J Korean Neurosurg Soc.  2012 Jul;52(1):7-13. 10.3340/jkns.2012.52.1.7.

Association Study of Fibroblast Growth Factor 2 and Fibroblast Growth Factor Receptors Gene Polymorphism in Korean Ossification of the Posterior Longitudinal Ligament Patients

• Jun JK
• Kim SM

• KMID: 2190516
• DOI: http://doi.org/10.3340/jkns.2012.52.1.7

Abstract

OBJECTIVE
The aim of this study was to determine whether single nucleotide polymorphisms (SNPs) of fibroblast growth factor (FGF) 2 gene and fibroblast growth factor receptor (FGFR) genes are associated with ossification of the posterior longitudinal ligament (OPLL).
METHODS
A total of 157 patients with OPLL and 222 controls were recruited for a case control association study investigating the relationship between SNPs of FGF2, FGFR1, FGFR2 and OPLL. To identify the association among polymorphisms of FGF2 gene, FGFR1, FGFR2 genes and OPLL, the authors genotyped 9 SNPs of the genes (FGF2 : rs1476217, rs308395, rs308397, and rs3747676; FGFR1 : rs13317 and rs2467531; FGFR2 : rs755793, rs1047100, and rs3135831) using direct sequencing method. SNPs data were analyzed using the SNPStats, SNPAnalyzer, Haploview, and Helixtree programs.
RESULTS
Of the SNPs, a SNP (rs13317) in FGFR1 was significantly associated with the susceptibility of OPLL in the codominant (odds ratio=1.35, 95% confidence interval=1.01-1.81, p=0.048) and recessive model (odds ratio=2.00, 95% confidence interval=1.11-3.59, p=0.020). The analysis adjusted for associated condition showed that the SNP of rs1476217 (p=0.03), rs3747676 (p=0.01) polymorphisms in the FGF2 were associated with diffuse idiopathic skeletal hyperostosis (DISH) and rs1476217 (p=0.01) in the FGF2 was associated with ossification of the ligament flavum (OLF).
CONCLUSION
The results of the present study revealed that an FGFR1 SNP was significantly associated with OPLL and that a SNP in FGF2 was associated with conditions that were comorbid with OPLL (DISH and OLF).

Keyword

OPLL; FGF2 gene; FGFR 1 & 2 genes; Polymorphism

MeSH Terms

Case-Control Studies
Fibroblast Growth Factor 2
Fibroblast Growth Factors
Fibroblasts
Humans
Hyperostosis, Diffuse Idiopathic Skeletal
Ligaments
Longitudinal Ligaments
Polymorphism, Single Nucleotide
Receptors, Fibroblast Growth Factor
Receptors, Growth Factor
Fibroblast Growth Factor 2
Fibroblast Growth Factors
Receptors, Fibroblast Growth Factor
Receptors, Growth Factor

Figure

• 

  Fig. 1 Block and frequency of linkage disequilibrium (LD) of selected four SNPs in FGF2. SNP : single nucleotide polymorphism, FGF : fibroblast growth factor.

Reference

1. Chung WS, Nam DH, Jo DJ, Lee JH. Association of toll-like receptor 5 gene polymorphism with susceptibility to ossification of the posterior longitudinal ligament of the spine in Koean population. J Korean Neurosurg Soc. 2011; 49:8–12. PMID: 21494356.

2. Dunham-Ems SM, Lee YW, Stachowiak EK, Pudavar H, Claus P, Prasad PN, et al. Fibroblast growth factor receptor-1 (FGFR1) nuclear dynamics reveal a novel mechanism in transcription control. Mol Biol Cell. 2009; 20:2401–2412. PMID: 19261810.

3. Ellman MB, An HS, Muddasani P, Im HJ. Biological impact of the fibroblast growth factor family on articular cartilage and intervertebral disc homeostasis. Gene. 2008; 420:82–89. PMID: 18565695.

4. Horikoshi T, Maeda K, Kawaguchi Y, Chiba K, Mori K, Koshizuka Y, et al. A large-scale genetic association study of ossification of the posterior longitudinal ligament of the spine. Hum Genet. 2006; 119:611–616. PMID: 16609882.

5. Inamasu J, Guiot BH, Sachs DC. Ossification of the posterior longitudinal ligament: an update on its biology, epidemiology, and natural history. Neurosurgery. 2006; 58:1027–1039. discussion 1027-1039. PMID: 16723881.

6. Key GA. On paraplegia depending on the ligament of the spine. Guy Hospital Report. 1839; 3:17–34.

7. Kong Q, Ma X, Li F, Guo Z, Qi Q, Li W, et al. COL6A1 polymorphisms associated with ossification of the ligamentum flavum and ossification of the posterior longitudinal ligament. Spine (Phila Pa 1976). 2007; 32:2834–2838. PMID: 18246005.

8. Li H, Jiang LS, Dai LY. Hormones and growth factors in the pathogenesis of spinal ligament ossification. Eur Spine J. 2007; 16:1075–1084. PMID: 17426989.

9. Marie PJ. Fibroblast growth factor signaling controlling osteoblast differentiation. Gene. 2003; 316:23–32. PMID: 14563548.

10. Katoh M. Cancer genomics and genetics of FGFR2 (Review). Int J Oncol. 2008; 33:233–237. PMID: 18636142.

11. Murakami M, Simons M. Fibroblast growth factor regulation of neovascularization. Curr Opin Hematol. 2008; 15:215–220. PMID: 18391788.

12. Nakamura I, Ikegawa S, Okawa A, Okuda S, Koshizuka Y, Kawaguchi H, et al. Association of the human NPPS gene with ossification of the posterior longitudinal ligament of the spine (OPLL). Hum Genet. 1999; 104:492–497. PMID: 10453738.

13. Oppenheimer A. Calcification and ossification of vertebral ligaments (spondylitis ossificans ligamentosa). Radiology. 1942; 38:160–173.

14. Sakou T, Matsunaga S, Koga H. Recent progress in the study of pathogenesis of ossification of the posterior longitudinal ligament. J Orthop Sci. 2000; 5:310–315. PMID: 10982675.

15. Tsukimoto H. [On an autopsied case of compression myelopathy with a callus formation in the cervical spinal canal]. Nihon-Geka-Hokan. 1960; 29:1003–1007.

16. Wang H, Liu D, Yang Z, Tian B, Li J, Meng X, et al. Association of bone morphogenetic protein-2 gene polymorphisms with susceptibility to ossification of the posterior longitudinal ligament of the spine and its severity in Chinese patients. Eur Spine J. 2008; 17:956–964. PMID: 18389292.