A Putative Association of a Single Nucleotide Polymorphism in GPR126 With Aggressive Periodontitis in a Japanese Population

PLoS One. 2016 Aug 10;11(8):e0160765. doi: 10.1371/journal.pone.0160765. eCollection 2016.

Abstract

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.

MeSH terms

  • Adolescent
  • Adult
  • Aggressive Periodontitis / genetics*
  • Aggressive Periodontitis / metabolism
  • Asian Continental Ancestry Group / genetics
  • Cell Differentiation / genetics
  • Exome
  • Female
  • Genome-Wide Association Study
  • Humans
  • Male
  • Periodontal Ligament / cytology
  • Polymorphism, Single Nucleotide*
  • Receptors, G-Protein-Coupled / genetics*
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction / genetics
  • Young Adult

Substances

  • ADGRG6 protein, human
  • Receptors, G-Protein-Coupled

Grant support

This work was supported by KAKENHI Grants-in-Aid for Scientific Research (No. 15K11385 to Jirouta Kitagaki and 15H025789 to Shinya Murakami) from the Japan Society for the Promotion of Science.