Association of Functional Polymorphisms in Matrix Metalloproteinase-9 and Glutathione S-Transferase T1 Genes with Temporomandibular Disorders

Aims: To investigate the potential role of polymorphisms in matrix metalloproteinase-9 (MMP-9), glutathione S-transferase M1 (GSTM1) and T1 (GSTT1), and methylenetetrahydrofolate reductase (MTHFR) genes as risk factors for development of temporomandibular disorders (TMD) in a Serbian population. Methods: This case-control study included 282 subjects: 100 with TMD and 182 healthy controls. Genotyping was done by means of polymerase chain reaction (PCR)/restriction fragment length polymorphism (RFLP) for single nucleotide polymorphisms (SNPs) analysis (C-1562T MMP-9 and C677T MTHFR) or multiplex PCR and real-time PCR methods for deletion analysis (GSTM1, GSTT1) of DNA obtained from buccal swabs. The association of gene variants with TMD risk was determined by calculating odds ratios (OR) and their 95% confidence intervals (CI). Results: A statistically significant difference in genotype and allele frequencies was found between the TMD group and controls for the MMP-9 SNP. Heterozygotes (CT) were significantly more frequent in the TMD group than in the control group and carriers of the T allele had an approximately twofold increase of TMD risk (OR = 2.13, 95% CI = 1.24–3.67, P = .005). The null GSTT1 genotype as well as the combined non-null GSTM1/null GSTT1 were associated with lower risk of TMD (OR = 0.28, CI = 0.10–0.74, P = .004 and OR = 0.16, CI = 0.03–0.58, P < .001, respectively). GSTM1 alone and MTHFR polymorphisms did not show an association with TMD. Conclusion: The C-1562T SNP in the promoter region of the MMP-9 gene, the GSTT1 null, as well as the combined GSTM1 non-null and GSTT1 null genotypes are modulators of TMD risk in a Serbian population.

genetic polymorphisms; GSTs; MMP; MTHFR; temporomandibular disorders

1. Oakley M, Vieira AR. The many faces of the genetics contribution to temporomandibular joint disorder. Orthod Craniofac Res 2008;11:125–135.

2. Okeson JP. Management of Temporomandibular Disorders and Occlusion. St Louis, Mo: CV Mosby, 1998:169–171.

3. Gonçalves DA, Dal Fabbro AL, Campos JA, Bigal ME, Speciali JG. Symptoms of temporomandibular disorders in the population: An epidemiological study. J Orofac Pain 2010;24:270–278.

4. Schmid-Schwap M, Bristela M, Kundi M, Piehslinger E. Sex-specific differences in patients with temporomandibular disor-ders. J Orofac Pain 2013;27:42–50.

5. Warren MP, Fried JL. Temporomandibular disorders and hormones in women. Cells Tissues Organs 2001;169:187–192.

6. Wang J, Chao Y, Wan Q, Zhu Z. The possible role of estrogen in the incidence of temporomandibular disorders. Med Hypotheses 2008;71:564–567.

7. Seligman DA, Pullinger AG. The role of functional occlusal relationships in temporomandibular disorders: A review. J Craniomandib Disord 1991;5:265–279.

8. Rugh JD, Solberg WK. Psychological implications in temporo-mandibular pain and dysfunction. Oral Sci Rev 1976;7:3–30.

9. Eversole LR, Stone CE, Matheson D, Kaplan H. Psychometric profiles and facial pain. Oral Surg Oral Med Oral Pathol 1985; 60:269–274.

10. Smythe HA. Temporomandibular joint disorder and other medically unexplained symptoms in rheumatoid arthritis, osteoarthritis, and fibromyalgia. J Rheumatol 2005;32:2288–2290.

11. Suma S, Veerendra Kumar B. Temporomandibular disorders and functional somatic syndromes: Deliberations for the dentist. Indian J Dent Res 2012;23:529–536.

12. Durham J, Steele JG, Wassell RW, Exley C. Living with uncertainty: Temporomandibular disorders. J Dent Res 2010;89: 827–830.

13. Leonardi R, Caltabiano M, Cascone P, Loreto C. Expression of heat shock protein 27 (HSP27) in human temporomandibular joint discs of patients with internal derangement. J Craniofac Surg 2002;13:713–717; discussion 8–20.

14. Leonardi R, Villari L, Piacentini C, et al. Immunolocalization of vimentin and alphasmooth muscle actin in dysfunctional human temporomandibular joint disc samples. J Oral Rehabil 2002;29: 282–286.

15. Leonardi R, Almeida LE, Trevilatto PC, Loreto C. Occurrence and regional distribution of TRAIL and DR5 on temporoman-dibular joint discs: Comparison of disc derangement with and without reduction. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;109:244–251.

16. Loreto C, Leonardi R, Musumeci G, Pannone G, Castorina S. An ex vivo study on immunohistochemical localization of MMP-7 and MMP-9 in temporomandibular joint discs with internal derangement. Eur J Histochem 2013;57:e12.

17. Ricks ML, Farrell JT, Falk DJ, et al. Osteoarthritis in tem-poromandibular joint of Col2a1 mutant mice. Arch Oral Biol 2013;58:1092–1099.

18. Huang B, Takahashi K, Sakata T, et al. Increased risk of tem-poromandibular joint closed lock: A case-control study of ANKH polymorphisms. PLoS One 2011;6:e25503.

19. Meloto BC, Smith S, Maixner W, Seltzer Ze, Diatchenko L. Genetic risk factors for orofacial pain: Insights from human experimental studies. In: Sessle BJ (ed). Orofacial Pain: Recent Advances in Assessment, Management, and Understanding of Mechanisms. Washington, DC: IASP Press, 2014:455–477.

20. Seltzer Z, Dorfman R. Identifying genetic and environmental risk factors for chronic orofacial pain syndromes: Human models. J Orofac Pain 2004;18:311–317.

21. Smith SB, Maixner DW, Greenspan JD, et al. Potential genetic risk factors for chronic TMD: Genetic associations from the OPPERA case control study. J Pain 2011;12(11 Suppl): T92–T101.

22. Smith SB, Mir E, Bair E, et al. Genetic variants associated with development of TMD and its intermediate phenotypes: The genetic architecture of TMD in the OPPERA prospective cohort study. J Pain 2013;14(12 Suppl):T91–101.e1–e3.

23. Michelotti A, Liguori R, Toriello M, et al. Catechol-O-methyltransferase (COMT) gene polymorphisms as risk factor in temporomandibular disorders patients from Southern Italy. Clin J Pain 2014;30:129–133.

24. Schwahn C, Grabe HJ, Meyer zu Schwabedissen H, et al. The effect of catechol-O-methyltransferase polymorphisms on pain is modified by depressive symptoms. Eur J Pain 2012; 16:878–889.

25. Mutlu N, Erdal ME, Herken H, Oz G, Bayazit YA. T102C poly-morphism of the 5-HT2A receptor gene may be associated with temporomandibular dysfunction. Oral Dis 2004;10:349–352.

26. Kang SC, Lee DG, Choi JH, et al. Association between es-trogen receptor polymorphism and pain susceptibility in female temporomandibular joint osteoarthritis patients. Int J Oral Maxillofac Surg 2007;36:391–394.

27. Planello AC, Campos MI, Meloto CB, et al. Association of matrix metalloproteinase gene polymorphism with temporoman-dibular joint degeneration. Eur J Oral Sci 2011;119:1–6.

28. Aneiros-Guerrero A, Lendinez AM, Palomares AR, et al. Genetic polymorphisms in folate pathway enzymes, DRD4 and GSTM1 are related to temporomandibular disorder. BMC Med Genet 2011;12:75.

29. Fernandes KS, Brum DG, Palei AC, et al. Functional MMP-9 polymorphisms modulate plasma MMP-9 levels in multiple sclerosis patients. J Neuroimmunol 2012;249:56–59.

30. Tew KD, Townsend DM. Glutathione-s-transferases as determinants of cell survival and death. Antioxid Redox Signal 2012;17:1728–1737.

31. Hayes JD, Strange RC. Glutathione S-transferase polymor-phisms and their biological consequences. Pharmacology 2000;61:154–166.

32. Eaton DL, Bammler TK. Concise review of the glutathione S- transferases and their significance to toxicology. Toxicol Sci 1999;49:156–164.

33. Strange RC, Spiteri MA, Ramachandran S, Fryer AA. Glutathione-S-transferase family of enzymes. Mutat Res 2001; 482:21–26.

34. Friso S, Choi SW. Gene-nutrient interactions in one-carbon metabolism. Curr Drug Metab 2005;6:37–46.

35. Ho V, Massey TE, King WD. Effects of methionine synthase and methylenetetrahydrofolate reductase gene polymorphisms on markers of one-carbon metabolism. Genes Nutr 2013; 8:571–580.

36. Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: A common mutation in methylenetet-rahydrofolate reductase. Nat Genet 1995;10:111–113.

37. Dworkin SF, LeResche L. Research diagnostic criteria for temporomandibular disorders: Review, criteria, examinations and specifications, critique. J Craniomandib Disord 1992;6: 301–355.

38. Ferrand PE, Parry S, Sammel M, et al. A polymorphism in the matrix metalloproteinase-9 promoter is associated with increased risk of preterm premature rupture of membranes in African Americans. Mol Hum Reprod 2002;8:494–501.

39. Voso MT, D’Alo’ F, Putzulu R, et al. Negative prognostic value of glutathione S-transferase (GSTM1 and GSTT1) deletions in adult acute myeloid leukemia. Blood 2002;100:2703–2707.

40. Saiki RK, Gelfand DH, Stoffel S, et al. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 1988;239(4839):487–491.

41. Campbell MJ, Machin D, Walters SJ. Medical Statistics: A Textbook for the Health Sciences, ed 4. Chichester, UK: Wiley, 2007.

42. Kontogiorgis CA, Papaioannou P, Hadjipavlou-Litina DJ. Matrix metalloproteinase inhibitors: A review on pharmacophore mapping and (Q)SARs results. Curr Med Chem 2005; 12:339–355.

43. Taskin N, Ulucan K, Degin G, et al. [Investigation of the MMP1 and MMP3 promoter polymorphisms in temporomandibular joint disorder.] J Cell Mol Biol 2011;9:63–68.

44. Sun ZM, Miao L, Zhang YG, Ming L. Association between the- 1562 C/T polymorphism of matrix metalloproteinase-9 gene and lumbar disc disease in the young adult population in North China. Connect Tissue Res 2009;50:181–185.

45. Tang ST, Wang CJ, Tang HQ, Zhang Q, Wang Y. Evaluation of glutathione S-transferase genetic variants affecting type 2 diabetes susceptibility: A meta-analysis. Gene 2013;530: 301–308.

46. Piacentini S, Polimanti R, Squitti R, et al. GSTM1 null genotype as risk factor for late-onset Alzheimer’s disease in Italian patients. J Neurol Sci 2012;317:137–140.

47. Wang X, Li W, Liu W, et al. GSTM1 and GSTT1 gene polymorphisms as major risk factors for bronchopulmonary dysplasia in a Chinese Han population. Gene 2014;533:48–51.

48. Santl Letonja M, Letonja M, Ikolajevic´-Starcevi´ JN, Petrovic D. Association of manganese superoxide dismutase and glutathi-one S-transferases genotypes with carotid atherosclerosis in patients with diabetes mellitus type 2. Int Angiol 2012;31:33–41.

49. Bennett RM. The fibromyalgia syndrome. In: Kelley WN, Haris ED, Ruddy S, Sledge CB (eds). Textbook of Rheumatology. Philadelphia: Saunders, 1997:511–519.

50. De Luca C, Raskovic D, Pacifico V, Thai JC, Korkina L. The search for reliable biomarkers of disease in multiple chemical sensitivity and other environmental intolerances. Int J Environ Res Public Health 2011;8:2770–2797.

51. Gremillion HA. Multidisciplinary diagnosis and management of orofacial pain. Gen Dent 2002;50:178–186; quiz 87–88.

52. Singh N, Sinha N, Kumar S, Pandey CM, Agrawal S. Glutathione S-transferase gene polymorphism as a suscepti-bility factor for acute myocardial infarction and smoking in the North Indian population. Cardiology 2011;118:16–21.

53. Bekris LM, Shephard C, Peterson M, et al. Glutathione-s-transferase M1 and T1 polymorphisms and associations with type 1 diabetes age-at-onset. Autoimmunity 2005;38: 567–575.

54. Blom HJ, Smulders Y. Overview of homocysteine and folate metabolism. With special references to cardiovascular disease and neural tube defects. J Inherit Metab Dis 2011;34:75–81.

55. Mehra P, Wolford LM. Serum nutrient deficiencies in the patient with complex temporomandibular joint problems. Proc (Bayl Univ Med Cent) 2008;21:243–247.