PD1 as a common candidate susceptibility gene of subacute sclerosing panencephalitis

Abstract

Although the exact pathogenesis of subacute sclerosing panencephalitis (SSPE) remains to be determined, our previous data suggested a genetic contribution to the host susceptibility to SSPE. During chronic viral infection, virus-specific cytotoxic T lymphocytes display poor effector functions. Since co-inhibitory molecules are involved in the suppression of T lymphocytes, we investigated whether single nucleotide polymorphisms (SNPs) of genes encoding co-inhibitory molecules contributed to a susceptibility to SSPE. Association studies on a total of 20 SNPs in 8 genes (CTLA4, CD80, CD86, PD1, PDL1, PDL2, BTLA and HVEM) and subsequent haplotype analysis of 4 SNPs in the PD1 genes were performed in Japanese and Filipino SSPE patients and controls. Then, we investigated a functional difference in promoter activity of two haplotypes and compared the expression levels of PD1 between SSPE and controls. The frequency of GCG(C) haplotype of PD1 containing -606G allele was significantly higher in SSPE patients than in controls both in Japanese and in Filipinos. The promoter activity was significantly higher in the construct with -606G allele than in that with -606A allele. The expression levels of PD1 were significantly higher in SSPE patients than in the controls. Our results suggested that the PD1 gene contributed to a genetic susceptibility to SSPE.

Association of polymorphisms of programmed cell death–1 gene with chronic hepatitis B virus infection

“…One recent report demonstrated a significant association of PD-1.1 SNP and the expression levels of PD-1 with subacute sclerosing panencephalitis (SSPE) in Japanese and Filipinos population [36]. We showed a significant association of PD-1.6 SNP rather than PD-1.1 SNP with chronic HBV infection in Chinese population.…”

“…The PD-1.6 SNPs with G allele, which showed lower frequencies in chronic HBV infection, may be involved in the downregulation of PD-1 expression in the T cells associated with the immune responses, including T-cell activation and the production of antiviral cytokines, such as interferon-␥ and tumor necrosis factor, via so far unknown mechanism in chronic HBV infection, conferring a protective effect. Recently, it has been demonstrated that the promoter activity in the construct with Ϫ606A allele was significantly lower than that with Ϫ606G allele [36]. In our study, the combination of PD-1.6 genotype containing G allele (GA or GG) with the PD-1.1 GG genotype decreased the OR from 0.667 to 0.381 and the PD-1 haplotype comprising PD-1.6 G and PD-1.1 G alleles decreased the OR from 0.662 in PD-1.6 G allele to 0.530.…”

PD-1 gene promoter polymorphisms correlate with a poor prognosis in non-small cell lung cancer

“…This -606 G/A single-nucleotide polymorphism (SNP) resides in the putative binding site for UCE-2 transcription regulators (GGCCG at position -610 to -606). A haplotype of the -606 G allele with a high promoter activity was correlated with the development of SSPE (15). The relative PD-1 expression was higher in SSPE patients compared to the control (15), however, the correlation between this Asian-specific PD-1 SNP and NSCLC has not been well investigated.…”

“…The PD-1 -606 G allele at the promoter showed a significant correlation with Japanese subacute sclerosing panencephalitis (SSPE) (15). This -606 G/A single-nucleotide polymorphism (SNP) resides in the putative binding site for UCE-2 transcription regulators (GGCCG at position -610 to -606).…”

“…Ishizaki et al (15) demonstrated that a haplotype with the -606 G allele and a high promoter activity was associated with the development of Japanese SSPE (15). The haplotype frequency of PD-1 containing the -606 G allele was significantly higher in SSPE patients compared to controls in the Japanese population.…”