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Human Genetics

, Volume 121, Issue 2, pp 223–232 | Cite as

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

  • Ronghua Ni
  • Kenji IharaEmail author
  • Kenichi Miyako
  • Ryuichi Kuromaru
  • Mika Inuo
  • Hitoshi Kohno
  • Toshiro Hara
Original Investigation

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.

Keywords

Costimulatory Pathway Estimate Haplotype Frequency ICOS Gene Rheumatoid Athritis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

T1D

Type 1 diabetes mellitus

SLE

Systemic lupus erythematosus

DC

Dendritic cell

RFLP

Restriction fragment length polymorphism

SSCP

Single strand conformation polymorphism

Notes

Acknowledgment

This work was supported by a Grant-in Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Ronghua Ni
    • 1
  • Kenji Ihara
    • 1
    Email author
  • Kenichi Miyako
    • 1
  • Ryuichi Kuromaru
    • 1
  • Mika Inuo
    • 1
  • Hitoshi Kohno
    • 2
  • Toshiro Hara
    • 1
  1. 1.Department of Pediatrics, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
  2. 2.Department of Endocrinology and MetabolismFukuoka Children’s HospitalFukuokaJapan

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