PD-1 gene haplotype is associated with the development of type 1 diabetes mellitus in Japanese children
PD-1 gene haplotype is associated with the development of type 1 diabetes mellitus in Japanese children
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DOI：
10.1007/s00439-006-0309-8
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发表时间：
2007-04-01
期刊：
影响因子：
5.3
通讯作者：
Hara, Toshiro
中科院分区：
文献类型：
--
作者：
Ni, Ronghua;Ihara, Kenji;Hara, Toshiro
共刺激分子成员程序性细胞死亡-1 （PD-1）及其受体程序性细胞死亡-1配体1 （PD-L1）和程序性细胞死亡-1配体2 （PD-L2）之间的相互作用在免疫反应的负调控中起重要作用。研究表明，PD-1基因调控位点的多态性与不同种族人群对几种自身免疫性疾病的易感性有关，而PD-1基因或其配体基因在日本人群中对1型糖尿病（T1D）发病的贡献尚不清楚。我们首先筛选了日本人群中PD-1、PD-L1和PD-L2基因的多态性，然后研究了T1D患者与健康对照者的多态性频率。我们在这些基因中鉴定出26个多态性位点，然后在患者和对照组中集中分析23个次要等位基因频率大于5%的多态性，进行基因分型。因此，PD-1基因多态性数2、3、4、5、6、8的等位基因和基因型频率在患者与对照组之间存在一定差异，P < 0.05，经多次比较校正，差异无统计学意义。PD-L1或PD-L2基因中任何snp的等位基因或基因型频率在患者和对照组之间没有显示差异。PD-1中多态性数为2、3、4、5、6、8的估计单倍型的频率在患者与对照组之间存在显著差异（P = 0.00095）。通过荧光素酶测定对PD-1基因的每个单倍型的转录活性的体外评估没有显示单倍型之间的功能差异。综上所述，通过关联研究的遗传评价表明PD-1基因是日本人群发生T1D的易感基因。
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.