PD-1 gene haplotype is associated with the development of type 1 diabetes mellitus in Japanese children

Abstract

Interaction between Programmed cell death-1 (PD-1), a member of costimulatory molecules, and its receptors Programmed cell Death-1 Ligand 1 (PD-L1) and Programmed cell Death-1 Ligand 2 (PD-L2), play an important role in the negative regulation of immune reactions. It was shown that a polymorphism in a regulatory site of the PD-1 gene was associated with susceptibility to several autoimmune diseases in various ethnic groups, whereas the contribution of the PD-1 gene or its ligand genes to the onset of type 1 diabetes (T1D) mellitus in the Japanese population remains unknown. We first screened PD-1, PD-L1, and PD-L2 genes for polymorphisms in the Japanese population, and then investigated the frequencies of polymorphisms in patients with T1D mellitus in comparison with healthy controls. In total, we identified 26 polymorphic sites within these genes, and then 23 polymorphisms with minor allele frequencies greater than 5% were intensively analyzed for genotyping in the patients and the controls. As a result, allele and genotype frequencies of the polymorphism numbers 2, 3, 4, 5, 6, and 8 in the PD-1 gene were different to some extent between the patients and the controls with P < 0.05, which did not reach statistical significance after the correction of multiple comparisons. Allele or genotype frequencies of any SNPs in the PD-L1 or PD-L2 gene did not show differences between the patients and the controls. The frequencies of the estimated haplotypes, those of which consisted of polymorphism numbers 2, 3, 4, 5, 6, and 8 in the PD-1, were significantly different between the patients and the controls (P = 0.00095). The in vitro assessment for a transcription activity of each haplotype of the PD-1 gene by luciferase assay did not demonstrate a functional difference between the haplotypes. In conclusion, the genetic evaluation by association study demonstrated that the PD-1 gene was a predisposing gene to the development of T1D mellitus in the Japanese population.

Association of an A/C single nucleotide polymorphism in programmed cell death-ligand 1 gene with Graves' disease in Japanese patients.

“…PD-1 gene polymorphisms have been reported to be associated with SLE (9, 10), AS (15), MS (14), T1D (12), and GD (17). The genotype frequency of PD-L2 47103 T/T, in comparison with 47103 C/C, has been reported to significantly increase in patients with SLE (16).…”

“…It does not affect an amino acid substitution. One possible explanation is that the polymorphism is near or within transcriptional factorbinding sites (12), and it may also modify the binding affinity of transcriptional factors. This may influence the PD-L1 gene expression.…”

“…PD-1 gene polymorphisms have been reported to be associated with systemic lupus erythematosus (SLE) (9,10), type 1 diabetes (T1D) (11,12), rheumatoid arthritis (13), multiple sclerosis (MS) (14), and ankylosing spondylitis (AS) (15). A PD-L2 gene polymorphism is associated with susceptibility to SLE (16).…”

“…html)). Several gene polymorphisms have been reported in PD-L1 gene (12). However, no association between PD-L1 gene polymorphisms and autoimmune diseases has yet been reported.…”

Co-Inhibitory Molecule Programmed Death-1 and Its Ligands: A New Alternative Therapy for Human Immunodeficiency Virus Infection?

“…The PD-1 gene (Pdcd1) has an extension of 2106 cDNA nucleotides, is located in the human chromosome 2q37.3 (Shinohara et al, 1994) and is encoded by 5 exons (Finger et al, 1997;Ni et al, 2007). PD-1 has a transmembrane region, an extra cellular region and a cytoplasmic region.…”