rs7453920 adds an additional polymorphism to the growing body of literature supporting a genetic component to HBV infection and clearance. It is located in intron 1 of the HLA-DQB2 gene at the 6p21.32 locus. Therefore, the SNP does not affect the structure of the protein by any direct means. The A allele of this SNP has been associated with increased HLA-DQB2 mRNA levels in circulating monocytes (which are critical for mounting immune responses), increased HBV clearance, and CHB infection. [PMID 24162738]
Alleles 1 and 2 at this location are A and G with G being the risk allele (p = 5.98E-28; OR = 1.81). [PMID 21750111]
The HLA-DQB1 (Human Leukocyte Antigen) and HLA-DQB2 genes belongs to the HLA class II beta chain class paralogues. Class II molecules are heterodimers comprised of alpha (DQA) and beta (DQB) chains that are both anchored in the membrane. They play an integral role in the immune system and more specifically HBV clearance by presenting peptide sequences from extracellular proteins and are predominantly expressed in antigen-presenting cells such as B lymphocytes, dendritic cells, and macrophages. Polymorphisms in the protein-coding portions of the genes for these heterodimers will result in the display of different kinds of peptides. The beta chain contains six exons and is approximately 26-28 kDa long. Exon 1 encodes the leader peptide, exons 2 and 3 encode the two extracellular domains, exon 4 encodes the transmembrane domain and exon 5 encodes the cytoplasmic tail. rs7453920 is a mutation in the first intron of the gene and therefore does not directly affect the structure and function of the protein.
Hepatitis B virus (HBV) is the most common cause of infectious liver disease, afflicting more than 400 million people worldwide. This chronic viral condition can be transmitted vertically during the neonatal period; horizontally during childhood via bites, lesions or sanitary habits; or during adulthood via sexual contact, drug use, or medical exposure. Though there are many factors that influence the expression of the disease including viral, host immunological, and environmental, there increasingly appears to be a strong genetic component to the body’s response to HBV.
Genes are impact five different pathways that affect the infection and clearance of HBV. These include (1) viral entry into the cells, (2) the immune response to HBV infection, (3) pathological alterations in liver tissue, (4) liver cirrhosis and subsequent hepatocellular carcinoma, and (5) resistance to antiviral therapies. [PMID 12679901] Mutations in HLA class I and II alleles, cytokine and chemokines, as well as mannose binding protein (MBP) have all demonstrated strong associations with HBV clearance. Specifically, mutations in the DRB1 gene are associated with self-limiting courses of acute HBV while DQA1 and DQB1 are linked to viral persistence. [PMID 10068598]
The varying release of cytokines and chemokines impacts the host’s immunological response to HBV as well as viral persistence. Tumor necrosis factor a (TNF-a) is associated with non-cytotoxic antiviral mechanisms. [PMID 9528902] Polymorphisms in the promotor region of TNF-a are associated with HBV and HCV persistence. [PMID 9515764] Finally, mannose binding protein (MBP) is an opsonin that activates the classical complement pathway of innate immunity and phagocytosis. Mutations in several codons including 52, 54, and 57 have impaired the functionality of MBP and therefore the phagocytotic defenses against HBV. [PMID 8965590]
Additionally, several studies have demonstrated genetically variable outcomes to HBV vaccine-induced immunity. Peak vaccine-induced anti-HBs level is directly related to antibody decay, risk of infection, and persistent carriage. Variation in the IFNG, MAPK8, AND IL10RA genes affect peak anti-HBs levels (p ≤ 0.001). [PMID 18365030]
[PMID 21750111] Significant association between SNP and chronic hepatitis B in a Japanese population. DQA1*0102-DQB1*0604 and DQA1*0101-DQB1*0501 [odds ratios (OR) =0.16, and 0.39, respectively] as protective haplotypes and DQA1*0102-DQB1*0303 and DQA1*0301-DQB1*0601 (OR = 19.03 and 5.02, respectively) as risk haplotypes.
[PMID 24162738] This study found an association with rs7453920 and CHB with an odds ratio of 0.53 and a Pmeta value of P = 4.93e-37.
[PMID 20502693] A transcriptome study demonstrated that the A allele of rs7453920 was associated with higher HLA-DQ mRNA levels in circulating monocytes, which are critical for mounting immune responses.
[PMID 24465366] The rs7453920 allele frequency is found more often in chronically infected patients than with clearance group infections, but did not reach significance when the association was examined between HBV infections in Saudi Arabian patients.
[PMID 22105689] Rs7453920 is associated with HBV clearance in Japanese populations. There is an association between rs7453920, two other SNPs and HBV clearance in Han Chinese populations (P = 7.61e-7). }}
[PMID 21750111] A Genome-Wide Association Study of Chronic Hepatitis B Identified Novel Risk Locus in a Japanese Population
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|Odds Ratio||1.19 [1.11-1.3]|
|Trait||Chronic hepatitis B infection|
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|Odds Ratio||2.00 [1.72-2.27]|
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|Odds Ratio||1.89 [1.69-2.08]|
|Trait||Chronic hepatitis B infection|
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|Odds Ratio||2.31 [1.87-2.85]|
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