Abstract
Aim
This study sought to evaluate the relationship between height of an individual and the presence of impaction of maxillary and mandibular third molars, and to determine the role of genetics in third molar impaction.
Materials and Methods
This was a case–control study, with cases consisted of 200 subjects with third molar impactions; and 200 controls without third molar impactions. Height of subjects was measured, and saliva samples were collected from all the subjects. DNA was extracted from saliva samples. To investigate the role of selected genes in the etiology of third molar impactions, Taqman Genotyping using SNPs identified for jaw growth, height and tooth agenesis was employed. Five candidate genes were investigated using 11 markers (SNPs).
Results
The mean height of cases was significantly lower than that of the control subjects (p = 0.04). No difference was found in allele frequency between cases and controls for 10 of the 11 SNPs. However, for rs6504591 the p value was near significance (p = 0.07) with odd ratio of 2.131. Subjects with lower third molar impactions were significantly shorter than those who have fully erupted third molars.
Conclusions
Subjects with lower third molar impactions were significantly shorter than those who have fully erupted third molars. We observed that individuals with third molar impaction tend to have T allele at the locus, suggesting that the T allele at the locus may increase the risk for having an impacted third molar. The rs6504591 G/T variation on human chromosome 17 (WNT9B gene) appears to increase risk by twofolds for impaction albeit with inability to detect significance due to small sample size.
Keywords: Third molars, Impactions, Height, Genetics, WNT9B
Introduction
Tooth impaction is a clinical condition in which a tooth cannot, or will not, erupt into its normal functioning position, unless facilitated by treatment [1]. Several systemic and local factors have been implicated in the etiology of permanent teeth impaction [1–3]. More commonly, local factors include prolonged deciduous tooth retention, malposed tooth germs, arch-length deficiency, supernumerary teeth, odontogenic tumors, abnormal eruption path and cleft lip and palate [1–4]. Cleidocranial dysplasia, Down syndrome, endocrine deficiencies (hypothyroidism and hypopituitarism), febrile diseases and irradiation are some of the systemic factors that may influence impaction of permanent teeth [1, 3–5].
The third molar is the last tooth to erupt in all races despite the racial variation in the eruption sequence [5, 6]. This late eruption is responsible for it being the most frequently impacted tooth [5–8]. The removal of the impacted third molar is a common dental procedure, and also one of the most frequent surgical events in the body [2, 6–10].
Racial variation in facial growth, jaw size and tooth size has been identified as crucial to the eruption pattern, impaction status and incidence of agenesis of third molars [4, 8–10]. Tooth impaction results from a disproportion between size of the teeth and length of the jaw [5–7]. However, it is not known whether there is a relationship between jaw length and the height of an individual. In addition, information regarding the effect of patient height on the pattern of third molar eruption is not available.
Furthermore, there are evidence in the literature, suggesting that genetics plays a role in height variations and body weight [11–13]. A recent genome-wide association study of permanent tooth eruption also suggests that the eruption of teeth is under some genetic influences [14]. The sequence and timing of permanent tooth eruption is thought to be highly heritable and can have important implications for the risk of malocclusion, crowding and periodontal disease [14]. Therefore, we hypothesize that the genetic factors that influence variation in height may also play a role in tooth impaction.
This study therefore sought to evaluate the relationship between height of an individual and the presence of impaction of maxillary and mandibular third molars in a Nigerian population. It also sought to determine the role of genetics in third molar impaction by exploring the association between third molar impaction and candidate genes for height, jaw growth and tooth agenesis.
Materials and Methods
This was a case–control study among Nigerian subjects. The study was approved by the Health Research and Ethics Committee of the Lagos University Teaching Hospital, Nigeria. Informed consent was obtained from patients and that the study was performed in accordance with the Declaration of Helsinki. Cases consisted of subjects with third molar impactions, and controls were those without third molar impactions. Using a matched case–control formula, the minimum sample size was calculated with 95% confidence level and 90% power.
Height of subjects was measured in meters. DNA was extracted from saliva samples collected from all subjects In order to investigate the role of selected genes in the etiology of third molar impactions, SNPs associated with jaw growth, height and tooth agenesis were selected. A total of 5 candidate genes (WNT9, AXIN2, MSX1, PAX9 and LINC01396) on chromosomes 4, 14 and 17 were investigated using 11 SNPs. Table 1 shows the SNPs genotyped, their loci and functions. The master mix contained 1.5 µl of TaqMan master mix which is the polymerase, 0.0375 µl of TaqMan probe (the marker for each gene investigated) and 1.4625 of double distilled H20 (ddH20) making a 3 µl of the master mix. At the completion of the PCR process, the plates were read using the 7900HT fast real-time PCR system controlled by the SDS software version 2.4. All the files with samples and markers were imported into Progeny version 7.6.04 from Progeny software LLC USA to check for Mendelian errors and discrepancies in each file. We then conducted case–control analyses to determine association using PLINK. For this test, we used alpha p < 0.05 to denote statistical significance.
Table 1.
SNPs genotyped for third molar impaction
| SNPS | Chromosomes | Gene Loci | Functions |
|---|---|---|---|
| rs735510 | 4 | 4p16.2 | Craniofacial development, odontogenesis |
| rs1042484 | 4 | MSX1 | Craniofacial development, odontogenesis |
| rs115200552 | 4 | MSX1 | Craniofacial development, odontogenesis |
| rs12532 | 4 | MSX1 | Craniofacial development, odontogenesis |
| rs2295218 | 14 | PAX9 | Odontogenesis, craniofacial development |
| rs731120 | 17 | 17q21.32 | Odontogenesis, craniofacial development |
| rs6504591 | 17 | WNT9B | Regulation of cell fate and patterning during embryogenesis, skeletal growth, jaw development |
| rs7224837 | 17 | AXIN2 | Odontogenesis, craniofacial formation |
| rs11867417 | 17 | AXIN2 | Odontogenesis, craniofacial formation |
| rs3923086 | 17 | AXIN2 | Odontogenesis, craniofacial formation |
| rs2240308 | 17 | AXIN2 | Odontogenesis, craniofacial formation |
Genetics home reference (2018)
The height of the cases and controls was analyzed and compared using independent T-test. Alpha of p < 0.05 was set to determine statistical significance.
Results
There were 200 cases (third molar impaction) and 200 controls (fully erupted third molar). There were 217 females and 183 males, with no difference in gender distribution between the cases and controls (p > 0.05). The mean age (SD) of the participants was 24.2 (5.50) years (age range, 17–69 years). There was no significant difference in the mean age of cases and control (p > 0.05). The mean height of cases (1.68 0 ± .09 m) was significantly lower than that of the control (1.70 ± 0.09 m) subjects (p = 0.04).
Table 2 shows case–control association analysis using PLINK. No difference was found in allele frequency between cases and controls in all the 5 SNPs on chromosomes 4 (rs735510, rs1042484, rs115200552, rs12532) and 14 (rs2295218) near MSX1, and on chr.4p16.2. Of the 6 genotyped SNPs on chromosome 17, no difference was found in allele frequency between cases and controls for five of them (rs731120, rs7224837, rs11867417, rs3923086, rs2240308) (Table 2). However, for rs6504591 the p value was near significance (p = 0.07) with odd ratio of 2.131 (Table 2). The SNP (rs6504591 with G/T variation) is located on human chromosome 17 (WNT9B gene). We observed that individuals with impacted third molars tend to carry the T allele for rs6504591 G > T near WNT9B.
Table 2.
Case–control association analysis using PLINK
| CHR | SNP | BP | A1 | F_A | F_U | A2 | CHISQ | p | OR | SE | L95 | U95 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 4 | rs735510 | 4,852,849 | 1 | 0.1813 | 0.1795 | 2 | 0.004539 | 0.9463 | 1.013 | 0.1867 | 0.7023 | 1.46 |
| 4 | rs1042484 | 4,864,381 | 2 | 0.1051 | 0.07436 | 1 | 2.26 | 0.1328 | 1.462 | 0.254 | 0.8889 | 2.406 |
| 4 | rs115200552 | 4,864,991 | 1 | 0.04359 | 0.0425 | 2 | 0.005694 | 0.9399 | 1.027 | 0.3506 | 0.5165 | 2.041 |
| 4 | rs12532 | 4,865,146 | 2 | 0.4695 | 0.4925 | 1 | 0.419 | 0.5174 | 0.9121 | 0.1421 | 0.6904 | 1.205 |
| 14 | rs2295218 | 3,713,4491 | 1 | 0.1846 | 0.19 | 2 | 0.03761 | 0.8462 | 0.9652 | 0.1824 | 0.6751 | 1.38 |
| 17 | rs731120 | 44,924,136 | 2 | 0.2128 | 0.171 | 1 | 2.147 | 0.1429 | 1.31 | 0.1848 | 0.9122 | 1.882 |
| 17 | rs6504591 | 44,944,828 | 1 | 0.04315 | 0.02073 | 2 | 3.16 | 0.07548 | 2.131 | 0.4349 | 0.9085 | 4.997 |
| 17 | rs7224837 | 63,528,123 | 2 | 0.1223 | 0.1237 | 1 | 0.003488 | 0.9529 | 0.9871 | 0.2192 | 0.6424 | 1.517 |
| 17 | rs11867417 | 63,537,898 | 1 | 0.2718 | 0.2613 | 2 | 0.1109 | 0.7392 | 1.055 | 0.1612 | 0.7693 | 1.447 |
| 17 | rs3923086 | 63,549,488 | 2 | 0 | 0.002513 | 1 | 0.9862 | 0.3207 | 0 | inf | 0 | nan |
| 17 | rs2240308 | 63,554,591 | 1 | 0.03333 | 0.05528 | 2 | 0.9312 | 0.3345 | 0.5893 | 0.5538 | 0.199 | 1.745 |
Discussion
In the present study, subjects with lower third molar impactions were significantly shorter in stature than those who have fully erupted third molars. This suggests that the eruption status of lower third molars may be related to the height of an individual. Previous reports in the literature have also suggested a positive correlation between the height of an individual and mandibular length [15–17]. In addition, earlier reports in the literature have also reported a correlation between the length of the mandible and the eruption status of the third molar [18, 19]. Akinbami and Didia [18] reported that the length of the mandible is a strong determinant factor in the erupting status of lower third molars. Capelli [20] also showed that the diminution in the total length of the mandible is a factor indicative of lower third molar impaction. The clinical implication of the above findings is that individuals who are short in stature are more likely to have a shorter mandibular length compared with those who are tall in stature; hence, they are more likely to have their lower third molars impacted.
The SNPs genotyped in this study to investigate the role of genetics in third molar impactions have been reported to play roles in jaw development, craniofacial development, skeletal growth, odontogenesis and regulation of cell fate and patterning during embryogenesis. No difference was found in allele frequency between cases and controls in all the genotyped SNPs except for rs6504591 which was near statistical significance (p = 0.07). The rs6504591 G > T is on human chromosome 17 near WNT9B gene. We observed that individuals with third molar impaction tend to have T allele at the locus, suggesting that the T allele at the locus may increase the risk for having an impacted third molar.
WNT9B is involved in tooth development, and polymorphisms in this gene may contribute to the risk of agenesis and impaction. WNT signaling has also been implicated in skeletal growth and maturation, and regulation of cell fate and patterning during embryogenesis. The near significant p value of 0.07 for rs6504591 near WNT9B with OR = 2.131 suggests that this observation may be clinically relevant. Therefore, future studies with an increase in sample size may be needed to authenticate this finding.
The relationship between the height of an individual and the eruption status found in the present study may also be related to the distinct role of WNT signaling. WNT signaling has also been implicated in skeletal growth and height [21]. Height growth in humans is distinctly different from growth in other mammals and is characterized in infancy by rapid but decelerating growth, a prolonged childhood phase of slow growth and a pubertal growth “spurt” before final height is reached—termed the Infancy/Childhood/Puberty (ICP) growth model [21]. Height is a continuous variation. Continuous variations tend to be polygenic, normally distributed, and the effects are often quantitative, often influenced by environment; and one can measure the differences between and across phenotypic range. Height is heritable, and very complex, so hundreds of genes contribute to height [21]. The biological mechanism is unclear for most of the genes that have been associated with height. Although genetics can play a big role in height, height may also be influenced by non-genetic factors like diet and malnutrition.
Conclusions
The findings from this study have the potentials for clinical application as well as for personalized medicine. The correlation between height and tooth impaction may be an additional consideration when planning for surgical treatment or patient selection. The increased OR with a SNP near WNT9B and the identification of T alleles in individuals with impacted third molars when confirmed in large scale studies can be applied to personalized medicine where the genotype of an individual can be used to predict risk for tooth impaction. The current study adds to the growing literature around height and tooth impaction as well as the role of genetics in tooth impaction. More studies are warranted to confirm our observations.
Acknowledgements
This research was conducted with supports from University of Lagos Central Research Committee (CRC) Grant (CRC NO/2014/05) to WLA and K99/R00 Grant DE0223/Robert Wood Johnson Foundation Grant (72429) to AB.
Compliance with Ethical Standards
Conflict of interest
All authors declare that they have no conflict 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 Declaration of Helsinki and its later amendments or comparable ethical standards.
Informed Consent
Informed consent was obtained from all individual participants included in the study.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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