A Putative Association of a Single Nucleotide Polymorphism in GPR126 with Aggressive Periodontitis in a Japanese Population.
A Putative Association of a Single Nucleotide Polymorphism in GPR126 with Aggressive Periodontitis in a Japanese Population.
复制标题
GPR126中单个核苷酸多态性与日本人群中侵略性牙周炎的推定关联。
DOI：
10.1371/journal.pone.0160765
复制
发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Murakami S
中科院分区：
文献类型：
--
作者：
Kitagaki J;Miyauchi S;Asano Y;Imai A;Kawai S;Michikami I;Yamashita M;Yamada S;Kitamura M;Murakami S
牙周炎是一种引起支持牙齿的牙周组织丧失的炎症性疾病。疾病易感性的快速进展形式牙周炎，侵袭性牙周炎（AgP），似乎是由遗传风险因素的影响。为了在日本人群中识别这些，我们对41名不相关的全身性或局部性AgP患者进行了全外显子组测序。我们发现AgP与g蛋白偶联受体126基因GPR126的单核苷酸多态性（SNP） rs536714306相关[c.3086]G > (p.Arg1029Gln)]。由于GPR126激活cAMP/PKA信号通路，我们对cAMP浓度进行了cAMP ELISA分析，发现rs536714306破坏了GPR126的信号交换激活。此外，将含有rs536714306的野生型或突变型GPR126转染人牙周韧带（HPDL）细胞后发现，野生型GPR126显著增加了骨唾液蛋白、骨桥蛋白和Runx2基因的mRNA表达，而突变型GPR126对这些钙化相关基因的表达没有影响。这些基因的表达增加是通过gpr126诱导骨形态发生蛋白-2、DNA结合抑制剂（id2）和ID4表达的增加。这些数据表明，GPR126可能通过调节HPDL细胞的分化，在维持牙周韧带组织的稳态中发挥重要作用。GPR126 SNP rs536714306对这种内稳态产生负面影响，导致AgP的发展，这表明它是日本人群中AgP的候选遗传危险因素。
Periodontitis is an inflammatory disease causing loss of tooth-supporting periodontal tissue. Disease susceptibility to the rapidly progressive form of periodontitis, aggressive periodontitis (AgP), appears to be influenced by genetic risk factors. To identify these in a Japanese population, we performed whole exome sequencing of 41 unrelated generalized or localized AgP patients. We found that AgP is putatively associated with single nucleotide polymorphism (SNP) rs536714306 in the G-protein coupled receptor 126 gene, GPR126 [c.3086 G>A (p.Arg1029Gln)]. Since GPR126 activates the cAMP/PKA signaling pathway, we performed cAMP ELISA analysis of cAMP concentrations, and found that rs536714306 impaired the signal transactivation of GPR126. Moreover, transfection of human periodontal ligament (HPDL) cells with wild-type or mutant GPR126 containing rs536714306 showed that wild-type GPR126 significantly increased the mRNA expression of bone sialoprotein, osteopontin, and Runx2 genes, while mutant GPR126 had no effect on the expression of these calcification-related genes. The increase in expression of these genes was through the GPR126-induced increase of bone morphogenic protein-2, inhibitor of DNA binding (ID) 2, and ID4 expression. These data indicate that GPR126 might be important in maintaining the homeostasis of periodontal ligament tissues through regulating the cytodifferentiation of HPDL cells. The GPR126 SNP rs536714306 negatively influences this homeostasis, leading to the development of AgP, suggesting that it is a candidate genetic risk factor for AgP in the Japanese population.