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

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.