| #610424 | |||||||||||||||||||||||||||||||||||||||
| HEPATITIS B VIRUS, SUSCEPTIBILITY TO | |||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | |||||||||||||||||||||||||||||||||||||||
| HBV, SUSCEPTIBILITY TO | |||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | |||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||
| TEXT | |||||||||||||||||||||||||||||||||||||||
| A number sign (#) is used with this entry because variation in several different genes likely influences susceptibility to hepatitis B virus (HBV) infection. | |||||||||||||||||||||||||||||||||||||||
| Description | |||||||||||||||||||||||||||||||||||||||
| HBV is a DNA virus that enters the liver via the bloodstream, and replication occurs only in liver tissue. Transmission occurs by percutaneous or mucosal exposure to infected blood or other body fluids. Approximately one third of all cases of cirrhosis and half of all cases of hepatocellular carcinoma (HCC; 114550) can be attributed to chronic HBV infection. Worldwide, 2 billion people have been infected with HBV, 360 million have chronic infection, and 600,000 die each year from HBV-related liver disease or HCC. However, there is marked geographic variability in HBV prevalence, with chronic infection affecting less than 2% of the populations of North America and western and northern Europe; between 2 and 7% of the populations of eastern and central Europe, the Amazon basin, the Middle East, and the Indian subcontinent; and more than 8% of the populations of Asia, sub-Saharan Africa, and the Pacific (Seeff and Hoofnagle, 2006; Shepard et al., 2006). | |||||||||||||||||||||||||||||||||||||||
| Clinical Features | |||||||||||||||||||||||||||||||||||||||
| HBV infection may result in subclinical or asymptomatic infection, acute self-limited hepatitis, or fulminant hepatitis requiring liver transplantation. Persons with acute hepatitis B can show signs and symptoms that include nausea, abdominal pain, vomiting, fever, jaundice, dark urine, changes in stool color, and hepatomegaly or splenomegaly. More than 90% of infected infants, 25 to 50% of children infected between 1 and 5 years of age, and 6 to 10% of acutely infected older children and adults develop chronic HBV infection, which can lead to cirrhosis or HCC. Immunosuppressed persons are also at higher risk of developing chronic infection. Chronically infected individuals who develop HBV-related cirrhosis or HCC may be asymptomatic until diagnosis, or they may encounter periodic signs and symptoms of acute hepatitis. Extrahepatic complications can also occur, including polyarteritis nodosa, membranous glomerulonephritis, and membranoproliferative glomerulonephritis (Shepard et al., 2006). | |||||||||||||||||||||||||||||||||||||||
| Pathogenesis | |||||||||||||||||||||||||||||||||||||||
| Viral Replication HBV has only 4 open reading frames, 3 of which encode the capsid, envelope, and polymerase proteins. The fourth encodes HBX, a poorly expressed protein required for viral replication (Ganem, 2001). Bouchard et al. (2001) showed that HBX induces release of calcium into the cytoplasm, presumably from mitochondria or endoplasmic reticulum. HBX expression thereby induces activation of PYK2 (PTK2B; 601212), which activates SRC (190090) and HBV DNA replication. Inhibition of PYK2 or calcium signaling mediated by mitochondrial calcium channels could block HBV DNA replication, and enhancement of cytoplasmic calcium was able to substitute for HBX in stimulating HBV DNA replication. Host Immune Response Using FACS analysis, Wang et al. (2010) found that CD137L (TNFSF9; 606182) expression in peripheral CD14 (158120)-positive monocytes was significantly higher in patients with chronic hepatitis B than in healthy controls. Furthermore, CD137L expression in CD14-positive monocytes was significantly increased in patients with chronic hepatitis B and liver cirrhosis compared with patients with no cirrhosis. Wang et al. (2010) found that injection of anti-CD137 (TNFRSF9; 602250), a mimic of CD137L, in HBV-transgenic mice promoted liver disease progression from hepatitis to fibrosis, cirrhosis, and, ultimately, liver cancer. Flow cytometric analysis demonstrated an increase in the percentage of Cd8 (see 186910)-positive intrahepatic lymphocytes in HBV-transgenic mice treated with anti-CD137. Depletion of Cd8-positive, Cd4 (186940)-positive, or natural killer cells showed that Cd8-positive T cells, which were not specific for HBV and produced gamma-interferon (IFNG; 147570), were the main mediators of liver fibrosis induced by CD137 stimulation. Ifng, in turn, induced macrophage production of other fibrosis-promoting cytokines and chemokines, including Tnf (191160), Il6 (147620), and Mcp1 (CCL2; 158105). Wang et al. (2010) proposed that sustained CD137 stimulation is a contributing factor for liver immunopathology in chronic HBV infection, suggesting that a common defense pathway against viral infection also causes chronic hepatic diseases. | |||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | |||||||||||||||||||||||||||||||||||||||
| Variation in Genes Involved in Host Immune Response By adulthood, 90% of the population in West Africa have been infected with HBV. Thursz et al. (1997) noted that in most people this is manifest as an asymptomatic self-limiting infection during childhood, but approximately 15% of patients develop a persistent infection, and this often results in chronic liver disease and HCC. Because HBV-induced HCC is commonly a disease of working-age males in West Africa, resistance to HBV persistence probably confers some reproductive advantage. Almarri and Batchelor (1994) found that particular HLA class II region haplotypes affect the probability that an HBV infection will become persistent. Thursz et al. (1997) presented evidence supporting models of overdominant selection in which MHC homozygotes are less likely to clear an HBV infection and thus more likely to become persistently infected. In tests of 632 Gambian subjects of whom 223 had evidence of persistent infection and 409 had successfully cleared the virus, they found no differences in the class I loci; however, significantly fewer subjects with persistent infection were heterozygous for haplotypes of the HLA class II region genes, HLA-DR (see 142860) and HLA-DQ (see 146880). To investigate whether TNF (191160) promoter polymorphisms are associated with clearance of HBV infection, Kim et al. (2003) genotyped 1,400 Korean subjects, 1,109 of whom were chronic HBV carriers and 291 who spontaneously recovered. The TNF promoter alleles that were previously reported to be associated with higher plasma levels (presence of -308A or the absence of -863A alleles), were strongly associated with the resolution of HBV infection. Haplotype analysis revealed that TNF haplotype 1 (-1031T; -863C; -857C; -308G; -238G; -163G) and haplotype 2 (-1031C; -863A; -857C; -308G; -238G; -163G) were significantly associated with HBV clearance, showing protective antibody production and persistent HBV infection, respectively (P = 0.003-0.02). Thio et al. (2005) genotyped 2 promoter SNPs and 3 exon 1 SNPs in the MBL2 gene (154545) in a large cohort of individuals with either HBV persistence or recovery. They found that a promoter SNP, -221G-C, which leads to deficient MBL production, was more common in subjects with HBV persistence. Individuals homozygous for the combination of promoter and exon 1 genotypes associated with the highest amount of functional MBL had highly increased odds of recovery from infection. In contrast, those homozygous for the combination of promoter and exon 1 genotypes associated with the lowest amount of functional MBL were more likely to have viral persistence. Thio et al. (2004) genotyped 6 SNPs in CTLA4 (123890) in a large cohort of individuals with either HBV clearance or persistence. They found that the wildtype haplotype, which contains -1722T and +49A, was associated with viral persistence. In contrast, haplotypes containing +49G either alone or with -1722C were associated with viral clearance. The association with viral clearance was stronger for individuals homozygous for +49G. Thio et al. (2004) concluded that genes important in immune system couterregulation are also important in recovery from chronic viral illness. By microsatellite analysis of Gambian families, Frodsham et al. (2006) identified a class II cytokine receptor gene cluster on chromosome 21q22 as a major susceptibility locus for HBV persistence. They found that coding SNPs in 2 genes within this cluster, phe8 to ser (F8S; 602376.0001) in IFNAR2 and lys47 to glu (K47E; 123889.0001) in IL10RB (123889), were associated, both independently and as a haplotype, with a higher risk of HBV persistence. In both cases, the more common variant (F8 and K47, respectively) was associated with HBV persistence. Kamatani et al. (2009) performed a 2-stage genomewide association study using 786 Japanese chronic hepatitis B cases and 2,201 controls, and identified a significant association of chronic hepatitis B with 11 SNPs in a region including HLA-DPA1 (142880) and HLA-DPB1 (142858). Kamatani et al. (2009) validated these associations by genotyping 2 SNPs from the region in 3 additional Japanese and Thai cohorts consisting of 1,300 cases and 2,100 controls (combined P = 6.34 x 10(-39) and 2.31 x 10(-38), odds ratio = 0.57 and 0.56, respectively). Subsequent analyses revealed risk haplotypes (HLA-DPA1*0202-DPB1*0501 and HLA-DPA1*0202-DPB1*0301, odds ratio = 1.45 and 2.31, respectively) and protective haplotypes (HLA-DPA1*0103-DPB1*0402 and HLA-DPA1*0103-DPB1*0401, odds ratio = 0.52 and 0.57, respectively). Kamatani et al. (2009) concluded that genetic variants in the HLA-DP locus are strongly associated with risk of persistent infection with hepatitis B virus in Asians. Zhou et al. (2009) investigated SNPs in the IFNGR1 gene (107470) and their associations with susceptibility to HBV in a Chinese population. Using PCR and RFLP analysis, they identified 7 SNPs in the IFNGR1 gene. Comparison of 361 chronic hepatitis B patients, 256 individuals who spontaneously recovered from HBV infection, and 366 healthy controls showed that the -56C and -56T alleles of a promoter polymorphism (107470.0012) were associated with viral clearance and viral persistence, respectively (P = 0.014). Luciferase reporter analysis showed that the -56C variant exhibited a higher transcription level than the -56T variant in a liver cell line. Zhou et al. (2009) concluded that the -56C/T SNP in the IFNGR1 promoter is associated with the clinical outcome of HBV infection in Chinese adults. | |||||||||||||||||||||||||||||||||||||||
| REFERENCES | |||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||