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Salivary protein polymorphisms and risk of dental caries: a systematic review

Abstract

Dental caries is an oral pathology associated with both lifestyle and genetic factors. The caries process can be influenced by salivary composition, which includes ions and proteins. Studies have described associations between salivary protein polymorphisms and dental caries experience, while others have shown no association with salivary proteins genetic variability. The aim of this study is to assess the influence of salivary protein polymorphisms on the risk of dental caries by means of a systematic review of the current literature. An electronic search was performed in PubMed, Scopus, and Virtual Health Library. The following search terms were used: “dental caries susceptibility,” “dental caries,” “polymorphism, genetics,” “saliva,” “proteins,” and “peptides.” Related MeSH headings and free terms were included. The inclusion criteria comprised clinical investigations of subjects with and without caries. After application of these eligibility criteria, the selected articles were qualified by assessing their methodological quality. Initially, 338 articles were identified from the electronic databases after exclusion of duplicates. Exclusion criteria eliminated 322 articles, and 16 remained for evaluation. Eleven articles found a consistent association between salivary protein polymorphisms and risk of dental caries, for proteins related to antimicrobial activity (beta defensin 1 and lysozyme-like protein), pH control (carbonic anhydrase VI), and bacterial colonization/adhesion (lactotransferrin, mucin, and proline-rich protein Db). This systematic review demonstrated an association between genetic polymorphisms and risk of dental caries for most of the salivary proteins.

Dental Caries; Polymorphism, Genetic; Saliva; Proteins

Introduction

Dental caries is the most prevalent human infectious oral disease and is linked to both lifestyle and socioeconomic and genetic factors,11. Luna ACA, Rodrigues MJ, Menezes VA, Marques KMG, Santos FA. Caries prevalence and socioeconomic factors in children with sickle cell anemia. Braz Oral Res. 2012;26(1):43-9. https://doi.org/10.1590/S1806-83242012000100008
https://doi.org/10.1590/S1806-8324201200...
as well as to characteristics of the oral environment.22. Hara AT, Zero DT. The caries environment: saliva, pellicle, diet, and hard tissue ultrastructure. Dent Clin North Am. 2010;54(3):455-67. https://doi.org/10.1016/j.cden.2010.03.008
https://doi.org/10.1016/j.cden.2010.03.0...
Tooth surface colonization by cariogenic microorganisms is initiated by their interaction with proteins in the acquired pellicle,33. Lagerlöf F, Oliveby A. Caries-protective factors in saliva. Adv Dent Res. 1994;8(2):229-38. https://doi.org/10.1177/08959374940080021601
https://doi.org/10.1177/0895937494008002...
and in vitro studies have shown that salivary proteins can interact with oral bacteria in different ways. Proteins such as lysozymes, interleukins, mucins, and lactotransferrin (LTF) can promote cell aggregation, inhibition, and/or bacterial adherence.44. Van Nieuw Amerongen A, Bolscher JGM, Veerman ECI. Salivary proteins: protective and diagnostic value in cariology? Caries Res. 2004;38(3):247-53. https://doi.org/10.1159/000077762
https://doi.org/10.1159/000077762...
,55. Kidd EAM, Fejerskov O. What constitutes dental caries? Histopathology of carious enamel and dentin related to the action of cariogenic biofilms. J Dent Res. 2004;83 Spec No:C(Spe No):C35-8. https://doi.org/10.1177/154405910408301s07
https://doi.org/10.1177/154405910408301s...
,66. Cogulu D, Onay H, Ozdemir Y, I Aslan G, Ozkinay F, Kutukculer N et al. Associations of interleukin (IL)-1β, IL-1 receptor antagonist, and IL-10 with dental caries. J Oral Sci. 2015;57(1):31-6. https://doi.org/10.2334/josnusd.57.31
https://doi.org/10.2334/josnusd.57.31...
,77. Andrade FB, Oliveira JC, Yoshie MT, Guimarães BM, Gonçalves RB, Schwarcz WD. Antimicrobial activity and synergism of lactoferrin and lysozyme against cariogenic microorganisms. Braz Dent J. 2014;25(2):165-9. https://doi.org/10.1590/0103-6440201302257
https://doi.org/10.1590/0103-64402013022...
Other proteins, such as beta defensins, have direct antibacterial effects.88. Dale BA, Tao R, Kimball JR, Jurevic RJ. Oral antimicrobial peptides and biological control of caries. BMC Oral Health. 2006;6 Suppl 1:S13. https://doi.org/10.1186/1472-6831-6-S1-S13
https://doi.org/10.1186/1472-6831-6-S1-S...
Therefore, studies of salivary proteins and peptides indicate that these substances have diagnostic and interventional potential in several clinical situations,44. Van Nieuw Amerongen A, Bolscher JGM, Veerman ECI. Salivary proteins: protective and diagnostic value in cariology? Caries Res. 2004;38(3):247-53. https://doi.org/10.1159/000077762
https://doi.org/10.1159/000077762...
which may allow the development of prevention programs or individualized treatment.99. Prokopovic V, Popovic M, Andjelkovic U, Marsavelski A, Raskovic B, Gavrovic-Jankulovic M et al. Isolation, biochemical characterization and anti-bacterial activity of BPIFA2 protein. Arch Oral Biol. 2014;59(3):302-9. https://doi.org/10.1016/j.archoralbio.2013.12.005
https://doi.org/10.1016/j.archoralbio.20...

Given the role of salivary proteins in caries pathophysiology, their related genes may also be strong candidates for explaining genetic variation in caries experience in human populations. However, the boom of genetic association studies in recent decades has given rise to controversy and conflicting or irreproducible results, mainly due to differences in study design, statistical analysis, and interpretation of findings.1010. Vieira AR, Modesto A, Marazita ML. Caries: review of human genetics research. Caries Res. 2014;48(5):491-506. https://doi.org/10.1159/000358333
https://doi.org/10.1159/000358333...
,1111. Neale BM, Sham PC. The future of association studies: gene-based analysis and replication. Am J Hum Genet. 2004;75(3):353-62. https://doi.org/10.1086/423901
https://doi.org/10.1086/423901...
Actually, in the context of salivary proteins and caries, while some results suggest an association between polymorphisms and caries susceptibility,1212. Pol J. [Association of the polymorphism of MUC7 gene encoding the low-molecular-weight mucin MG2 with susceptibility to caries]. Ann Acad Med Stetin. 2011;57(2):85-91. Polish.,1313. Azevedo LF, Pecharki GD, Brancher JA, Cordeiro CA, Medeiros KG, Antunes AA et al. Analysis of the association between lactotransferrin (LTF) gene polymorphism and dental caries. J Appl Oral Sci. 2010;18(2):166-70. https://doi.org/10.1590/S1678-77572010000200011
https://doi.org/10.1590/S1678-7757201000...
other studies have not identified such associations.1414. Brancher JA, Pecharki GD, Doetzer AD, Medeiros KG, Cordeiro Junior CA, Sotomaior VS et al. Analysis of polymorphisms in the lactotransferrin gene promoter and dental caries. Int J Dent. 2011;571726. https://doi.org/10.1155/2011/571726
https://doi.org/10.1155/2011/571726...
,1515. Yarat A, Ozturk LK, Ulucan K, Akyuz S, Atala H, Isbir T. Carbonic anhydrase VI exon 2 genetic polymorphism in Turkish subjects with low caries experience (preliminary study). In Vivo. 2011;25(6):941-4. In order to shed some light on this issue, the present work aimed to systematically assess the available literature to report and discuss the main findings contributing to the focused question: are salivary protein polymorphisms a risk factor for dental caries?

Methodology

Search strategy

This systematic review was registered in PROSPERO database (CRD42016036030) and was conducted based on the guidelines of the Prisma Statement (www.prismastatement.org). An electronic search was conducted in the PubMed, Scopus and Virtual Health Library (BVS) databases. The following MeSH terms (Medical Subject Headings) (www.nlm.nih.gov/mesh/meshhome.html) were used in the search: “dental caries susceptibility,” “dental caries,” “polymorphism, genetic,” “saliva,” “proteins,” and “peptides.” Furthermore, MeSH synonyms, related terms, and free terms were also used, including the main salivary proteins cited in the literature1616. Levine MJ. Salivary macromolecules. A structure/function synopsis. Ann N Y Acad Sci. 1993;694:11-6. https://doi.org/10.1111/j.1749-6632.1993.tb18337.x
https://doi.org/10.1111/j.1749-6632.1993...
(Figure 1). A broad search was conducted for papers published before March 18, 2016.

Figure 1
Terms for each database search strategy

Eligibility criteria

The inclusion criteria outline articles written in any language according to the population, exposure, comparator, outcome, and study design (PECOS), where:

  1. Population (P): healthy humans who were not taking any medication that could affect salivary composition;

  2. Exposure (E): involvement of salivary protein polymorphisms in dental caries;

  3. Comparator (C): individuals with and without caries or individuals with high or low caries experience;

  4. Outcome (O): dental caries in primary or permanent dentition;

  5. Study design (S): Clinical trials, case-control studies, cross-sectional studies, or cohort studies published in scientific journals.

Exclusion criteria were as follows: case reports, review articles, book chapters, theses, guidelines, and in vitro studies. Articles that did not evaluate salivary protein polymorphisms through a molecular biology approach or did not evaluate caries experience by comparing groups with low and high caries experience were also excluded.

Study selection and quality assessment

Two of the authors selected abstracts according to the above criteria, and the classification agreement was checked for the randomly selected 10% of the publications with a kappa statistic of 0.97. Any disagreement was discussed and solved by consensus or discussion with a third author. After selection of eligible abstracts, the respective full articles were read.

Quality assessment and bias control were performed at the methodological level for genetic polymorphism studies, according to a previous work,1717. Clark MF, Baudouin SV. A systematic review of the quality of genetic association studies in human sepsis. Intensive Care Med. 2006;32(11):1706-12. https://doi.org/10.1007/s00134-006-0327-y
https://doi.org/10.1007/s00134-006-0327-...
based on an 11-point scoring sheet (Figure 2). A final quality score was obtained by sum of all components, ranging from 0 to 11, and a decision was made about whether the methods were appropriate or not for producing useful information. Studies with at least seven items were considered to have “low risk of bias” and high level of evidence.

Figure 2
Criteria for quality assessment of the selected articles, adapted from1717. Clark MF, Baudouin SV. A systematic review of the quality of genetic association studies in human sepsis. Intensive Care Med. 2006;32(11):1706-12. https://doi.org/10.1007/s00134-006-0327-y
https://doi.org/10.1007/s00134-006-0327-...
.

Data collection

The data were organized according to different categories, such as study population, sample size and age, caries index (DMFT – Decayed, Missing, Filled Teeth), and the values attributed to low and high caries experience, target proteins, genetic variations, molecular biology technique employed, and study outcome.

Results

The electronic search identified 338 non-duplicated records (Figure 3). After applying the exclusion and inclusion criteria, 16 studies were selected for the systematic review. All articles were classified as having high level of evidence (Table 1).

Figure 3
Summary of systematic steps according to Prisma Statement 2009.

Table 1
Methodological scoring protocol based on quality assessment for selected studies.

The characteristics of the studies are described in Table 2. U.S. patients were studied in five articles, Brazilian patients in three, Polish individuals in two, and Turkish subjects in one. The sample sizes were notably variable, including from 30 to 920 individuals. About half of the selected studies analyzed children,1313. Azevedo LF, Pecharki GD, Brancher JA, Cordeiro CA, Medeiros KG, Antunes AA et al. Analysis of the association between lactotransferrin (LTF) gene polymorphism and dental caries. J Appl Oral Sci. 2010;18(2):166-70. https://doi.org/10.1590/S1678-77572010000200011
https://doi.org/10.1590/S1678-7757201000...
,1414. Brancher JA, Pecharki GD, Doetzer AD, Medeiros KG, Cordeiro Junior CA, Sotomaior VS et al. Analysis of polymorphisms in the lactotransferrin gene promoter and dental caries. Int J Dent. 2011;571726. https://doi.org/10.1155/2011/571726
https://doi.org/10.1155/2011/571726...
,1818. Tao R, Jurevic RJ, Coulton KK, Tsutsui MT, Roberts MC, Kimball JR et al. Salivary antimicrobial peptide expression and dental caries experience in children. Antimicrob Agents Chemother. 2005;49(9):3883-8. https://doi.org/10.1128/AAC.49.9.3883-3888.2005
https://doi.org/10.1128/AAC.49.9.3883-38...
,1919. Peres RCR, Camargo G, Mofatto LS, Cortellazzi KL, Santos MCLG, Santos M et al. 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(2):114-9. https://doi.org/10.1038/tpj.2009.37
https://doi.org/10.1038/tpj.2009.37...
,2020. 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(12):1176-80. https://doi.org/10.1177/154405910708601207
https://doi.org/10.1177/1544059107086012...
evaluating primary and permanent dentition, while the other half studied only adults.1212. Pol J. [Association of the polymorphism of MUC7 gene encoding the low-molecular-weight mucin MG2 with susceptibility to caries]. Ann Acad Med Stetin. 2011;57(2):85-91. Polish.,1515. Yarat A, Ozturk LK, Ulucan K, Akyuz S, Atala H, Isbir T. Carbonic anhydrase VI exon 2 genetic polymorphism in Turkish subjects with low caries experience (preliminary study). In Vivo. 2011;25(6):941-4.,2121. Ozturk A, Famili P, Vieira AR. The antimicrobial peptide DEFB1 is associated with caries. J Dent Res. 2010;89(6):631-6. https://doi.org/10.1177/0022034510364491
https://doi.org/10.1177/0022034510364491...
,2222. Buczkowska-Radlińska J, Pol J, Szmidt M, Bińczak-Kuleta A. The influence of polymorphism of the MUC7 gene on the teeth and dental hygiene of students at a faculty of dentistry in Poland. Postepy Hig Med Dosw (Online). 2012;66:204-9. https://doi.org/10.5604/17322693.991490
https://doi.org/10.5604/17322693.991490...
,2323. Fine DH, Toruner GA, Velliyagounder K, Sampathkumar V, Godboley D, Furgang D. A lactotransferrin single nucleotide polymorphism demonstrates biological activity that can reduce susceptibility to caries. Infect Immun. 2013;81(5):1596-605. https://doi.org/10.1128/IAI.01063-12
https://doi.org/10.1128/IAI.01063-12...
,2424. Shaffer JR, Feingold E, Wang X, Lee M, Tcuenco K, Weeks DE et al. GWAS of dental caries patterns in the permanent dentition. J Dent Res. 2013;92(1):38-44. https://doi.org/10.1177/0022034512463579
https://doi.org/10.1177/0022034512463579...

Table 2
Description of the selected studies.

Dental caries prevalence was evaluated according to the number of decayed, missing, and filled teeth. There has been no distinction between primary (dmft) and permanent (DMFT) dentition for indexing low and high risk of caries. Pol1717. Clark MF, Baudouin SV. A systematic review of the quality of genetic association studies in human sepsis. Intensive Care Med. 2006;32(11):1706-12. https://doi.org/10.1007/s00134-006-0327-y
https://doi.org/10.1007/s00134-006-0327-...
evaluated only adults and considered DMFT < 7 as low risk of caries, while Brancher et al.1919. Peres RCR, Camargo G, Mofatto LS, Cortellazzi KL, Santos MCLG, Santos M et al. 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(2):114-9. https://doi.org/10.1038/tpj.2009.37
https://doi.org/10.1038/tpj.2009.37...
classified individuals with DMFT/dmft = 0 as low risk and DMFT/dmft > 4 as high risk (Table 2), indicating an important methodological source of variability in results across different studies.

Eleven articles found an association between salivary protein polymorphism and risk of dental caries, while five articles did not (Table 2). It is important to note that association with caries experience was identified when these same target proteins with negative results (mucin, HBD1, LTF, and CA VI) were assessed for other polymorphisms, usually with larger sample sizes1313. Azevedo LF, Pecharki GD, Brancher JA, Cordeiro CA, Medeiros KG, Antunes AA et al. Analysis of the association between lactotransferrin (LTF) gene polymorphism and dental caries. J Appl Oral Sci. 2010;18(2):166-70. https://doi.org/10.1590/S1678-77572010000200011
https://doi.org/10.1590/S1678-7757201000...
,1919. Peres RCR, Camargo G, Mofatto LS, Cortellazzi KL, Santos MCLG, Santos M et al. 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(2):114-9. https://doi.org/10.1038/tpj.2009.37
https://doi.org/10.1038/tpj.2009.37...
,2121. Ozturk A, Famili P, Vieira AR. The antimicrobial peptide DEFB1 is associated with caries. J Dent Res. 2010;89(6):631-6. https://doi.org/10.1177/0022034510364491
https://doi.org/10.1177/0022034510364491...
,2323. Fine DH, Toruner GA, Velliyagounder K, Sampathkumar V, Godboley D, Furgang D. A lactotransferrin single nucleotide polymorphism demonstrates biological activity that can reduce susceptibility to caries. Infect Immun. 2013;81(5):1596-605. https://doi.org/10.1128/IAI.01063-12
https://doi.org/10.1128/IAI.01063-12...
. From the five conflicting pairs of studies (i.e., one article reporting the existence and another the absence of association for the same protein), three included different age groups (children and adults), increasing the possible impact of methodological variability.

Discussion

It is difficult to establish a single genetic variable as predictive for dental caries severity due to its multifactorial etiology.2525. Fine DH. Lactoferrin: A roadmap to the borderland between caries and periodontal disease. J Dent Res. 2015;94(6):768-76. https://doi.org/10.1177/0022034515577413
https://doi.org/10.1177/0022034515577413...
Nevertheless, the present study reviewed the scientific literature, showing that genetic variants of salivary proteins, in general, affect dental caries experience.

The molecular techniques employed varied considerably, but all of them are commonly used in genetic studies, going from RFLP, which involves gene identification by digestion with restriction enzymes, gel electrophoresis, and southern hybridization,2626. Dai S, Long Y. Genotyping analysis using an RFLP assay. Methods Mol Biol. 2015;1245:91-9. https://doi.org/10.1007/978-1-4939-1966-6_7
https://doi.org/10.1007/978-1-4939-1966-...
to DNA-sequencing performed with beadchip microarray for genome-wide genotyping.2424. Shaffer JR, Feingold E, Wang X, Lee M, Tcuenco K, Weeks DE et al. GWAS of dental caries patterns in the permanent dentition. J Dent Res. 2013;92(1):38-44. https://doi.org/10.1177/0022034512463579
https://doi.org/10.1177/0022034512463579...
All the selected articles were qualified methodologically as having high levels of evidence. With such techniques, for each salivary protein investigated, at least one study identified genetic components as important factors for caries susceptibility, comprising the main groups of salivary function related to caries pathophysiology (Figure 4).

Figure 4
Salivary proteins and functions (black) that present polymorphisms associated positively (red) or negatively (blue) with dental caries experience.

One work2424. Shaffer JR, Feingold E, Wang X, Lee M, Tcuenco K, Weeks DE et al. GWAS of dental caries patterns in the permanent dentition. J Dent Res. 2013;92(1):38-44. https://doi.org/10.1177/0022034512463579
https://doi.org/10.1177/0022034512463579...
suggested significant associations in a genome wide association study (GWAS), but did not identify caries experience using global caries phenotypes (DMFT and dmft). Instead, that work was innovative in suggesting novel caries phenotypes, developed by hierarchical clustering analysis on tooth-surface-level data. Previously, the authors have shown that relevant categories were obtained by grouping surfaces based on caries co-occurrence.2727. Shaffer JR, Feingold E, Wang X, Weeks DE, Weyant RJ, Crout R et al. Clustering tooth surfaces into biologically informative caries outcomes. J Dent Res. 2013;92(1):32-7. https://doi.org/10.1177/0022034512463241
https://doi.org/10.1177/0022034512463241...
This suggests that new models of phenotypes may capture more biologically informative patterns of tooth decay. This method indicated that bacteriolytic LYZL2 polymorphism was implicated in reducing caries on mandibular anterior tooth surfaces (incisors, canines, and first premolars).2424. Shaffer JR, Feingold E, Wang X, Lee M, Tcuenco K, Weeks DE et al. GWAS of dental caries patterns in the permanent dentition. J Dent Res. 2013;92(1):38-44. https://doi.org/10.1177/0022034512463579
https://doi.org/10.1177/0022034512463579...
Unfortunately, it is still unclear by which mechanisms LYZL2 affects dental caries. Nevertheless, the protein related to this gene belongs to the family of c-type lysozymes, well-recognized bacteriolytic host defense factors.2828. Zhang K, Gao R, Zhang H, Cai X, Shen C, Wu C et al. Molecular cloning and characterization of three novel lysozyme-like genes, predominantly expressed in the male reproductive system of humans, belonging to the c-type lysozyme/alpha-lactalbumin family. Biol Reprod. 2005;73(5):1064-71. https://doi.org/10.1095/biolreprod.105.041889
https://doi.org/10.1095/biolreprod.105.0...
Its putative bacterial function and the genetic association findings suggest this protein is a potential dental caries biomarker.2424. Shaffer JR, Feingold E, Wang X, Lee M, Tcuenco K, Weeks DE et al. GWAS of dental caries patterns in the permanent dentition. J Dent Res. 2013;92(1):38-44. https://doi.org/10.1177/0022034512463579
https://doi.org/10.1177/0022034512463579...

Mucin, another important protein within the oral cavity, can be of two types: high-molecular-weight mucin (MG1), encoded by the MUC5B gene, and low-molecular-weight mucin (MG2), encoded by the MUC7 gene.2929. Oppenheim FG, Salih E, Siqueira WL, Zhang W, Helmerhorst EJ. Salivary proteome and its genetic polymorphisms. Ann N Y Acad Sci. 2007;1098(1):22-50. https://doi.org/10.1196/annals.1384.030
https://doi.org/10.1196/annals.1384.030...
Both types of mucins are involved in dental plaque formation and in bacterial adhesion. Two Polish studies have added to this knowledge by considering the role of their polymorphisms in caries experience, albeit with conflicting results. While Pol1212. Pol J. [Association of the polymorphism of MUC7 gene encoding the low-molecular-weight mucin MG2 with susceptibility to caries]. Ann Acad Med Stetin. 2011;57(2):85-91. Polish. has found an association between the MUC7 6/6 genotype and high dental caries experience (p=0.09), in a study with 158 young adults, Buczkowska-Radlinska et al.2222. Buczkowska-Radlińska J, Pol J, Szmidt M, Bińczak-Kuleta A. The influence of polymorphism of the MUC7 gene on the teeth and dental hygiene of students at a faculty of dentistry in Poland. Postepy Hig Med Dosw (Online). 2012;66:204-9. https://doi.org/10.5604/17322693.991490
https://doi.org/10.5604/17322693.991490...
have reported that the distribution of the value of the DMFT index was similar to that of the control group. Vieira et al.1010. Vieira AR, Modesto A, Marazita ML. Caries: review of human genetics research. Caries Res. 2014;48(5):491-506. https://doi.org/10.1159/000358333
https://doi.org/10.1159/000358333...
suggested that these conflicting results might be related to study design issues such as population heterogeneity and statistical power, therefore not yet refuting the results of the original study.

Lactotransferrin (LTF), a specific glycoprotein that can affect dental biofilm aggregation by inhibiting S. mutans adhesion and present antimicrobial activity through activation of the immune system, had polymorphisms associated with low caries experience in Turkish children3030. Abbasoğlu Z, Tanboğa İ, Küchler EC, Deeley K, Weber M, Kaspar C et al. Early childhood caries is associated with genetic variants in enamel formation and immune response genes. Caries Res. 2015;49(1):70-7. https://doi.org/10.1159/000362825
https://doi.org/10.1159/000362825...
, Brazilian 12-year-old students,1313. Azevedo LF, Pecharki GD, Brancher JA, Cordeiro CA, Medeiros KG, Antunes AA et al. Analysis of the association between lactotransferrin (LTF) gene polymorphism and dental caries. J Appl Oral Sci. 2010;18(2):166-70. https://doi.org/10.1590/S1678-77572010000200011
https://doi.org/10.1590/S1678-7757201000...
,3131. Doetzer AD, Brancher JA, Pecharki GD, Schlipf N, Werneck R, Mira MT et al. Lactotransferrin gene polymorphism associated with caries experience. Caries Res. 2015;49(4):370-7. https://doi.org/10.1159/000366211
https://doi.org/10.1159/000366211...
and North American adults.2525. Fine DH. Lactoferrin: A roadmap to the borderland between caries and periodontal disease. J Dent Res. 2015;94(6):768-76. https://doi.org/10.1177/0022034515577413
https://doi.org/10.1177/0022034515577413...
Whole saliva from American individuals, homozygous for a lysine variant, presented increased antimicrobial activity against S. mutans as compared to “wild-type” arginine from LTF,2323. Fine DH, Toruner GA, Velliyagounder K, Sampathkumar V, Godboley D, Furgang D. A lactotransferrin single nucleotide polymorphism demonstrates biological activity that can reduce susceptibility to caries. Infect Immun. 2013;81(5):1596-605. https://doi.org/10.1128/IAI.01063-12
https://doi.org/10.1128/IAI.01063-12...
supported by a reduction in caries prevalence in the lysine group (p = 0.001; relative risk: 3.6; 95%CI:1.5–11.13). Furthermore, the creation of a lysine variant peptide demonstrated the broad spectrum of antimicrobial activity that this variant can have on gram-positive, acid-producing/caries-associated bacteria. Two Brazilian studies1313. Azevedo LF, Pecharki GD, Brancher JA, Cordeiro CA, Medeiros KG, Antunes AA et al. Analysis of the association between lactotransferrin (LTF) gene polymorphism and dental caries. J Appl Oral Sci. 2010;18(2):166-70. https://doi.org/10.1590/S1678-77572010000200011
https://doi.org/10.1590/S1678-7757201000...
,3131. Doetzer AD, Brancher JA, Pecharki GD, Schlipf N, Werneck R, Mira MT et al. Lactotransferrin gene polymorphism associated with caries experience. Caries Res. 2015;49(4):370-7. https://doi.org/10.1159/000366211
https://doi.org/10.1159/000366211...
also have shown that lactotransferrin A/G (exon 2, Lys/Arg, rs 1126478) and a tag SNP located outside and downstream of the LTF gene (rs6441989) were associated with dental caries susceptibility, especially in the presence of gingivitis (p = 0.020) or plaque (p = 0.035),3131. Doetzer AD, Brancher JA, Pecharki GD, Schlipf N, Werneck R, Mira MT et al. Lactotransferrin gene polymorphism associated with caries experience. Caries Res. 2015;49(4):370-7. https://doi.org/10.1159/000366211
https://doi.org/10.1159/000366211...
confirming the influence of LTF lysine variants on the caries process. More recently, a study3030. Abbasoğlu Z, Tanboğa İ, Küchler EC, Deeley K, Weber M, Kaspar C et al. Early childhood caries is associated with genetic variants in enamel formation and immune response genes. Caries Res. 2015;49(1):70-7. https://doi.org/10.1159/000362825
https://doi.org/10.1159/000362825...
observed an association (p = 0.036, OR:0.47 95%CI:0.23–0.95) for the CT genotype in rs4547741 with reduced caries in the primary dentition of 2-to-5-year-old Turkish children, confirming the protective role of this polymorphism in Early Childhood Caries (ECC).

Beta defensins are small cationic antimicrobial peptides with an important role in the innate immune system. Salivary levels of human beta defensin 1 (HBD1) have been correlated with the risk for periodontal disease or caries.3232. Chung WO, Dommisch H, Yin L, Dale BA. Expression of defensins in gingiva and their role in periodontal health and disease. Curr Pharm Des. 2007;13(30):3073-83. https://doi.org/10.2174/138161207782110435
https://doi.org/10.2174/1381612077821104...
One study,2121. Ozturk A, Famili P, Vieira AR. The antimicrobial peptide DEFB1 is associated with caries. J Dent Res. 2010;89(6):631-6. https://doi.org/10.1177/0022034510364491
https://doi.org/10.1177/0022034510364491...
after adjusting results by age, gender, ethnicity, and smoking status, found two polymorphisms in the promoter region of the gene responsible for HBD1 (DEFB1) associated with caries experience: rs11362 (G-20A) (p = 0.007; OR = 5.28 95%CI:1.99–14.05), which increased DMFT up to 5 times, and rs1799946 (G-52A), which was associated with lower caries experience (OR = 0.32, p = 0.014). Another recent study confirmed rs11362 as a risk factor for caries in Turkish adults (p = 0.000) with contributing environmental factors such as high level of dental plaque, age, and saliva buffer capacity.3333. Yildiz G, Ermis RB, Calapoglu NS, Celik EU, Türel GY. Gene-environment interactions in the etiology of dental caries. J Dent Res. 2016;95(1):74-9. https://doi.org/10.1177/0022034515605281
https://doi.org/10.1177/0022034515605281...
Literature findings actually indicate that HBD1 is reduced in the saliva of patients with DEFB-1 polymorphisms.3434. Polesello V, Zupin L, Di Lenarda R, Biasotto M, Ottaviani G, Gobbo M, et al. Impact of DEFB1 gene regulatory polymorphisms on hBD-1 salivary concentration. Arch Oral Biol. 2015;60(7):1054-8. https://doi.org/10.1016/j.archoralbio.2015.03.009
https://doi.org/10.1016/j.archoralbio.20...
However, while the antibiotic action of defensins comes from unspecific pore formation from electrostatic interactions with microbial membranes, leading to cell leakage and death, HBD1 presented the lowest in vitro antimicrobial activity against cariogenic bacteria when compared with other beta defensins.3535. Ouhara K, Komatsuzawa H, Yamada S, Shiba H, Fujiwara T, Ohara M et al. Susceptibilities of periodontopathogenic and cariogenic bacteria to antibacterial peptides, {beta}-defensins and LL37, produced by human epithelial cells. J Antimicrob Chemother. 2005;55(6):888-96. https://doi.org/10.1093/jac/dki103
https://doi.org/10.1093/jac/dki103...
Nevertheless, a study3636. Schroeder BO, Wu Z, Nuding S, Groscurth S, Marcinowski M, Beisner J et al. Reduction of disulphide bonds unmasks potent antimicrobial activity of human β-defensin 1. Nature. 2011;469(7330):419-23. https://doi.org/10.1038/nature09674
https://doi.org/10.1038/nature09674...
provided an explanation to this paradoxical production of an “ineffective molecule,” showing that, after reduction of disulfide bridges, HBD1 becomes a potent antimicrobial peptide. This is even more relevant if we consider that the oral cavity may provide anaerobic niches that are favorable to such reduction.3737. Schroeder BO, Stange EF, Wehkamp J. Waking the wimp: redox-modulation activates human beta-defensin 1. Gut Microbes. 2011;2(4):262-6. https://doi.org/10.4161/gmic.2.4.17692
https://doi.org/10.4161/gmic.2.4.17692...

Acidic proline-rich proteins (PRPs) represent 37% of salivary proteins adhered to freshly cleaned teeth and may be responsible for differences in bacterial interactions with the tooth surface, having an impact on biofilm colonization.3838. Yoshida Y, Palmer RJ, Yang J, Kolenbrander PE, Cisar JO. Streptococcal receptor polysaccharides: recognition molecules for oral biofilm formation. BMC Oral Health. 2006;6 Suppl 1:S12. https://doi.org/10.1186/1472-6831-6-S1-S12
https://doi.org/10.1186/1472-6831-6-S1-S...
Acidic PRPs are encoded by two genes, PRH1 and PRH2, with three different alleles at PRH1 (Db, Pa, and Pif).3939. Levine M. Susceptibility to dental caries and the salivary proline-rich proteins. Int J Dent. 2011;2011:ID 953412. http://dx.doi.org/10.1155/2011/953412
http://dx.doi.org/10.1155/2011/953412...
When the allele Db was studied,2020. 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(12):1176-80. https://doi.org/10.1177/154405910708601207
https://doi.org/10.1177/1544059107086012...
it was present in 72% of African Americans and in 26% of Caucasians. Curiously enough, large groups of African American children, regardless of the presence of Db, had significantly less caries experience than Caucasian subjects (p < 0.01). The racial difference between subjects with high caries experience compared to those with low caries experience was significant for Db-negative individuals (p < 0.01) but not significant for Db-positive individuals, suggesting that alleles linked to Db may explain racial differences in caries experience.2020. 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(12):1176-80. https://doi.org/10.1177/154405910708601207
https://doi.org/10.1177/1544059107086012...

Four studies on Carbonic Anhydrase VI (CA VI) have assessed the impact of polymorphisms on caries experience. The study reported on two SNPs (rs2274327 [C/T], rs2274328 [A/C]) in exon 2 of CA VI 1515. Yarat A, Ozturk LK, Ulucan K, Akyuz S, Atala H, Isbir T. Carbonic anhydrase VI exon 2 genetic polymorphism in Turkish subjects with low caries experience (preliminary study). In Vivo. 2011;25(6):941-4. has found no association between these SNPs and dental caries, salivary pH, or buffering capacity in children and adults. However, Peres et al.2222. Buczkowska-Radlińska J, Pol J, Szmidt M, Bińczak-Kuleta A. The influence of polymorphism of the MUC7 gene on the teeth and dental hygiene of students at a faculty of dentistry in Poland. Postepy Hig Med Dosw (Online). 2012;66:204-9. https://doi.org/10.5604/17322693.991490
https://doi.org/10.5604/17322693.991490...
studied the same SNPs and reported that the variant rs2274327 was associated with a decreased activity of the enzyme in saliva buffer capacity of Brazilian children (p=0.046). Similar results were found later with Brazilian adults, and polymorphism rs2274333 was also associated with decreased CA VI concentration.4040. Aidar M, Marques R, Valjakka J, Mononen N, Lehtimäki T, Parkkila S et al. Effect of genetic polymorphisms in CA6 gene on the expression and catalytic activity of human salivary carbonic anhydrase VI. Caries Res. 2013;47(5):414-20. https://doi.org/10.1159/000350414
https://doi.org/10.1159/000350414...
Recently, a study with a northwestern Chinese population indicated yet another genotype (TT, rs17032907) with an increased risk of dental caries (OR = 2.144, 95%CI:1.096–4.195).4141. Li ZQ, Hu XP, Zhou JY, Xie XD, Zhang JM. Genetic polymorphisms in the carbonic anhydrase VI gene and dental caries susceptibility. Genet Mol Res. 2015;14(2):5986-93. https://doi.org/10.4238/2015.June.1.16
https://doi.org/10.4238/2015.June.1.16...
Intriguingly, CA VI concentration in the saliva has been previously shown to not regulate alone salivary pH or buffer capacity, and this enzyme may have a different role or may participate in these processes together with other CA types.4242. Kivelä J, Parkkila S, Parkkila AK, Rajaniemi H. A low concentration of carbonic anhydrase isoenzyme VI in whole saliva is associated with caries prevalence. Caries Res. 1999;33(3):178-84. https://doi.org/10.1159/000016514
https://doi.org/10.1159/000016514...
,4343. Kivelä J, Laine M, Parkkila S, Rajaniemi H. Salivary carbonic anhydrase VI and its relation to salivary flow rate and buffer capacity in pregnant and non-pregnant women. Arch Oral Biol. 2003;48(8):547-51. https://doi.org/10.1016/S0003-9969(03)00096-7
https://doi.org/10.1016/S0003-9969(03)00...
It is known that bicarbonate in the saliva diffuses into dental plaque and combines with H+ to form carbonic acid. CA VI contributes to the neutralization of plaque acid, whose buffering is mainly provided by bicarbonate, which may contribute to dental caries development.4444. Bardow A, Moe D, Nyvad B, Nauntofte B. The buffer capacity and buffer systems of human whole saliva measured without loss of CO2. Arch Oral Biol. 2000;45(1):1-12. https://doi.org/10.1016/S0003-9969(99)00119-3
https://doi.org/10.1016/S0003-9969(99)00...

Saliva as a diagnostic medium for various biochemical tests provides a noninvasive and accessible tool, with advantages over other body fluids, such as blood and urine, and readily available appropriate technologies enable the use of saliva in the diagnosis and monitoring of disease progression.4545. Malamud D. Saliva as a diagnostic fluid. Dent Clin North Am. 2011;55(1):159-78. https://doi.org/10.1016/j.cden.2010.08.004
https://doi.org/10.1016/j.cden.2010.08.0...
Consequently, the search for salivary disease biomarkers has motivated the cataloguing of the human salivary proteome.33. Lagerlöf F, Oliveby A. Caries-protective factors in saliva. Adv Dent Res. 1994;8(2):229-38. https://doi.org/10.1177/08959374940080021601
https://doi.org/10.1177/0895937494008002...
,4646. Rudney JD, Staikov RK, Johnson JD. Potential biomarkers of human salivary function: a modified proteomic approach. Arch Oral Biol. 2009;54(1):91-100. https://doi.org/10.1016/j.archoralbio.2008.08.007
https://doi.org/10.1016/j.archoralbio.20...
In the present systematic review, even though it is clear that high methodological variability (age, sample size, and caries identification procedures) still makes it difficult to compare results from different studies, it is shown that scientific literature strongly indicates a series of different salivary protein polymorphisms that impact on caries experience, for all proteins (even though not for all polymorphic loci) investigated.

Conclusion

Scientific evidence confirms the general pattern of association between risk of dental caries and salivary protein polymorphisms.

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    Malamud D. Saliva as a diagnostic fluid. Dent Clin North Am. 2011;55(1):159-78. https://doi.org/10.1016/j.cden.2010.08.004
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Publication Dates

  • Publication in this collection
    2017

History

  • Received
    01 Sept 2015
  • Reviewed
    27 Mar 2017
  • Accepted
    12 Apr 2017
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