Genes Involved in Resistance or Susceptibility to Hepatitis B Virus
Condition: Hepatitis, Viral, Human
MeSH terms: Hepatitis A; Hepatitis B; Hepatitis, Viral, Human; Hepatitis
Study type: Observational

Summary: 
      This study, conducted by the Beijing University First Hospital of China and the National
      Cancer (NCI), will try to identify genes associated with either susceptibility or resistance
      to chronic infection by the hepatitis B virus (HBV). Some people recover from HBV infection;
      others become chronically infected and may go on to develop severe liver disease such as
      cirrhosis or liver cancer. About 350 million people worldwide have chronic HBV infection. Of
      120 million infected Chinese, 90 percent of children infected at less than 5 years of age and
      10 percent of infected adults develop persistent infection.

      HBV-infected and non-infected healthy persons of Han ethnicity born before 1963 may be
      eligible for this study. Offspring of infected candidates (born in any year) may also be
      enrolled. Infected adults must have at least one infected parent or sibling. Persons who
      resided in Fusui County of Guangxi Zhuang Autonomous Region or in the Qidong district of
      Jiangsu Province for at least 6 months before 1986 may not participate.

      All participants (except offspring of the study subjects) will fill out a health
      questionnaire (providing information about eating, drinking, and smoking habits and a
      personal and family health history) and will donate no more than 20 milliliters of blood. The
      blood will be tested for antibodies, antigens, and other substances that may indicate
      infection with hepatitis viruses. Some of the blood will be sent to the NCI for DNA analysis
      to identify genetic factors that may influence clearance of the hepatitis virus after
      infection or progression to liver diseases associated with HBV infection. Infected patients
      who have had a liver biopsy in the past will be asked permission to examine tissue from the
      biopsy and to review laboratory results of any tests done for diagnostic and treatment
      purposes.

      When the study is completed, specimens sent to the NCI will have identifiers linking the
      material to the donor removed. The anonymous samples may then be used for other genetic
      studies. Specimens remaining in China will continue to have identifiers linked to them and
      may be used for future studies designed to identify who is at greatest risk of developing
      serious liver diseases. Participants who do not want their blood used for future studies may
      request that the samples be destroyed.

      Because children inherit one-half of their DNA from each parent, DNA samples from HBV
      infected study participants may provide additional information about the parent s DNA
      structure. Offspring who participate in this study will provide a DNA sample. The sample is
      obtained by swishing a mouthwash in the mouth for 30 seconds and then spitting the mouth wash
      into a cup. The DNA is then isolated from the mouth cells.
    

Detailed description: 
      Persistent hepatitis B viral (HBV) infection is a significant public health problem because
      of the occurence of chronic liver disease, cirrhosis, and hepatocarcinoma (HCC) [1-3].
      Roughly one-third of the world population has been infected with HBV and there are about 350
      million (5-6%) persistent carriers. HBV causes 80% of all liver cancer and is the second most
      important carcinogen, after smoking tobacco. There is an approximate 90% risk of becoming a
      persistent carrier following perinatal infection in infants born to e antigen positive
      carrier mothers and 30% risk in pre-school children. Only 5-10% of adults become persistent
      carriers following infection. Like HIV, HBV is transmitted by contaminated blood through
      transfusion or intravenous drug use and by high-risk sexual behavior.

      The purpose of this investigation is to study how different outcomes of hepatitis B exposure
      and infection are affected by host genetic factors in the Chinese population, where more than
      120 million individuals are infected with HBV. Of people persistently infected with HBV,
      10-30% will develop liver cirrhosis (LC) and hepatocellular carcinoma (HCC). These highly
      variable outcomes in both clearance rates and disease outcomes in persistently infected
      individuals cannot be fully explained by differences in viral or environmental factors. Thus,
      differences in host genetic factors may affect hepatitis B natural history.

      Blood will be collected from volunteers in China. Healthy donors unexposed to HBV or HCV,
      individuals who have cleared HBV, and asymptomatic carriers of HBV will be identified by the
      Peking University hospitals and blood bank. HBV infected individuals with chronic hepatitis,
      cirrhosis or HCC will be identified by the Peking University hospital hepatitis clinics.
      Targeted individuals will be asked to participate by letter or a telephone interview by
      trained hospital staff. A database of clinical and family information will be created from a
      questionnaire completed by hospital staff. A database of clinical and family information will
      be created from a questionnaire completed by hospital staff interviewers. Blood will be
      separated into plasma and peripheral blood mononuclear cells (PBMCs) and cryopreserved in
      China. Serum will be tested in China for hepatitis viral markers, HBV genotypes, and HBV
      viral load. Two vials of PBMC will be transferred to the LGD, NCI-USA, for mRNA expression
      assays and host genetic analysis. Lymphoblastoid cell lines will be established by the
      LGD-NCI as a source of renewable DNA. RNA will be extracted from PBMCs for determination of
      mRNA expression by the microarray method. Results of mRNA expression assays and literature
      searches will be used to identify candidate genes. DNA extracted from cell lines will be
      genotyped for single nucleotide polymorphisms (SNPs) in candidate genes and DNA markers,
      including HLA, cytokines, chomokines, and their receptors, and putative HBV cell entry
      targets by DNA genotyping methods. SNPs in candidate genes will be identified using public
      and private SNP databases and SNP discovery methods. SNPs will be genotyped study
      participants and analyzed to detect associations between polymorphisms and phenotypes
      obtained from clinical and laboratory testing. If a genetic marker associated with the
      development of a disease phenotype is found, there are potential applications in diagnostics
      and therapy. The identification of allelic polymorphisms in genes involved in the pathway
      from chronic viral infection to LC and ultimately HCC would provide insight into the
      carcinogenic process.
    

Observational model: Family-Based
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        Healthy donors and those infected with HBV
      
Keywords: China; Cancer; Hepatitis B; Genetics; Liver Disease; HBV