Identified OAS3 gene variants associated with coexistence of HBsAg and anti‐HBs in chronic HBV infection

Abstract

The underlying mechanism of coexistence of hepatitis B surface antigen (HBsAg) and hepatitis B surface antigen antibody (anti-HBs) is still controversial. To identify the host genetic factors related to this unusual clinical phenomenon, a two-stage study was conducted in the Chinese Han population. In the first stage, we performed a case-control (1:1) age- and gender-matched study of 101 cases with concurrent HBsAg and anti-HBs and 102 controls with negative HBsAg and positive anti-HBs using whole exome sequencing. In the second validation stage, we directly sequence the 16 exons on the OAS3 gene in two dependent cohorts of 48 cases and 200 controls. Although, in the first stage, a genome-wide association study of 58,563 polymorphism variants in 101 cases and 102 controls found no significant loci (P-value ≤ .05/58563), and neither locus achieved a conservative genome-wide significance threshold (P-value ≤ 5e-08), gene-based burden analysis showed that OAS3 gene rare variants were associated with the coexistence of HBsAg and anti-HBs. (P-value = 4.127e-06 ≤ 0.05/6994). A total of 16 rare variants were screened out from 21 cases and 3 controls. In the second validation stage, one case with a stop-gained rare variant was identified. Fisher's exact test of all 149 cases and 302 controls showed that the rare coding sequence mutations were more frequent in cases vs controls (P-value = 7.299e-09, OR = 17.27, 95% CI [5.01-58.72]). Protein-coding rare variations on the OAS3 gene are associated with the coexistence of HBsAg and anti-HBs in patients with chronic HBV infection in Chinese Han population.

Genetic analysis of a Taiwanese family identifies a DMRT3-OAS3 interaction that is involved in human sexual differentiation through the regulation of ESR1 expression

“…Of them, OAS3 is the major RNase L-activating protein and is capable of blocking viral replication in infected cells. Genetic alterations in OAS3 have been previous correlated with hepatitis B virus (21) and enterovirus 71 infections (21), chronic lymphocytic leukemia (22), and hypertension in males (23).…”

Clinical and virological characteristics of coexistent hepatitis B surface antigen and antibody in treatment-naive children with chronic hepatitis B virus infection

“…The discovery of this specific serological pattern could be traced back as early as 1976 (18), while the reason for such difference in concurrently positive for HBsAg and anti-HBs is enigmatic. Firstly, prior studies (19)(20)(21)(22) have proved the relationship between persistent detectability of anti-HBs and escape mutants of HBsAg caused by variations in key regions of HBV genome. Therefore, genetic difference of HBV in various races and regions may contribute to explain the variance in prevalence.…”

T-Cell Receptor β Chain and B-Cell Receptor Repertoires in Chronic Hepatitis B Patients with Coexisting HBsAg and Anti-HBs

“…The presence of heterologous subtype-specific anti-HBs, particularly in clinical immunosuppression, should be considered in the immune mechanism [ 16 , 17 , 18 ]. Host genetic factors also play a role, and the human gene oligoadenylate synthetase 3 (OAS3) variants may be associated with the coexistence of HBsAg and anti-HBs [ 19 ].…”

“…With the immune pressures coming from antiviral treatment and vaccination, HBV mutations are not limited to open reading frames (ORFs) but are also found in all viral genes and regulatory elements clustered in the preS/S gene, reverse transcriptase region (RT) in the polymerase gene, the pre-core region, basal core promoter (BCP), and the X gene, resulting in the reduced or even abolished binding of neutralizing antibodies and eliciting the detection of HBsAg and anti-HBs at the same time [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. In terms of host factors, the presence of heterologous subtype-specific anti-HBs along with human gene oligoadenylate synthetase 3 (OAS3) variants may be associated with the coexistence of HBsAg and anti-HBs [ 16 , 17 , 18 , 19 ].…”