Searching for a Quantitative Trait Locus in HLA Region for Host Control of HBV Replication in Families with Hepatocellular Carcinoma
Date Issued
2009
Date
2009
Author(s)
Chou, Shih-Yun
Abstract
Background: Hepatitis B virus (HBV) load measured in terms of HBV DNA levels in blood is an index of viral replication activity and an important risk factor for hepatocellular carcinoma (HCC). Many genes in human leukocyte antigen (HLA) region encode proteins critical in activating immune response to viral infection. This study aimed to localize quantitative trait loci for host control of HBV viral load in this region. Materials and Methods: The family sample consisted of 846 HBsAg-positive subjects (474 men and 372 women) from 309 different families; each was ascertained through a single HBsAg-positive index patient with HCC. We performed family-based association analysis by using QTDT with a high-density map of genetic markers across a 7.2-Mb region at 6p21.3. To further determine whether HLA alleles may affect HBV viremia and thus the development of HCC, we analyzed a copy number polymorphism (CNP) located near an implicated region identified by QTDT in a case-control sample containing 115 HCC cases and 345 age-matched controls nested within a longitudinal cohort study. Result: Significant associations with HBV viremia were found with QTDT for 4 genetic markers (D6S273, D6S1629, D6S1202i and D6S1611i), with marker D6S1629 showing maximal association (nominal P=0.0006; permutated P=0.0010). The association with marker D6S1629 remained significant even after the most conservative correction for multiple tests by Bonferroni procedure (p=0.05). We consistently observed an inverse association between the number of a CNP, located ~130 kb apart from marker D6S1629, and reduced viral load in both family and nested case-control studies. In addition, copy loss was observed to be a risk factor for the development of liver cirrhosis (one vs two copies: adjusted odds ratio=3.05; 95% confidence interval=1.46-6.37) and HCC (one vs two copies: adjusted odds ratio=3.22; 95% confidence interval=1.63-6.35). Conclusions: The data indicate that a CNV in HLA region may be associated with high viremia of HBV and predisposition to HCC. Further functional studies focusing on the investigation of the nature of this CNV that is underling our observed association are warranted.
Subjects
Hepatitis B virus
viral load
family-based association study
QTDT
CNV
nested case-control study
SDGs
Type
thesis
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