The Association Between The Polymorphisms Of PD-1 And Genetic Susceptibility Of Chronic HBV Infection Family

Background Chronic hepatitis B virus(HBV) infection is one of the major infectious diseases and causes a great harm to human health. To investigate the mechanism of chronic HBV infection susceptibility, always is liver researchers'concern and research hotspot.But after infection, the diversity of the HBV disease spectrum and clinical course was attributed, in a very large extent, to the host genetic factors including single nucleotide polymorphisms (SNPs) of a variety of genes, besides with immunological factors ,viral factors and environmental factors.From the host of genetic predisposition, to explore the mechanism of chronic HBV infection susceptibility, for it as genetic markers of forecasting HBV infection occurrence, development and ending provides possibility. However, in gene association studies, biological function related gene as a candidate gene, which is the main research strategy for the genetic susceptibility of infectious diseases'research currently.Molecular immunology research suggests programmed cell death-1(PD-1) and its ligands(PD-L) pathway can provide inhibitory signals that can regulate the fine-tuning,inhibition and activation of T-cell and APC-cell responses.It plays an important role in the chronic HBV infection.So this study firstly investigated the association between the polymorphisms of PD-1 and genetic susceptibility of chronic HBV infection family by family-based association analysis method in Chinese patients. Methods Two SNPs, PD-1.1G>A and PD-1.2G>A, were genotyped in 539 patients with chronic HBV infection and 353 other family members (HBsAg-) from 256 nuclear families using polymerase chain reactiorestriction fragment length polymorphisms (PCR-RFLP) assay. The associations between PD-1 polymorphisms and genetic susceptibility of chronic HBV infection family were analyzed using the family-based association test (FBAT) analysis method.Results (1) A total of 539 patients with chronic HBV infection from 256 nuclear families that contained complete genotype were employed in the data analysis. At the same time, 353 family members of these patients were genotyped. Stratified by PD-1.1G>A and PD-1.2G>A genotypes among 539 patients, the frequencies of PD-1.1G>A, AA, AG and GG genotypes were 16.6%, 63.7% and 19.7% respectively and the A and G allele frequencies were 48.4% and 51.6% respectively. PD-1.2G>A, AA, AG and GG genotype frequencies were 22.8%, 59.8% and 17.4% respectively and the A and G allele frequencies were 52.7% and 47.3% respectively. The genotype distributions of PD-1.1 and PD-1.2 polymorphisms were in Hardy-Weinberg equilibrium (PD-1.1,χ~2 = 3.032, P= 0.082; PD-1.2,χ~2=0.25, P = 0.616);(2)Univariate (single-marker) FBAT demonstrated that there were no associations between genotypes and chronic HBV infection (P > 0.05). In PD-1.1G>A and PD-1.2G>A, single loci analysis by FBAT showed that the alleles of A and G were also not associated with chronic HBV infection in the additive model [(PD-1.1, Z = -0.265, P = 0.790993; Z = 0.265, P = 0.790993 respectively); (PD-1.2, Z = 0.640, Z = -0.640, P = 0.522127 respectively)], the dominant model [(PD-1.1, Z = -0.617, P = 0.537018; Z = -0.193, P = 0.846892 respectively); (PD-1.2, Z = -0.080, P = 0.936343; Z = -1.001, P = 0.316939 respectively)] and the recessive model [(PD-1.1, Z = 0.193, P = 0.846892; Z = 0.617, P = 0.537018 respectively); (PD-1.2, Z = 1.001, P = 0.316939; Z = 0.080, P = 0.936343 respectively)]; (3) Transmission disequilibrium test (TDT) and Transmsslon disequilibrium of patient-normal siblings test (SDT) analysis revealed no increased transmission for the major alleles from heterozygous parents to affected offspring (P = 0.688880, P = 1.000000 respectively); (4) Haplotype analysis showed that four haplotypes, PD-1.1A/PD-1.2A (46.3%), PD-1.1G/PD-1.2G (45.4%), PD-1.1G/PD-1.2A (4.7%) and PD-1.1A/PD-1.2G (3.5%), were reconstructed. FBAT was utilized in analyzing the data from 256 nuclear families. The transmitted haplotypes were not associated with genetic susceptibility of chronic HBV infection in each of additive, dominant and recessive models (P > 0.05).Conclusion The data demonstrated that PD-1.1 and PD-1.2 polymorphisms are not associated with chronic HBV infection in Chinese patients. The SNPs of PD-1 gene may not be used as a potential genetic marker to predict the chronic HBV infection.