓国宏,王宇明,等.重庆地区乙肝病毒基因型分布及其临床意义[J].第三军医大学学报.2008,30(24)：2321-2323.
[121]曾爱中,黄爱龙,郭进军,等.型特异引物PCR法分析238株乙肝病毒基因型[J].重庆医科大学学报.2008,33(1)：53-56.
[122]邓少丽,黄恒柳,陈伟,等.乙型肝炎病毒耐药变异与基因型检测在临床上的应用[J].重庆医学.2008,37(3)：249-251.
[123]熊杰,邹东花,白生华.成都地区乙型肝炎病毒基因型分布特点及其意义[J].四川医学.2009,30(4)：578-579.
[124]邹立新,杜琼,黄桂香,等.四川部分地区乙型肝炎病毒基因分型分析[J].实用医院临床杂志.2008,5(6)：63-64.
[125]童文彬,孙莉,何吉兰,等.四川省两县区乙型肝炎病毒基因型、血清亚型分析[J].现代预防医学.2009,36(4)：763-765.
[126]赖辉,陈涛,候莉,等.川南地区乙型肝炎病毒基因型的分布及临床意义[J].西南国防医药.2009,19(6)：581-584.
[127]丁静娟,张权,彭亮,等.贵州乙型肝炎病毒基因型分布及意义分析[J].中华实验和临床病毒学杂志.2006,20(3)：241-243.
[128]李威,张烜榕,申元英,等.云南大理白族人群乙型肝炎病毒基因型和亚型的分布[J].中国病原生物学杂志.2008,3(3)：166-169.
[129]任来峰,张烜榕,申元英,等.大理白族自治州乙型肝炎病毒基因型分布研究[J].中国热带医学.2009,9(3)：428-429,458.
[130]庄林,游晶,陈红英,等.云南地区乙型肝炎病毒基因型分布与临床的相关性[J].世界华人消化杂志.2007,15(19)：2120-2127.
[131]曹占良,高英堂,王玮,等.某地区乙型肝炎病毒基因型分布及特点[J].武警医学院学报.2009,18(7)：608-611.
[132]曹占良,阿西,苏旭,等.拉萨地区乙型肝炎病毒携带者感染基因型的实验研究[J].武警医学院学报.2007,16(2)：130-132.
[133]谢本维,汪中涛,郑必海,等.世居藏族患者乙肝病毒基因型及其临床特点分析[J].临床肝胆病杂志.2008,24(6)：410-412.
[134]张岩,白雪帆,李新红,等.陕西地区乙型肝炎患者血清中病毒的基因分型[J].第四军医大学学报.2002,23(8)：746-748.
[135]薛红安,王媛,杨倩.乙型肝炎病毒相关性原发性肝癌患者前-X基因的分子流行病学意义[J].第四军医大学学报.2007,28(10)：935-937.
[136]李永勤,田亚丽,李建元,等.陕西地区不同类型乙型肝炎感染者HBV基因的分型研究[J].齐齐哈尔医学院学报.2008,29(8)：917-918.
[137]刘娜,徐光华,冯继红,等.延安市乙型肝炎病毒基因型分子流行病学研究[J].延安大学学报(医学科学版).2009,7(2)：1-4.
[138]李天一,陈青锋,肖萍,等.兰州地区乙肝病毒基因亚型的感染情况[J].临床消化病杂志.2002,15(3)：99-100.
[139]李天一,陈青锋,吴国琳.乙肝病毒基因分型的临床意义[J].临床肝胆病杂志.2007,23(2)：119-120.
[140]姜双应,易虎,邵锡如,等.青海省同德地区藏族人群乙型肝炎病毒基因型的探讨[J].病毒学报.2006,22(5)：400-402.
[141]杨少奇,王战会,杨力,等.回族乙型肝炎病毒基因型分布及其临床意义[J].中华肝脏病杂志.2006,14(6)：466-467.
[142]王复元,吴秀娟,张大军,等.克拉玛依地区HBV基因分型及进化分析[J].中国卫生检验杂志.2007,17(3)：479-480.
[143]周晓明,俞顺章,陈启明,等.主成分法分析肝癌危险因素[J].中国卫生统计.2001,18(2)：88-89.
[144]叶小华,郜艳晖,张敏,等.HBV感染与肝癌关系的Meta分析[J].数理医药学杂志.2007,20(6)：810-813.
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