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. Author manuscript; available in PMC: 2022 Oct 1.
Published in final edited form as: Arch Oral Biol. 2021 Jul 30;130:105221. doi: 10.1016/j.archoralbio.2021.105221

Genome-Wide Family-Based Study in Torus Palatinus Affected Individuals

Mariana Bezamat 1, Yuqiao Zhou 2, Timothy Park 1, Alexandre R Vieira 1,*
PMCID: PMC8434990  NIHMSID: NIHMS1730720  PMID: 34352448

Abstract

Objective:

Tori or exostoses are bony growths that appear in different oral regions. Torus palatinus, more specifically, develop in the palate midline and can impair proper word pronunciation and hinder the fabrication and use of dentures. Even though a multifactorial inheritance model has been suggested for torus palatinus appearance, precise genetic factors involved in its etiology remain unclear. Hence, in this study we aimed to identify variants across the genome of individuals from 46 Filipino families that associate with torus palatinus.

Design:

All families were composed of fishermen or landless rural dwellers who provided blood samples for DNA extraction and genotyping. A total of 3,519 single nucleotide polymorphisms (SNPs) were analyzed through a transmission disequilibrium test in individuals affected by torus palatinus and their unaffected family members.

Results:

Fourteen SNPs showed trends for associations to the level of p<.005 threshold and several others were nominally (p<.05) associated with torus palatinus. We highlight SNP rs6582285, which is located in the CAPS2 gene, being the C allele less transmitted than the T allele in our sample. The C allele of CAPS2 rs6582285 protects from having torus palatinus whereas the other associations found were linked to an increased risk of developing the condition.

Conclusions:

Trends for associations were identified for several markers across the genome, supporting the hypothesis that torus palatinus has a multifactorial mode of inheritance. We hope that our study contributes to a better understanding of torus palatinus etiology and helps guide future research in examining genes for this often-overlooked condition in different populations.

Keywords: Torus palatinus, exostosis, genetic variation, transmission disequilibrium test, GWAS

Introduction

Torus palatinus is an exostosis usually formed at the longitudinal ridge of the palate, mainly composed of dense cortical bone and a thin and poorly vascularized mucosa (Garcia-Garcia et al., 2010). Torus palatinus may develop from the biomechanical forces of biting, that act in the growth region, decreasing cortical and increasing trabecular bone masses development (Padbury et al., 2006; Tai et al., 2018). These exostoses are usually not pathological, but they create problems in fabricating and wearing dentures (Belsky et al., 2003), they limit tongue movement that can impair pronunciation of certain words (Auskalnis et al., 2015), and they can occur concomitantly with additional sclerosing bone dysplasia phenotypes, which are characterized by a group of disorders with a generalized increase in bone mass (Van Wesenbeeck et al., 2003). Significantly greater incidence of torus palatinus has also been found in patients with hyperparathyroidism which affects bone remodeling and causes hypercalcemia. Thus, torus palatinus could be a potential marker for hyperparathyroidism in clinical practice (Padbury et al., 2006). Likewise, because the presence of torus palatinus in postmenopausal women is an indicator of high bone density, (Belsky et al., 2003) it’s presence can possibly help rule out individual susceptibility to osteoporosis or indicate an overall skeletal mass increase. Oral health professionals diagnose torus palatinus by a simple clinical examination, but in cases where there are extremely large bony growths, radiographs are indicated to exclude any potential bone pathology (Kannan et al., 2015).

In different studies the prevalence of torus palatinus ranges from as low as approximately 1% to as much as 62%, often reflecting the genetic differences among different populations (Garcia-Garcia et al., 2010). A recent report on a multiethnic cohort found torus palatinus to be present at approximately twice the rate in individuals of East Asian ancestry compared with individuals of West African ancestry and that difference seemed to be limited to females (El Sergani et al., 2020). Further research studies have shown that 85.7% of children with torus palatinus have had at least one parent with the torus as well and that about 60% of affected individuals were females, indicating potential genetic and sexual-linked associations (Barbujani et al., 1986). Additionally, edentulous European American females were found to be more frequently affected by torus palatinus (Lease, 2021). Regarding age, torus palatinus is rarely found in children (Lease, 2021), but frequently observed in young adults and middle-aged patients (Telang et al., 2019).

Torus formations are suggested to have multifactorial inheritance (Singh, 2010), with environmental factors such as diet, and functional factors such as masticatory stress potentially involved (Telang et al., 2019), but their exact cause remains unknown. Genetics is the most plausible explanation for torus palatinus development (Garcia-Garcia et al., 2010), though it has not yet been possible to establish a major gene effect for its appearance. Gregson et al. reported associations between common variation and a rare mutation in the SMAD family member 9 (SMAD9) gene and extreme high bone density phenotypes, including the presence of torus palatinus (Gregson et al., 2020). A different study aiming to unravel genetic associations related to sclerosing bone dysplasia reported the presence of LDL Receptor Related Protein 5 (LRP5) gene missense mutations in families and isolated patients affected by tori as one of the conditions indicating increased bone density (Van Wesenbeeck et al., 2003).

Given the evidence of genetics associated with the appearance of torus palatinus and the fact that there is a limited number of studies in this subject, we performed a genome-wide family-based scan using the transmission disequilibrium test in a cohort of 46 families from the Philippines. Our objective was to identify genes across the genome that associate with the presence of torus palatinus. Elucidation of the genetic markers that associate with torus palatinus will not only inform the risk for this specific condition but could also help identify risk for other correlated diseases such as hyperparathyroidism.

Methods

Subjects

The cohort used in this study was obtained previously with the goal of studying orofacial characteristics and genetic profiles of individuals that shared both similar cultural backgrounds and influence of environmental factors (Vieira et al., 2008). It constituted 737 individuals (376 males and 361 females) from 46 families from the central part of the Philippines, mostly Cebu Island, and the surrounding islands. This cohort was originally ascertained for having orofacial clefts. In this present study, out of the 737 individuals included in the analysis, eighty-nine were diagnosed with clefts and ten were diagnosed with both torus palatinus and clefts concomitantly. Additional oral conditions identified in this population included gingivitis, presence of plaque, dental caries and malocclusion, all of which are common oral conditions in the general population.

One hundred and sixteen individuals were diagnosed with torus palatinus (37 males and 79 females) by clinical evaluation. All families are composed of small-scale fishermen or landless rural dwellers. Since we compared individuals living in the same area and with similar cultural backgrounds, their access to care and influence of environmental factors were also similar, reducing potential confounders. All participants provided blood samples for DNA extraction and genotyping and each individual was evaluated by an experienced dentist who defined an affected status regarding torus palatinus. The clinical criteria used to make the diagnosis was the presence of an elevation in the palatal bone midline, and all morphologies subtypes of torus palatinus such as flat, spindle, nodular and lobular were considered (Neville, 2018). Informed consent was obtained from all participants and the project had appropriate local Filipino and University of Pittsburgh Institutional Review Board approvals.

Genotyping and analyses

Genotyping data were generated at the Center for Inherited Disease Research (CIDR) using a 3,519 single nucleotide polymorphism (SNP) custom panel. The criteria used to select the custom panel included the linkage disequilibrium structure of the region accounting for the genes nearby, the minor allele frequencies of the SNPs, the SNP location in the gene, and the potential function of the gene. To test for inconsistencies due to non-paternity or other errors, each marker was accessed with the PedCheck program (O’Connell & Weeks, 1998). Using PLINK software (Purcell et al., 2007), we performed a family-based transmission disequilibrium test (TDT). This analysis tested for overtransmission of alleles of the 3,519 markers and torus palatinus in the cohort of Filipino families. The TDT is suitable and the test of choice because it can avoid the issue of potential deceptive associations that can be present in case-control studies since it measures the transmission of marker alleles of heterozygous parents to the affected offspring, and the non-transmitted alleles act as controls to the transmitted ones (Floros et al., 2001). We ran an analysis in the total sample and an analysis excluding individuals who had clefts, considering that both torus palatinus and clefts affect the same or surrounding craniofacial structures and that could provide additional insight by discriminating genetic contributors that are potentially also involved with clefts. Because some of the SNPs tested are in linkage disequilibrium and the Bonferroni correction might be too stringent, we considered a significance threshold of p < 0.005.

Results

After running the transmission disequilibrium test in the 46 families in the total sample, we found the most relevant SNPs (p value < 0.005) to be present in chromosomes 5, 7, 9, 11, 12, 13, 15, 17, 19 and 22. The lowest p-values associated with increased likelihood of torus palatinus development were rs12856863 in GRTP1 (p=0.002, OR = 5.67, 95% C.I. .66 – 19.34), rs1329088 in PLPPR1 (p=0.002, OR = 5.67, 95% C.I. 1.66 – 19.34), and the intergenic rs9523070 (p=0.002, OR = 4.20, 95% C.I. 1.58 – 11.14) and rs346416 (located nearby IPO11, p=0.002, OR = 3.43, 95% C.I. 1.48 – 7.96). The SNP rs6582285, located in CAPS2 (p=0.001, OR = 0.30, 95% C.I. 0.13 – 0.65), associated with less likelihood of developing torus palatinus (Table 1).

Table 1.

Most relevant results (p<0.005) of the transmission disequilibrium test.

Chromosome SNP Minor allele Major allele Odds Ratio Lower 95% CI Upper 95% CI Chi square P-value
5 rs346416 A C 3.43* 1.48 7.96 9.32 0.002
7 rs1013920 G T 0.29 NA NA 8.33 0.004
9 rs1329088 C T 5.67* 1.66 19.34 9.80 0.002
11 rs1404524 A C 0.20 0.06 0.69 8.00 0.0047
12 rs6582285 C T 0.30 0.13 0.65 10.31 0.001
13 rs9523070 A G 4.20* 1.58 11.14 9.85 0.002
rs12856863 A G 5.67* 1.66 19.34 9.80 0.002
15 rs281265 A C 0.30 0.13 0.71 8.53 0.003
17 rs1877497 A G 4.50* 1.52 13.30 8.91 0.003
19 rs879689 T C 0.24 0.08 0.70 8.05 0.0046
22 rs2839377 T C 0.33 0.15 0.74 8.00 0.0047
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*

The minor allele increases the risk of having torus palatinus.

The prevalence of torus palatinus in our family-based cohort was 15% with 68% of affected individuals being females. We further broke down the genotyping results by sex in the group of patients affected by torus palatinus, and identified a significant underrepresentation of the homozygous for the less common allele of rs6582285 in females as compared to the frequency of the same SNP in males (Table 2). When breaking down the genotyping results by torus palatinus status, and comparing affected and unaffected individuals (Table 3), we did not find significant differences. Using age as a covariate also did not substantially change the results.

Table 2.

Genotyping frequencies and chi square results for each of the most associated (p<0.003) markers by sex in the group of patients affected by torus palatinus.

Sex rs346416 rs1329088 rs6582285 rs9523070 rs12856863
Males 4 AA 2 CC 10 CC 3 AA 2 AA
14 AC 14 TC 9 TC 8 AG 9 AG
14 CC 17 TT 14 TT 21 GG 22 GG
Females 7 AA 7 CC 8 CC 3 AA 2 AA
29 AC 24 TC 34 TC 29 AG 17 AG
32 CC 38 TT 26 TT 36 GG 50 GG
Chi square (p-value) 0.92 0.66 0.02 0.18 0.69
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Table 3.

Genotyping frequencies and chi square results for each of the most associated (p<0.003) markers by phenotype status in the sample.

Torus palatinus status rs346416 rs1329088 rs6582285 rs9523070 rs12856863
Affected 11 AA 9 CC 18 CC 6 AA 4 AA
44 AC 37 TC 43 TC 37 AG 25 AG
46 CC 55 TT 40 TT 112 GG 72 GG
Unaffected 11 AA 7 CC 25 CC 5 AA 8 AA
53 AC 70 TC 83 TC 41 AG 39 AG
94 CC 81 TT 50 TT 36 GG 111 GG
Chi square (p-value) 0.08 0.22 0.28 0.06 0.91
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When we excluded individuals who had clefts, the only association that remained under the p<0.005 significance level was the rs12856863 in GRTP1 (p=0.0045, OR = 6.50, 95% C.I. 1.46 – 28.8). However, new associations were identified in chromosomes 13, 17, and 18, with the lowest p-value for rs920783 in chromosome 18 (p=0.001, OR = 6.00, 95% C.I. 1.76 – 20.37).

Discussion

Our results showed an association of several SNPs across the genome with torus palatinus in Filipinos. Although none of the results met multiple testing significance if applying a Bonferroni threshold, nominal associations between SNPs and torus palatinus were found. These results suggest a more complex mode of inheritance for torus palatinus as opposed to a major gene effect suggested previously (Gorsky et al., 1998; Gould, 1964).

Variants in GRTP1 and PLPPR1 which are protein coding genes, were associated with increased risk of developing torus palatinus, with the GRTP1 remaining associated when we excluded individuals who had clefts from the analysis. This gene encodes for the growth hormone TBC protein 1, which is likely involved in GTPase activity and intracellular protein transport. This gene is expressed at highest levels in testes (Lu et al., 2001). Growth hormones are potent anabolic hormones for bone and calcium metabolism (Wuster, 1993), and this finding may suggest that this association may be specifically relevant for torus palatinus, whereas the association found in the total sample may be more relevant for individuals that are at risk for developing torus palatinus with a background genetic susceptibility for cleft lip and palate. As a member of the plasticity-related gene (PRG) family, PLPPR1 mediates lipid phosphate phosphatase activity and is strongly expressed in the brain (Rouillard et al., 2016).

The association with the lowest p-value in the total sample was found between the SNP rs6582285 and the presence of torus palatinus. The C allele was less frequent (MAF=0.33) than the T allele in our studied population, which was consistent with the range reported by the National Center of Biotechnology Information for different populations (MAF between 0.20 and 0.45). Asians have a slightly higher frequency of the less common alleles, between 0.26 and 0.4. This polymorphism is an intron variant located in the CAPS2 gene, being the less frequent allele protective from having torus palatinus. CAPS2 encodes calcyphosine-2, which is a calcium-binding protein (Wang et al., 2002) and may explain its interplay with torus palatinus as a bone density phenotype. Interestingly, when we analyzed this same SNP but breaking down the results by sex within the group of patients affected by torus palatinus, we identified a significant underrepresentation of the homozygous for the less common allele in females (12%) as compared to the frequency of this same SNP in males (30%). These results can indicate that males, that more frequently carry the protective allele as compared to females, might be genetically protected from having torus palatinus.

Limitations of our study included the sample size with 116 individuals affected by torus palatinus and that the age distribution for all participants was not very remarkable (patients and family members were relatively young). Our results need to be confirmed with larger cohorts, different populations, and the inclusion of age as a variable. The advantage of using this cohort was the homogeneity of the population which is under similar environmental influences. On the other hand, these similar influences and exposures did not allow for the possibility to evaluate environmental factors, such as diet, as a modifier for the etiology of torus palatinus. However, Telang et al. reported a relatively high frequency of torus palatinus in Malaysia, which is not far from the Philippines, and suggested it to be the result of their diet (Telang et al., 2019). Similarly, a study from Norway implies a role of diet as modulating higher frequency of torus palatinus as one of the multifactorial causes. Individuals that consumed softer diets and diets based on saltwater fish, omega 3 polyunsaturated fatty acids, and vitamin D were more affected by torus palatinus (Eggen et al., 1994).

Because we were not able to confirm a strong genetic effect with our results, environmental factors may play a role in developing torus palatinus in this population. Nutritional deficiencies and dietary habits such as excessive consumption of fish or fish supplements as well as consumption of foods rich in calcium are within environmental factors reported as associated with torus palatinus appearance (Kannan et al., 2015). Since the population studied here is mostly composed of fisherman, their diet could be contributing to the tori development associated with their genetics.

Another limitation of this present study was that we did not have data on functional/parafunctional activities, such as mastication habits or bruxism, which are variables that could also impact the occurrence of torus palatinus. Additional strengths of this present study included the transmission disequilibrium technique used, and family-based data in general which eliminates potential population stratification, and increases the confidence of the control group being representative of the case group (Lasky-Su, 2017).

We hope that our study contributes to a better understanding of torus palatinus etiology and guides future research in examining environmental factors such as dietary influence on this phenotype, given our sample characteristics. Another possibility for future studies is to test the frequency of the associated SNPs in a different population of unrelated patients with and without torus palatinus to verify differences in frequencies. Because our sample was constituted of patients and their relatives, the lack of genotypic differences when comparing affected and unaffected individuals may be due to similar genetic profiles between them. Additionally, the genetic findings from these results can potentially help in providing clues for work focusing on tissue regeneration in humans, since the metabolism and physiology of bone structures are of great interest for the current regenerative effort.

Torus palatinus is an often-overlooked condition that impacts phonation, dental care and could be an efficient marker for an increased bone mass phenotype and hyperparathyroidism. Multiple SNPs showed trends for associations with torus palatinus. To the best of our knowledge, we performed the first genome-wide family-based study and found trends for genetic associations underlying this phenotype, we hope that our results contribute to a better understanding of its etiology.

Table 4.

Most relevant results (p<0.005) of the transmission disequilibrium test excluding individuals that had clefts.

Chromosome SNP Minor allele Major allele Odds Ratio Lower 95% CI Upper 95% CI Chi square P-value
13 rs1412953 A G 0.15 0.03 0.68 8.06 0.0045
rs12856863 A G 6.50* 1.46 28.8 8.07 0.0045
17 rs1266160 G A 0.15 0.03 0.68 8.06 0.0045
18 rs920783 C T 6.00* 1.76 20.37 10.71 0.001
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*

The minor allele increases the risk of having torus palatinus.

Highlights.

  • Fourteen SNPs had statistical evidence for an association with torus palatinus.

  • The CAPS2 gene showed the biggest difference in genotype distribution.

  • The C allele of the CAPS2 variant confers lower risk of developing torus palatinus.

  • Genotyping frequencies of CAPS2 variant were different between females and males.

Acknowledgements

Original family ascertainment and genotyping data generation was done under the auspices of Jeffrey C. Murray, with the support of Sandra Daack-Hirsch. Administrative support on the genotyping data and family structures were provided by Mary L. Marazita and Nandita Mukhopadhyay. We thank Kyle Chappel for proofreading the article.

Funding

The torus palatinus phenotyping work was originally done with the support of NIDCR/NIH R21-DE16718 (A.R.V.). Mariana Bezamat was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award number TL1TR001858 (Kraemer). The content is solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.

Footnotes

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Conflict of Interest

All authors declare that they have no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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