A functional variant in the OAS1 gene is associated with Sjögren’s syndrome complicated with HBV infection

Abstract

Hepatitis B virus (HBV) has been suspected to contribute to several autoimmune diseases, including Sjögren’s syndrome (SS), although the exact mechanism is unknown. The 2′–5′ oligoadenylate synthetase (OAS1) is one of the most important components of the immune system and has significant antiviral functions. We studied a polymorphism rs10774671 of OAS1 gene in Han Chinese descent. The minor allele G was significantly associated with a decreased risk for SS, anti-SSA-positive SS, and anti-SSA-positive SS complicated with HBV infection, which have not been seen in anti-SSA-negative SS and HBcAb-negative SS patients. Gene expression analysis showed that the risk-conferring A allele was correlated with lower expression of p46 and increased expression of p42, p48, and p44. A functional study of enzymatic activities revealed that the p42, p44, and p48 isoforms display a reduced capacity to inhibit HBV replication in HepG2 cells compared to the normal p46 isoform. Our data demonstrated that the functional variant, rs10774671, is associated with HBV infection and anti-SSA antibody-positive SS. The SAS variant switches the primary p46 isoform to three alternatives with decreased capacities to inhibit HBV replication. These data indicated that individuals harboring the risk allele might be susceptible to hepatitis B infection and SS development.

Genetic regulation of gene expression and splicing during a 10-year period of human aging

“…HLA-DRA , NCOR2 , and PLEKHO2 show a significant gain of AI with age (likelihood ratio test (LRL); P =9.7×10 −6 , 4.1×10 −5 , and 4.2×10 −5 , respectively) while CLEC7A , OAS1 , and HLA-DQB1 show a significant loss of AI with age (LRT; P =7.7×10 −6 , 4.1×10 −5 , and 3.9×10 −6 , respectively). Most of these genes are involved in the immune system and have been previously implicated in the aging process [42, 43]. Most notably, NCOR2 expression and its occupancy on peroxisome proliferator-activated receptor (PPAR) target gene promoters are increased with age in major metabolic tissues.…”

Human OAS1 activation is highly dependent on both RNA sequence and context of activating RNA motifs

“…There is also accumulating evidence for essential roles played by OAS1 in normal cell function. For example, OAS1 SNPs have also been implicated in altered cellular function leading to diseases including diabetes ( 37 ), multiple sclerosis ( 38 , 39 ), prostate cancers ( 40 ), and Sjögren's syndrome ( 41 , 42 ), as well as susceptibility to tuberculosis infection ( 43 ). OAS1 has also been recently implicated in cancer cell survival after treatment with DNA damaging agents ( 44 ) and in mediating the cytotoxicity of 5-azacytidine (AZA), a DNA methyltransferase inhibitor widely used in cancer treatment ( 45 ).…”

The Cellular Localization of the p42 and p46 Oligoadenylate Synthetase 1 Isoforms and Their Impact on Mitochondrial Respiration

“…The rs10774671 SNP and in extension the discrepancy between the p42 and p46 isoforms have been directly associated with several viral diseases including West Nile Virus infections [10], susceptibility to hepatitis B virus (HBV) infections and Sjögren's syndrome development [11], liver fibrosis progression and response to interferon therapy during hepatitis C virus (HCV) infections [12,13] as well as in tuberculosis (TB) [14]. In all of these instances, it is the G allele (i.e., the OAS1 p46 isoform) that confers resistance, while the p42 variant is associated with a higher risk in these infectious diseases.…”