Skip to main content
SpringerLink
Log in

Quantitative evaluation of the relationship between COMP promoter methylation and the susceptibility and curve progression of adolescent idiopathic scoliosis

  • Original Article
  • Published:
European Spine Journal Aims and scope Submit manuscript

Abstract

Purpose

The cartilage oligomeric matrix protein (COMP) was reported to be down-regulated in adolescent idiopathic scoliosis (AIS). The purposes of the study were to evaluate the roles of COMP promoter methylation on the abnormal gene expression and the epigenetic phenotype in AIS.

Methods

DNA samples of 50 AIS patients and 50 healthy controls were analyzed. Five CpG sites of COMP gene were amplified and sequenced using the polymerase chain reaction (PCR) and the pyrophosphate sequencing technology, while the COMP gene expression was evaluated using real-time PCR. Comparisons were analyzed with the Chi-square test and independent t test. Pearson coefficients of correlation were used to evaluate the association between gene methylation and clinical phenotypes.

Results

The average COMP gene promoter methylation of the AIS and control groups was 12.26 ± 2.36 and 8.76 ± 1.94 (p < 0.0001), and correspondingly the relative expression of COMP gene expression was 0.52 ± 0.12 and 1.16 ± 0.52 (p < 0.001), respectively. The correlation analysis showed significantly negative correlation between methylation level and gene expression (p < 0.0001). The comparison analysis between AIS patients with positive and negative methylation showed significant difference in chronological age (p < 0.001) and Cobb angle of main curve (p = 0.011). The methylation level of the COMP promoters was significantly correlated with Cobb angle of main curve and age (p < 0.0001) among the five CpG sites.

Conclusions

AIS patients had significantly high COMP promoter methylation and low gene expression. Positive and high COMP promoter methylation was correlated with young age and high Cobb angle of main curve. Therefore, COMP gene promoter methylation may provide significant prognostic information in predicting the susceptibility and curve progression of AIS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Weinstein SL, Dolan LA, Cheng JC, Danielsson A, Morcuende JA (2008) Adolescent idiopathic scoliosis. Lancet 371:1527–1537. doi:10.1016/s0140-6736(08)60658-3

    Article  PubMed  Google Scholar 

  2. Weinstein SL, Dolan LA, Wright JG, Dobbs MB (2013) Effects of bracing in adolescents with idiopathic scoliosis. N Engl J Med 369:1512–1521. doi:10.1056/NEJMoa1307337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Zhu Z, Tang NL, Xu L, Qin X, Mao S, Song Y, Liu L, Li F, Liu P, Yi L, Chang J, Jiang L, Ng BK, Shi B, Zhang W, Qiao J, Sun X, Qiu X, Wang Z, Wang F, Xie D, Chen L, Chen Z, Jin M, Han X, Hu Z, Zhang Z, Liu Z, Zhu F, Qian BP, Yu Y, Wang B, Lee KM, Lee WY, Lam TP, Qiu Y, Cheng JC (2015) Genome-wide association study identifies new susceptibility loci for adolescent idiopathic scoliosis in Chinese girls. Nat Commun 6:8355. doi:10.1038/ncomms9355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Qiu XS, Tang NL, Yeung HY, Lee KM, Hung VW, Ng BK, Ma SL, Kwok RH, Qin L, Qiu Y, Cheng JC (2007) Melatonin receptor 1B (MTNR1B) gene polymorphism is associated with the occurrence of adolescent idiopathic scoliosis. Spine 32:1748–1753. doi:10.1097/BRS.0b013e3180b9f0ff

    Article  PubMed  Google Scholar 

  5. Xu L, Qiu X, Sun X, Mao S, Liu Z, Qiao J, Qiu Y (2011) Potential genetic markers predicting the outcome of brace treatment in patients with adolescent idiopathic scoliosis. Eur Spine J 20:1757–1764. doi:10.1007/s00586-011-1874-7

    Article  PubMed  PubMed Central  Google Scholar 

  6. Wu J, Qiu Y, Zhang L, Sun Q, Qiu X, He Y (2006) Association of estrogen receptor gene polymorphisms with susceptibility to adolescent idiopathic scoliosis. Spine 31:1131–1136. doi:10.1097/01.brs.0000216603.91330.6f

    Article  PubMed  Google Scholar 

  7. Inoue M, Minami S, Nakata Y, Kitahara H, Otsuka Y, Isobe K, Takaso M, Tokunaga M, Nishikawa S, Maruta T, Moriya H (2002) Association between estrogen receptor gene polymorphisms and curve severity of idiopathic scoliosis. Spine 27:2357–2362. doi:10.1097/01.brs.0000030305.30361.27

    Article  PubMed  Google Scholar 

  8. Chen Z, Tang NL, Cao X, Qiao D, Yi L, Cheng JC, Qiu Y (2009) Promoter polymorphism of matrilin-1 gene predisposes to adolescent idiopathic scoliosis in a Chinese population. Eur J Hum Genet EJHG 17:525–532. doi:10.1038/ejhg.2008.203

    Article  PubMed  Google Scholar 

  9. Burwell RG, Dangerfield PH, Moulton A, Grivas TB (2011) Adolescent idiopathic scoliosis (AIS), environment, exposome and epigenetics: a molecular perspective of postnatal normal spinal growth and the etiopathogenesis of AIS with consideration of a network approach and possible implications for medical therapy. Scoliosis 6:26. doi:10.1186/1748-7161-6-26

    Article  PubMed  PubMed Central  Google Scholar 

  10. Talens RP, Boomsma DI, Tobi EW, Kremer D, Jukema JW, Willemsen G, Putter H, Slagboom PE, Heijmans BT (2010) Variation, patterns, and temporal stability of DNA methylation: considerations for epigenetic epidemiology. FASEB J 24:3135–3144. doi:10.1096/fj.09-150490

    Article  CAS  PubMed  Google Scholar 

  11. Posey KL, Alcorn JL, Hecht JT (2014) Pseudoachondroplasia/COMP—translating from the bench to the bedside. Matrix Biol J Int Soc Matrix Biol 37C:167–173. doi:10.1016/j.matbio.2014.05.006

    Article  Google Scholar 

  12. Briggs MD, Hoffman SM, King LM, Olsen AS, Mohrenweiser H, Leroy JG, Mortier GR, Rimoin DL, Lachman RS, Gaines ES et al (1995) Pseudoachondroplasia and multiple epiphyseal dysplasia due to mutations in the cartilage oligomeric matrix protein gene. Nat Genet 10:330–336. doi:10.1038/ng0795-330

    Article  CAS  PubMed  Google Scholar 

  13. Hecht JT, Nelson LD, Crowder E, Wang Y, Elder FF, Harrison WR, Francomano CA, Prange CK, Lennon GG, Deere M et al (1995) Mutations in exon 17B of cartilage oligomeric matrix protein (COMP) cause pseudoachondroplasia. Nat Genet 10:325–329. doi:10.1038/ng0795-325

    Article  CAS  PubMed  Google Scholar 

  14. Hecht JT, Makitie O, Hayes E, Haynes R, Susic M, Montufar-Solis D, Duke PJ, Cole WG (2004) Chondrocyte cell death and intracellular distribution of COMP and type IX collagen in the pseudoachondroplasia growth plate. J Orthop Res 22:759–767. doi:10.1016/j.orthres.2003.11.010

    Article  CAS  PubMed  Google Scholar 

  15. Fendri K, Patten SA, Kaufman GN, Zaouter C, Parent S, Grimard G, Edery P, Moldovan F (2013) Microarray expression profiling identifies genes with altered expression in adolescent idiopathic scoliosis. Eur Spine J 22:1300–1311. doi:10.1007/s00586-013-2728-2

    Article  PubMed  PubMed Central  Google Scholar 

  16. Fendri K, Moldovan F (2011) Potential role of COMP as a biomarker for adolescent idiopathic scoliosis. Med Hypotheses 76:762–763. doi:10.1016/j.mehy.2011.01.038

    Article  CAS  PubMed  Google Scholar 

  17. Gerdhem P, Topalis C, Grauers A, Stubendorff J, Ohlin A, Karlsson KM (2015) Serum level of cartilage oligomeric matrix protein is lower in children with idiopathic scoliosis than in non-scoliotic controls. Eur Spine J 24:256–261. doi:10.1007/s00586-014-3691-2

    Article  CAS  PubMed  Google Scholar 

  18. Wong CC, Caspi A, Williams B, Craig IW, Houts R, Ambler A, Moffitt TE, Mill J (2010) A longitudinal study of epigenetic variation in twins. Epigenetics 5:516–526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cheng J, Wang Y, Zhou K, Wang L, Li J, Zhuang Q, Xu X, Xu L, Zhang K, Dai D, Zheng R, Li G, Zhang A, Gao S, Duan S (2014) Male-specific association between dopamine receptor D4 gene methylation and schizophrenia. PLoS One 9:e89128. doi:10.1371/journal.pone.0089128

    Article  PubMed  PubMed Central  Google Scholar 

  20. Bornstein P (1992) Thrombospondins: structure and regulation of expression. FASEB J 6:3290–3299

    Article  CAS  PubMed  Google Scholar 

  21. DiCesare P, Hauser N, Lehman D, Pasumarti S, Paulsson M (1994) Cartilage oligomeric matrix protein (COMP) is an abundant component of tendon. FEBS Lett 354:237–240

    Article  CAS  PubMed  Google Scholar 

  22. Kipnes J, Carlberg AL, Loredo GA, Lawler J, Tuan RS, Hall DJ (2003) Effect of cartilage oligomeric matrix protein on mesenchymal chondrogenesis in vitro. Osteoarthr Cartil 11:442–454

    Article  CAS  PubMed  Google Scholar 

  23. Chen FH, Thomas AO, Hecht JT, Goldring MB, Lawler J (2005) Cartilage oligomeric matrix protein/thrombospondin 5 supports chondrocyte attachment through interaction with integrins. J Biol Chem 280:32655–32661. doi:10.1074/jbc.M504778200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Otteby KE, Holmquist E, Saxne T, Heinegard D, Hesselstrand R, Blom AM (2013) Cartilage oligomeric matrix protein-induced complement activation in systemic sclerosis. Arthritis Res Ther 15:R215. doi:10.1186/ar4410

    Article  PubMed  PubMed Central  Google Scholar 

  25. Briggs MD, Chapman KL (2002) Pseudoachondroplasia and multiple epiphyseal dysplasia: mutation review, molecular interactions, and genotype to phenotype correlations. Hum Mutat 19:465–478. doi:10.1002/humu.10066

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (Grant no. 81301603) and the Nanjing Medical Science and Technique Development Foundation (QRX17125).

Author information

Authors and Affiliations

  1. Department of Spine Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Zhongshan Road 321, Nanjing, 210008, China

    Sai-hu Mao, Bang-ping Qian, Benlong Shi, Ze-zhang Zhu & Yong Qiu

Authors
  1. Sai-hu Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bang-ping Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Benlong Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ze-zhang Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yong Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bang-ping Qian.

Ethics declarations

Conflict of interest

All authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mao, Sh., Qian, Bp., Shi, B. et al. Quantitative evaluation of the relationship between COMP promoter methylation and the susceptibility and curve progression of adolescent idiopathic scoliosis. Eur Spine J 27, 272–277 (2018). https://doi.org/10.1007/s00586-017-5309-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00586-017-5309-y

Keywords

Search

Navigation