Class II cytokine receptor gene cluster is a major locus for hepatitis B persistence

Abstract

Persistent hepatitis B virus infection is a major risk factor for hepatocellular carcinoma, the most frequent cancer in some developing countries. Up to 95% of those infected at birth and 15% of those infected after the neonatal period fail to clear hepatitis B virus, together resulting in Ϸ350 million persistent carriers worldwide. Via a whole genome scan in Gambian families, we have identified a major susceptibility locus as a cluster of class II cytokine receptor genes on chromosome 21q22. Coding changes in two of these genes, the type I IFN receptor gene, IFN-AR2, and the IL-10RB gene that encodes a receptor chain for IL-10-related cytokines including the IFN-s, are associated with viral clearance (haplotype P value ‫؍‬ 0.0003), and in vitro assays support functional roles for these variants in receptor signaling.complex trait ͉ IL-10 ͉ interferon ͉ susceptibility ͉ virus T here are Ϸ350 million people with persistent hepatitis B virus (HBV) infection worldwide. Of these infected people, up to one-quarter will die from complications of the infection including cirrhosis and primary liver cancer. However, infection with HBV does not invariably lead to chronic hepatitis: When infection is acquired during childhood, as is normally the case in subSaharan Africa, up to 90% will eliminate the virus spontaneously. When infection is acquired during the early neonatal period from an HBV-infected mother, only 10% of children will eliminate the virus, but this situation, known as vertical transmission, is rare in Africa.Susceptibility to persistent infection is governed by a number of factors, in addition to the age at infection. Twin studies and limited genetic association study data indicate that host genetic background influences the outcome of infection (1). It is likely that genetic susceptibility to persistent HBV infection is polygenic, and that both MHC and non-MHC genes are involved (2).Current treatment for persistent HBV infection is partially effective, expensive, and impractical in developing countries where persistent HBV infection rates are at their highest (3). It is therefore crucial to identify factors that determine whether HBV becomes a self-limiting or persistent infection because these factors may reveal new therapeutic opportunities for patients with chronic HBV infection. This study was conducted to identify genetic determinants of persistent HBV infection by using a genomewide approach. ResultsTo search for major loci that might have some effect on viral persistence in a highly endemic area, 318 microsatellites were analyzed in 88 independent affected sibling pairs (ASPs) in 61 Gambian families. The most significant evidence of linkage was found on chromosome 21 [logarithm of odds (lod) ϭ 1.66; P ϭ 0.003] (Table 1, which is published as supporting information on the PNAS web site). This locus on chromosome 21 also showed evidence of linkage when a total of 31 markers (with SIBPAIR P value Ͻ0.1) were followed up in a further 106 independent ASPs in 74 families (D21S1252 screens 1 and 2 combined: ...

New genetic associations detected in a host response study to hepatitis B vaccine

“…7 Although an association with these HLA class II genotypes has become increasingly evident, case-control studies that analyzed potential non-major histocompatibility complex (MHC) candidate genes have so far yielded conflicting results or have not been confirmed by other investigators. [12][13][14][15][16] To date, most studies have examined the function of just one or two genes in the immune response to HBV. A more extensive approach has recently been taken by Hennig et al 17 who studied the association of 715 singlenucleotide polymorphisms (SNPs), across 133 candidate genes, measuring peak vaccine induced anti-HBs level and anti-HBc status in 662 infant vaccinees from the Gambia.…”

Multiple cytokine expression profiles reveal immune-based differences in occult hepatitis B genotype H-infected Mexican Nahua patients

“…Cytokines and receptors are both known to be key elements in liver disease progression (Akpolat et al 2005, Frodsham et al 2006. Additionally, it is accepted that liver damage is likely a result of the immune response to HBV infection (Racanelli & Rehermann 2006, Corazza et al 2009, Wang & Zhang 2009 OHB-infected Nahua natives to determine if cytokine expression levels distinguish OHB, genotype H-infected patients as a result of a coordinated immune response.…”

Host genetic factors in hepatitis B infection, liver cancer and vaccination response: A review with a focus on Africa

“…However, there appears to be only one report of a family-based linkage study from The Gambia [pic] (Frodsham et al, 2006). This study was based on the analysis of a panel of over 300 microsatellite markers in 162 independent affected sibling pairs in 135 families and identified a region of linkage on chromosome 21q22 with a logarithm of odds (LOD) score of 3.16 (P<0.001).…”