Genetic polymorphisms of regulatory T cell‐related genes modulate systemic inflammation induced by viral hepatitis

Abstract

Abstract Viral hepatitis is a devastating disease with the risk for cirrhosis and carcinogenicity. Regulatory T cells (Tregs) play important roles in the disease course of viral hepatitis via maintaining the balance between overt‐immune responses and viral replications. We hypothesized that genetic polymorphisms of Treg‐related genes, such as interleukin‐2, transforming growth factor‐β 1 (TGF‐β1), forkhead box P3 (FOXP3), and adenylyl cyclase type 9 modulate the hosts' immune regulation under circumstances of viral hepatitis. We examined the effect of five single nucleotide polymorphisms (SNPs) of Treg‐related genes on the levels of C‐reactive protein (CRP) and erythrocyte sedimentation rate (ESR), alanine aminotransferase, and non‐invasive hepatic fibrosis marker (Fibrosis‐4 index) in a total of 138 participants with viral hepatitis. The rs1800469 (a TGF‐β1 SNP) GG genotype is associated with higher serum CRP levels, and the rs3761547 (a FOXP3 SNP) C allele in the females is associated with higher ESR levels. Besides, female participants carrying the rs3761547 C allele had a significantly higher Fibrosis‐4 (FIB‐4) index than the females carrying the TT genotype, while the rs3761547 C allele had the opposite effect in males. With linear‐regression moderation analysis, we found that sex moderated the impact of the FOXP3 SNP on the levels of FIB‐4, whereas the FOXP3 SNP caused the opposite effect between males and females on the severity of hepatic fibrosis. These results provide evidence for the participation of TGF‐β1 and FOXP3 in the inflammatory responses associated with viral hepatitis, where FOXP3 function may be moderated by sex.

Keywords

• CRP
• ESR
• FOXP3
• TGF‐β1
• Treg