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

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.

Identification of genetic risk factors of aggressive periodontitis using genomewide association studies in association with those of chronic periodontitis

“…We demonstrated that wild‐type SMPD3 upregulated calcification‐related genes, whereas its SNP rs145616324 did not. These results indicate that GPR126 rs536714306 and SMPD3 rs145616324 are genetic risk factors for AgP in a Japanese population and rs145616324 negatively regulates the cytodifferentiation of HPDL cells in vitro; therefore, we concluded that rs536714306 and rs145616324 associate with the pathogenesis and progression of Japanese AgP . However, these studies had many pitfalls.…”

“…Recently, our group identified two genetic risk factors for AgP, G protein‐coupled receptor 126 ( GPR126 ) and Sphingomyelin Phosphodiesterase 3 ( SMPD3 ), in a Japanese population. We performed whole‐exome sequencing of 44 unrelated AgP patients; however, because the number of subjects was small, these genetic variants did not reach genomewide significance: A P ‐value of GPR126 SNP rs536714306 was 2.20 × 10 −3 (OR of 9.09 and 95% CI of 1.64‐50.36) and of SMPD3 SNP rs145616324 was 1.42 × 10 −2 (OR of 1.17 and 95% CI of 1.17‐4.89) . To overcome this limitation, we performed functional analysis of these genetic variants.…”

Novel rare frameshift variation in aggressive periodontitis: Exomic and familial‐screening analysis

“…Most previous studies evaluated specific single nucleotide polymorphisms (SNPs) in a limited number of candidate genes and did not capture the complete genetic information on a particular region of interest . Because of these limitations, it is essential to carry out unbiased large‐scale analysis to identify novel disease‐associated genetic variants for AgP . The emergence of genome‐wide association studies (GWAS) using whole genome sequencing (WGS) or whole exome sequencing (WES) improves comprehensive, open‐ended, and hypothesis‐free studies.…”

“…The emergence of genome‐wide association studies (GWAS) using whole genome sequencing (WGS) or whole exome sequencing (WES) improves comprehensive, open‐ended, and hypothesis‐free studies. However, regarding AgP disease, scarce information has been provided …”

“…10,11 Because of these limitations, it is essential to carry out unbiased large-scale analysis to identify novel disease-associated genetic variants for AgP. 13,14 The emergence of genome-wide association studies (GWAS) using whole genome sequencing (WGS) or whole exome sequencing (WES) improves comprehensive, openended, and hypothesis-free studies. However, regarding AgP disease, scarce information has been provided.…”