The Influence of B and T Lymphocyte Attenuator Genetic Variants on Susceptibility to Chronic Hepatitis B Virus Infection

Abstract

Background/Aims: B and T lymphocyte attenuator (BTLA) is an immune inhibitory receptor involved in the pathogenesis of chronic viral infections. Little is known about the effects of BTLA gene polymorphisms on chronic hepatitis B virus (HBV) infections. In this study, we investigated whether the polymorphisms of BTLA are associated with the progression of chronic HBV infection. Methods: A total of 382 chronic HBV carriers and 170 healthy individuals in the same region were recruited for this study. The chronic HBV carriers were divided into three groups: asymptomatic HBV carriers (ASC), moderate chronic hepatitis B group (MCHB), and severe chronic hepatitis B group (SCHB). Two BTLA functional single nucleotide polymorphisms (SNPs; rs76844316 and rs9288952) were genotyped by polymerase chain reaction and sequenced directly. Results: The results showed that the frequency of the G allele of rs76844316 was significantly lower in the SCHB group than in the other three groups. Subjects bearing at least one G allele (TG or GG genotype) at rs76844316 had decreased susceptibility to severe chronic hepatitis B compared with those bearing the TT genotype. Haplotype analysis of the two SNPs revealed that the frequency of the G-G haplotype was significantly lower in SCHB patients than in controls. Moreover, in the SCHB group, patients carrying the G allele of rs76844316 tended to have lower ALT levels than those without it. Conclusion: Our findings suggest that the genetic variants of rs76844316 in BTLA influence the susceptibility to severe chronic hepatitis B and might play a protective role against the progression of chronic hepatitis B.

BTLA/HVEM Signaling: Milestones in Research and Role in Chronic Hepatitis B Virus Infection

“…The human BTLA gene, located on chromosome 3 at 3q13, comprises 5 exons with a total length of 870 bp and 3 mRNA splice variants, which encode functional proteins that can be transcribed. Of note, a single nucleotide polymorphism (SNP) of BTLA, rs76844316, was reported to protect against chronic hepatitis B infection (31). BTLA is a type I transmembrane glycoprotein comprising 289 amino acids.…”

“…Critically, during the four different phases of HBV infection [immunotolerant phase, immune clearance phase, non-reactive or minimally (non-) replicative phase, and reactivation phase], the immune reactions produced by HBV are different. Additionally, Zhou et al established that the frequency of rs76844316 in the G allele of the BTLA gene was decreased in patients with severe CHB, which leads to increased sensitivity to HBV and association with severe disease (31). Therefore, the total BTLA expression level in CHB patients should not be viewed in isolation and BTLA expression in patients at different phases of HBV, across multiple severities of CHB should be analyzed.…”

Immune checkpoints on T and NK cells in the context of HBV infection: Landscape, pathophysiology and therapeutic exploitation

“…In HBV infection, BTLA is highly expressed in a subset of virus-specific T-cells, which can potentially have an inhibitory effect on T-cell proliferation and cytokine secretion ( 145 , 146 ). In addition, BTLA genetic variants seem to influence the susceptibility to severe chronic hepatitis B ( 147 ).…”

Immune Checkpoint Molecules—Inherited Variations as Markers for Cancer Risk

“…Even though the amino acid exchange is not within the ITIM motifs of BTLA, it is hypothesized that this substitution may alter the posttranslational modifications of BTLA, such as glycosylation of asparagine, or phosphorylation of threonine by serine/threonine kinase, which may influence the strength of BTLA signaling by SHP1/SHP2 ( 212 ). Hence, BTLAc.590*A allele was associated with decreased inhibitory activity of BTLA in Jurkat cells it may potentially constitute cancer risk factor.…”