Hep B infection @ Gene Variants in Asian populations

Persistent Hepatitis B Infection Associated With Gene Variants in Asian Populations

Jacquelyn K. Beals, PhD
Information from Industry
Assess clinically focused product information on Medscape.
Click Here for Product Infosites – Information from Industry.

April 7, 2009 — A genomewide association study in Japanese and Thai populations has found an association between the risk of developing chronic hepatitis B virus (HBV) infection and variants at 2 gene loci in the human leukocyte antigen (HLA) system — the major histocompatibility complex in humans. The report suggests that the variants influence antigen presentation on immune cells, with a weak or absent immune response permitting HBV infections to become chronic. More than 2 billion people currently alive have had HBV infections, and more than 400 million have chronic HBV infections. More than 4 million people worldwide develop acute hepatitis B each year, and 1 million will die of cirrhosis, chronic hepatitis, or primary liver cancer. HBV is transmitted by contact between broken skin or mucous membranes and infected body fluids or blood, or by sexual intercourse. The virus is too large to cross the placenta, but infected mothers may transmit HBV to their babies at birth, often leading to chronic HBV infections that can result in liver failure or, eventually, hepatic cancer. Senior author Yusuke Nakamura, MD, PhD, director of the Human Genome Center and professor, Laboratory of Molecular Medicine, Institute of Medical Science, University of Tokyo, and director of the Center for Genomic Medicine, RIKEN, Kanagawa, Japan, shared background information on HBV in his email to Medscape Pathology & Lab Medicine. According to Dr. Nakamura, the prevalence of HBV in Japan, the United States, and Western Europe ranges from 0.1% to 2%; prevalence in India, Russia, and the Middle East ranges from 2% to 8%; and prevalence in East Asia and sub-Saharan Africa is greater than 8%. The most common mode of transmission in East Asia (including Japan) is from mother to child during the neonatal period. In sub-Saharan Africa, transmission is most often from child to child. Transmission in the United States and Western Europe frequently occurs between adults via drug abuse and similar practices. Dr. Nakamura also cited a 1989 twin study showing greater concordance of hepatitis B surface antigen carriage (ie, the antigen persists in the blood 6 months after the initial infection) in monozygotic (identical) than in dizygotic (fraternal) twins. The goal of the current study was to identify genetic variants that predispose some individuals to chronic disease. The initial genomewide association analysis compared Japanese patients with chronic HBV infection (n = 179) with healthy individuals (n = 934). Single nucleotide polymorphisms (SNPs) with the smallest P values from the first study were further analyzed in 607 independent patients with HBV infection and 1267 control individuals, identifying 11 SNPs significantly associated with chronic HBV infection (P values = 3.62 × 10−8 to 1.16 × 10−13). All 11 SNPs were in or near HLA-DPA1 and HLA-DPB1. Replication studies in independent Japanese case-control groups found significant associations for 2 SNP loci in 274 patients with HBV infection and 274 control individuals, and in another study using 718 patients with HBV infection and 1280 control individuals (P values = 1.06 × 10−16 to 1.96 × 10−6). A third set of replications involving Thai patients with chronic HBV infection (n = 308) and healthy Thai individuals (n = 546) confirmed the association between chronic HBV infection and the same 2 loci (P = 6.53 × 10−6 and 6.52 × 10−8). Case-control analysis identified 2 haplotypes of HLA-DPA1 and HLA-DPB1 significantly associated (P < .05) with protection from chronic HBV infection, and 2 associated with susceptibility to chronic infection. "G" alleles in both of the 2 SNP loci were associated with chronic infection, while "A" alleles in both loci were associated with protection. In light of the geographic distribution of HBV, it is noteworthy that the A alleles are less frequent "in Asian and African populations, especially in the Chinese population, compared with European and Central American populations," the study reports. The mechanism by which these alleles affect HBV susceptibility is still under investigation. The authors suspect that "variations in HLA-DP molecules...affect the ability for antigen presentation of HLA...molecules on immune cells and result in weak (or no) immune response." Overall, the study makes a strong case for the influence of genetic factors — specifically variants of the HLA-DPA1 and HLA-DPB1 genes — on susceptibility to HBV infection. Laurent Abel, MD, PhD, from Human Genetics of Infectious Diseases, INSERM, Necker Medical School, University René Descartes, Paris, France, told Medscape Infectious Diseases by email: “At this step, it is much too early to envision practical implications. In particular, the precise mechanisms underlying this association should be dissected.” "The study is ongoing to clarify why individuals with a certain HLA type cannot eliminate the virus," Dr. Nakamura added. "When the mechanism becomes clear, we may be able to find the new way to treat the HBV infection." Dr. Nakamura and Dr. Abel have disclosed no relevant financial relationships.

Nat Genet. Published online April 5, 2009