Recent evidence suggests that genetic studies may contribute to a better understanding of individual susceptibility to caries. Matrix metalloproteinases (MMPs) and their tissue inhibitors have been suggested to be involved in the caries process. The purpose of this study was to determine if polymorphisms in MMP2 (rs243865), MMP9 (rs17576), MMP13 (rs2252070), and TIMP2 (rs7501477) were associated with caries. Eligible unrelated children and adolescents were evaluated using a cross-sectional design. Data on oral health habits was obtained through a questionnaire and caries data was collected by clinical examination. Genotyping of the selected polymorphisms was carried out by real-time PCR. Allele and genotype frequencies were compared between individuals with and without caries experience. Of 505 subjects, 212 were caries-free and most subjects (61.2%) had mixed dentition. Allele frequency of MMP2, MMP13 and TIMP2 was different between caries-affected and caries-free individuals, with significant association for MMP13 (p = 0.004). Mutant allele carriers for MMP13 demonstrated a significantly decreased risk for caries (OR = 0.538, 95% CI 0.313–0.926); this result remained significant after adjustment for candidate genes, type of dentition and dietary factors. Allelic and genotype frequencies of the polymorphism in MMP9 were similar in caries-affected and caries-free individuals. Genetic variations in MMP13 may contribute to individual differences in caries susceptibility. Our findings reinforce that susceptibility to caries results from gene-environment interactions.

Keywords:
Dental caries, Genetic susceptibility, Matrix metalloproteinases, Matrix metalloproteinase inhibitors, polymorphisms
1.
Brew K, Nagase H: The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity. Biochim Biophys Acta 2010;1803:55–71.
2.
Caron C, Xue J, Sun X, Simmer JP, Bartlett JD: Gelatinase A (MMP-2) in developing tooth tissues and amelogenin hydrolysis. J Dent Res 2001;80:1660–1664.
3.
Chaussain-Miller C, Fioretti F, Goldberg M, Menashi S: The role of matrix metalloproteinases (MMPs) in human caries. J Dent Res 2006;85:22–32.
4.
Crouch E, Sage H, Bornstein P: Structural basis for apparent heterogeneity of collagens in human basement membranes: type IV procollagen contains two distinct chains. Proc Natl Acad Sci USA 1980;77:745–749.
5.
Deeley K, Letra A, Rose EK, Brandon CA, Resick JM, Marazita ML, Vieira AR: Possible association of amelogenin to high caries experience in a Guatemalan-Mayan population. Caries Res 2008;42:8–13.
6.
De Soet JJ, van Gemert-Schriks MC, Laine ML, van Amerongen WE, Morre SA, van Winkelhoff AJ: Host and microbiological factors related to dental caries development. Caries Res 2008;42:340–347.
7.
Fernandez-Cadenas I, Mendioroz M, Domingues-Montanari S, Del Rio-Espinola A, Delgado P, Ruiz A, Hernandez-Guillamon M, Giralt D, Chacon P, Navarro-Sobrino M, Ribo M, Molina CA, Alvarez-Sabin J, Rosell A, Montaner J: Leukoaraiosis is associated with genes regulating blood-brain barrier homeostasis in ischaemic stroke patients. Eur J Neurol 2011;18:826–835.
8.
Goldberg M, Septier D, Bourd K, Hall R, George A, Goldberg H, Menashi S: Immunohistochemical localization of MMP-2, MMP-9, TIMP-1, and TIMP-2 in the forming rat incisor. Connect Tissue Res 2003;44:143–153.
9.
Hannas AR, Pereira JC, Granjeiro JM, Tjaderhane L: The role of matrix metalloproteinases in the oral environment. Acta Odontol Scand 2007;65:1–13.
10.
Hernandez-Barrantes S, Toth M, Bernardo MM, Yurkova M, Gervasi DC, Raz Y, Sang QA, Fridman R: Binding of active (57 kDa) membrane type 1-matrix metalloproteinase (MT1-MMP) to tissue inhibitor of metalloproteinase (TIMP)-2 regulates MT1-MMP processing and pro-MMP-2 activation. J Biol Chem 2000;275:12080–12089.
11.
IBGE: Contagem da população. Instituto Brasileiro de Estatística, 2007.
12.
Inada M, Wang Y, Byrne MH, Rahman MU, Miyaura C, Lopez-Otin C, Krane SM: Critical roles for collagenase-3 (Mmp13) in development of growth plate cartilage and in endochondral ossification. Proc Natl Acad Sci USA 2004;101:17192–17197.
13.
Knauper V, Lopez-Otin C, Smith B, Knight G, Murphy G: Biochemical characterization of human collagenase-3. J Biol Chem 1996;271:1544–1550.
14.
Küchler EC, Tannure PN, Falagan-Lotsch P, Lopes TS, Granjeiro JM, Amorin LMF: Buccal cells DNA extraction to obtain high quality human genomic DNA suitable for polymorphism genotyping by PCR-RFLP and real time PCR. J Appl Oral Sci 2012, in press.
15.
Morris-Wiman J, Burch H, Basco E: Temporospatial distribution of matrix metalloproteinase and tissue inhibitors of matrix metalloproteinases during murine secondary palate morphogenesis. Anat Embryol (Berl) 2000;202:129–141.
16.
Ozturk A, Famili P, Vieira AR: The antimicrobial peptide DEFB1 is associated with caries. J Dent Res 2010;89:631–636.
17.
Paiva KB, Zambuzzi WF, Accorsi-Mendonca T, Taga R, Nunes FD, Sogayar MC, Granjeiro JM: Rat forming incisor requires a rigorous ECM remodeling modulated by MMP/RECK balance. J Mol Histol 2009;40:201–207.
18.
Patir A, Seymen F, Yildirim M, Deeley K, Cooper ME, Marazita ML, Vieira AR: Enamel formation genes are associated with high caries experience in Turkish children. Caries Res 2008;42:394–400.
19.
Peres RC, Camargo G, Mofatto LS, Cortellazzi KL, Santos MC, Nobre-dos-Santos M, Bergamaschi CC, Line SR: Association of polymorphisms in the carbonic anhydrase 6 gene with salivary buffer capacity, dental plaque pH, and caries index in children aged 7–9 years. Pharmacogenomics J 2010;10:114–149.
20.
Peterson NB, Beeghly-Fadiel A, Gao YT, Long J, Cai Q, Shu XO and Zheng W: Polymorphisms in tissue inhibitors of metalloproteinases-2 and -3 and breast cancer susceptibility and survival. Int J Cancer 2009;125:844–850.
21.
Ranade K, Chang MS, Ting CT, Pei D, Hsiao CF, Olivier M, Pesich R, Hebert J, Chen YD, Dzau VJ, Curb D, Olshen R, Risch N, Cox DR, Botstein D: High-throughput genotyping with single nucleotide polymorphisms. Genome Res 2001;11:1262–1268.
22.
Rodriguez-Lopez J, Perez-Pampin E, Gomez-Reino JJ, Gonzalez A: Regulatory polymorphisms in extracellular matrix protease genes and susceptibility to rheumatoid arthritis: a case-control study. Arthritis Res Ther 2006;8:R1.
23.
Sahlberg C, Reponen P, Tryggvason K, Thesleff I: Timp-1, -2 and -3 show coexpression with gelatinases A and B during mouse tooth morphogenesis. Eur J Oral Sci 1999;107:121–130.
24.
Shimada Y, Ichinose S, Sadr A, Burrow MF, Tagami J: Localization of matrix metalloproteinases (MMPs-2, 8, 9 and 20) in normal and carious dentine. Aust Dent J 2009;54:347–354.
25.
Shuler CF: Inherited risks for susceptibility to dental caries. J Dent Educ 2001;65:1038–1045.
26.
Singh R, Srivastava P, Srivastava A, Mittal RD: Matrix metalloproteinase (MMP-9 and MMP-2) gene polymorphisms influence allograft survival in renal transplant recipients. Nephrol Dial Transplant 2010;25:3393–3401.
27.
Slayton RL, Cooper ME, Marazita ML: Tuftelin, mutans streptococci, and dental caries susceptibility. J Dent Res 2005;84:711–714.
28.
Steffensen B, Wallon UM, Overall CM: Extracellular matrix binding properties of recombinant fibronectin type II-like modules of human 72-kDa gelatinase/type IV collagenase. High affinity binding to native type I collagen but not native type IV collagen. J Biol Chem 1995;270:11555–11566.
29.
Sulkala M, Paakkonen V, Larmas M, Salo T, Tjaderhane L: Matrix metalloproteinase-13 (MMP-13, collagenase-3) is highly expressed in human tooth pulp. Connect Tissue Res 2004;45:231–237.
30.
Sulkala M, Wahlgren J, Larmas M, Sorsa T, Teronen O, Salo T, Tjaderhane L: The effects of MMP inhibitors on human salivary MMP activity and caries progression in rats. J Dent Res 2001;80:1545–1549.
31.
Tannure PN, Costa Mde C, Küchler EC, Romanos HF, Granjeiro JM, Vieira AR: Caries experience in individuals with cleft lip and palate. Pediatr Dent 2012a;34:127–131.
32.
Tannure PN, Küchler EC, Lips A, Costa Mde C, Luiz RR, Granjeiro JM, Vieira AR: Genetic variation in MMP20 contributes to higher caries experience. J Dent 2012b;40:381–386.
33.
Tjaderhane L, Larjava H, Sorsa T, Uitto VJ, Larmas M, Salo T: The activation and function of host matrix metalloproteinases in dentin matrix breakdown in caries lesions. J Dent Res 1998;77:1622–1629.
34.
Toledano M, Nieto-Aguilar R, Osorio R, Campos A, Osorio E, Tay FR, Alaminos M: Differential expression of matrix metalloproteinase-2 in human coronal and radicular sound and carious dentine. J Dent 2010;38:635–640.
35.
van Strijp AJ, Jansen DC, DeGroot J, ten Cate JM, Everts V: Host-derived proteinases and degradation of dentine collagen in situ. Caries Res 2003;37:58–65.
36.
Yamagiwa H, Tokunaga K, Hayami T, Hatano H, Uchida M, Endo N, Takahashi HE: Expression of metalloproteinase-13 (collagenase-3) is induced during fracture healing in mice. Bone 1999;25:197–203.
37.
Yoshiba N, Yoshiba K, Stoetzel C, Perrin-Schmitt F, Cam Y, Ruch JV, Lesot H: Temporospatial gene expression and protein localization of matrix metalloproteinases and their inhibitors during mouse molar tooth development. Dev Dyn 2003;228:105–112.
38.
Zakhary GM, Clark RM, Bidichandani SI, Owen WL, Slayton RL, Levine M: Acidic proline-rich protein Db and caries in young children. J Dent Res 2007;86:1176–1180.
© 2012 S. Karger AG, Basel
2012
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.