Genetic variants of programmed cell death 1 are associated with HBV infection and liver disease progression

Abstract

The inhibitory effects of programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) modulates T-cell depletion. T-cell depletion is one of the key mechanisms of hepatitis B virus (HBV) persistence, in particular liver disease progression and the development of hepatocellular carcinoma (HCC). This case-control study aimed to understand the significance of PD-1 polymorphisms (PD-1.5 and PD-1.9) association with HBV infection risk and HBV-induced liver disease progression. Genotyping of PD-1.5 and PD-1.9 variants was performed by direct Sanger sequencing in 682 HBV-infected patients including chronic hepatitis (CHB, n = 193), liver cirrhosis (LC, n = 183), hepatocellular carcinoma (HCC, n = 306) and 283 healthy controls (HC). To analyze the association of PD-1 variants with liver disease progression, a binary logistic regression, adjusted for age and gender, was performed using different genetic models. The PD-1.9 T allele and PD-1.9 TT genotype are significantly associated with increased risk of LC, HCC, and LC + HCC. The frequencies of PD-1.5 TT genotype and PD-1.5 T allele are significantly higher in HCC compared to LC patients. The haplotype CT (PD-1.5 C and PD-1.9 T) was significantly associated with increased risk of LC, HCC, and LC + HCC. In addition, the TC (PD-1.5 T and PD-1.9 C) haplotype was associated with the risk of HCC compared to non-HCC. The PD-1.5 CC, PD-1.9 TT, genotype, and the CC (PD-1.5 C and PD-1.9) haplotype are associated with unfavorable laboratory parameters in chronic hepatitis B patients. PD-1.5 and PD1.9 are useful prognostic predictors for HBV infection risk and liver disease progression.

Figure 1

Evaluation of clinical parameters in HBV patient subgroups. CHB chronic hepatitis B, LC liver cirrhosis, HCC hepatocellular carcinoma, PLT platelets, AST and ALT aspartate and alanine amino transferase, WBC white blood cells, RBC red blood cells, PLT platelet, IU international unit. Box-plots illustrate medians with 25 and 75 percentiles with whiskers to 10 and 90 percentiles. p-values were calculated by Kruskal–Wallis test.

Figure 2

Association of PD-1.5 variant with distinct laboratory parameters in HBV patients. Box-plots illustrate median values with 25 and 75 percentiles with whiskers to 10 and 90 percentiles; p-values were calculated by Mann–Whitney test.

Figure 3

Association of PD-1.9 variant with distinct laboratory parameters in HBV patients. Box-plots illustrate median values with 25 and 75 percentiles with whiskers to 10 and 90 percentiles; p-values were calculated by Mann–Whitney test.

Figure 4

Association of PD-1 haplotypes with distinct laboratory parameters in HBV patients. Box-plots illustrate median values with 25 and 75 percentiles with whiskers to 10 and 90 percentiles; p-values were calculated by Mann–Whitney test.