Trial Information

Human Genes Involved in Susceptibility or Resistance to Hepatitis B Virus

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.