Plasma levels of sPD-1 and PD-1 genetic variants are associated with hepatitis B infection and related liver disease progression

Background Programmed cell death-1 (PD-1) variants and circulating levels of soluble PD-1 are associated with susceptibility to malignant and infectious disease. This study aimed to examine the association of PD-1.5 and PD-1.9 variants, and plasma sPD-1 levels with HBV infection and disease progression. Methods The study cohort consists of HBV-infected adults (n = 513) stratified by clinical course, including chronic hepatitis B (CHB, n = 173), liver cirrhosis (LC, n = 134), hepatocellular carcinoma (HCC, n = 206), and matched healthy controls (HC, n = 196). The PD-1.5 (rs2227981 C/T) and PD-1.9 (rs2227982 C/T) genetic variants were genotyped by Sanger sequencing, and then sPD-1 levels were quantified by enzyme immunoassay. Results The plasma sPD-1 levels were significantly high among HBV patients. The highest plasma sPD-1 levels were observed in CHB patients, followed by the LC and HCC groups. In addition, the plasma sPD-1 levels correlated positively with liver inflammation (aspartate transaminase, AST: rho = 0.57, P < 0.0001 and alanine aminotransferase, ALT: rho = 0.57, P < 0.0001) and were positively correlated with liver fibrosis (AST to Platelet Ratio Index, APRI score: rho = 0.53, P < 0.0001). The PD-1.9 TT genotype was less frequent in CHB patients compared to LC, HCC and HCC + LC patients in both codominant and recessive models (P < 0.01) and was found to be a risk factor for HCC predisposition [HCC vs. non-HCC: OR = 2.0 (95% CI: 1.13–3.7), Padj=0.017]. The PD-1.5 CT genotype was associated with a reduced risk of acquiring HCC [OR = 0.6 (95%CI: 0.4–0.9), Padj=0.031]. Conclusion Our study concludes that sPD-1 levels are associated with liver inflammation and progression of liver fibrosis and the PD-1.5 and PD-1.9 variants are associated with HBV infection and progression of liver disease.