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J Dent Res 82(5): 356-360, 2003
© 2003 International and American Associations for Dental Research

RESEARCH REPORT
Clinical

Genetic Predisposition to External Apical Root Resorption in Orthodontic Patients: Linkage of Chromosome-18 Marker

R.A. Al-Qawasmi1, J.K. Hartsfield, Jr.1,2,*, E.T. Everett1, L. Flury2, L. Liu2, T.M. Foroud2, J.V. Macri1, and W.E. Roberts1

1 Department of Oral Facial Development, Indiana University School of Dentistry, 1121 West Michigan Street, Indianapolis, IN 46202-5186, USA;
2 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA;

* corresponding author, jhartsfi{at}iupui.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
External apical root resorption (EARR) is a common orthodontic treatment sequela. Previous studies implicate a substantial genetic component for EARR. Using a candidate gene approach, we investigated possible linkage of EARR associated with orthodontic treatment with the TNSALP, TNF{alpha}, and TNFRSF11A gene loci. The sample was comprised of 38 American Caucasian families with a total of 79 siblings who completed comprehensive orthodontic treatment. EARR was assessed by means of pre- and post-treatment radiographs. Buccal swab cells were collected for extraction and analysis of DNA. No evidence of linkage was found with EARR and the TNF{alpha} and TNSALP genes. Non-parametric sibling pair linkage analysis identified evidence of linkage (LOD = 2.5; p = 0.02) of EARR affecting the maxillary central incisor with the microsatellite marker D18S64 (tightly linked to TNFRSF11A). This indicates that the TNFRSF11A locus, or another tightly linked gene, is associated with EARR.

KEY WORDS: linkage • chromosome 18 • RANK • root resorption • orthodontics


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
External apical root resorption (EARR) is a common orthodontic treatment sequela and is of potential clinical concern. EARR occurs primarily in the maxillary anterior teeth with various degrees of incidence and severity. In a large study of more than 860 cases, > 2 mm of EARR was seen in 25% of treated patients (Sameshima and Sinclair, 2001). Earlier, Killiany (1999) reported EARR of > 3 mm to occur at a frequency of 30%, with only 5% of treated individuals found to have > 5 mm of root resorption. Various non-genetic factors account for approximately one-tenth to one-third of the total variations in EARR (Linge and Linge, 1991; Horiuchi et al., 1998).

Family clustering of EARR has been suggested, although the pattern of inheritance was not clear (Newman, 1975). Direct evidence for a genetic component was recently demonstrated with use of the sib-pair model and estimated the heritability to be 70% (Harris et al., 1997). Recently, Al-Qawasmi et al. (2003) identified linkage and linkage disequilibrium between the IL-1B gene and EARR in orthodontically treated individuals. Success with the IL-1B gene supports the candidate gene approach to a search for additional loci contributing to EARR during orthodontic treatment.

Another candidate gene for EARR is TNFRSF11A, which encodes the receptor activator of nuclear factor-kappa B (RANK), and maps to 18q21.2-21.3 (Hughes et al., 1994), the same region as do familial expansile osteolysis (FEO) and a form of familial Paget disease of bone (PDB) (Hughes et al., 2000). RANK is a member of the TNF-receptor superfamily and, together with the RANK ligand, mediates signaling leading to osteoclastogensis (Nakagawa et al., 1998). Another candidate gene for EARR in orthodontic treatment is tissue non-specific alkaline phosphatase (TNSALP), the product of which plays an important role in mineralization and cementum formation (Beertsen et al., 1991). The TNSALP gene maps to chromosome 1p36.1-34 (Whyte, 1994). Mice lacking a functional TNSALP gene have defective acellular cementum formation along the molar roots and delayed tooth eruption (Beertsen et al., 1999). Previous studies implicate TNF{alpha} in bone remodeling in vitro and in vivo (Le and Vilcek, 1987), supporting its inclusion as a candidate gene for EARR. Moreover, TNF{alpha} levels are elevated during orthodontic tooth movement in the human gingival sulcus (Lowney et al., 1995). The TNF{alpha} gene maps to 6p21.3. A single-nucleotide polymorphism (SNP) located at nucleotide -308 with respect to the TNF{alpha} transcriptional start site serves as a polymorphic marker for linkage studies (Kornman et al., 1997).

The purpose of this study was to investigate possible linkage and linkage disequilibrium (association) between polymorphic markers flanking or within the TNFRSF11A, TNSALP, and TNF{alpha} genes and EARR in a sample of Caucasian families with orthodontically treated offspring.


   MATERIALS & METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subject Selection
Families having at least two siblings who had received full-banded comprehensive treatment in a university graduate orthodontic clinic or private orthodontic practice were identified and invited to participate. Having EARR was not a prerequisite for participation. Additional family members (e.g., parents) were asked to enroll. In all, 124 subjects (79 siblings and 45 parents) from 38 families were genotyped for the candidate loci. The mean age at the first examination and the average duration between pre- and post-treatment records of study subjects were 12.3 ± 1.82 yrs and 2.77 ± 1.13 yrs, respectively. A summary of the family data is presented in Table 1Go. All subjects gave written informed consent. The IUPUI and Clarian Institutional Review Boards and Subcommittees Reviews approved this study.


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  		Table 1. Description of Treated Individuals Used in Linkage and Association Analyses
 
EARR Measurements
Measurements were made of the roots of three types of teeth on pre- and post-treatment lateral cephalometric and pan-oral radiographs: the maxillary central incisor with the longest root, the mandibular central incisor with the longest root, and the mesial and distal roots of both the mandibular first molars as described previously (Harris et al., 1997). For each patient, the difference in pre- and post-treatment lengths for the right and left first molars was averaged between the 2 sides for each root. The same examiner (R.A.A.) performed all measurements. The data for each of the 4 variables were considered separately for genetic analysis.

Error of the Method
The reproducibility of the measurements was assessed by statistical analysis of the difference between double measurements made two months apart on 18 randomly selected cephalograms and pan-oral radiographs. The method error was calculated from the equation:


where Sx is the error for measurement, D is the difference between duplicated measurements, and N is the number of double measurements (Dahlberg, 1940). The errors for tooth length and crown height measurements on the cephalograms did not exceed 0.31 mm and 0.14 mm and 0.38 mm and 0.22 mm on the pan-oral radiographs, respectively.

Sample Collection and Extraction of DNA
Using 10 strokes, we scraped the buccal mucosa with a sterile nylon bristle brush. Two brushes were collected from each individual and used for the preparation of genomic DNA according to the Puregene method (Gentra Systems, Minneapolis, MN, USA). Genomic DNA at a concentration of ~ 50 µg/mL in Tris-EDTA was stored at 4°C until genotyped.

Analysis of Genetic Polymorphisms
A reaction mix excluding Taq polymerase was prepared, and 1 µL of DNA was added. Taq polymerase (1.25 µL) was then added and polymerase chain-reaction (PCR) performed. All reactions were carried out in 20 mM Tris-HCl, 50 mM KCl, 0.2 mM each dNTP. The MgCl2 and primer concentrations varied in each type of reaction: TNFRSF11A (D18S64) forward primer, 5'-ATACTGGTGGTGGTTATACAACAT-3', reverse primer, 5'-AAATCAGGAAATCGGCA-3', both at 1.5 µM, and MgCl2 (1.5 mM). One primer was labeled at the 5' end with [{gamma}-33P] ATP as described previously (Jeunemaitre et al., 1992). Cycling was carried out for 1 cycle at 94°C for 10 min, 60°C for 1 min, and 72°C for 2 min; 35 cycles at 94°C for 2 min, 60°C for 1 min, and 72°C for 2 min. PCR reaction products were resolved over denaturing sequencing gels containing 6% polyacrylamide/8 M urea followed by autoradiography. The PCR products were distinguished with the use of a M13 reference-sequencing ladder (Sequenase version 2.0 DNA Sequencing kit; USB, Cleveland, OH, USA). For TNFRSF11A, products of 188 bp (allele 1), 190 bp (allele 2), 192 bp (allele 3), 194 bp (allele 4), 200 bp (allele 5), 204 bp (allele 6), 206 bp (allele 7), and 208 bp (allele 8) were observed (Fig. 1bGo): TNSALP (AL215L) forward primer, 5'-AGGATTCTGGGAGACAGCAA-3', reverse primer, 5'-CAAGTCCCTCTCCAATGATC-3', both at 1.65 µM, and MgCl2 (1.5 mM). Primer labeling, PCR cycling, and product visualization for AL215L were carried out similarly to what was described above for the TNFRSF11A gene and yielded products of 141 bp (allele 1) and 149 bp (allele 2): TNF{alpha} (-308) forward primer, 5'-AGGCAATAGGTTTTGAGGGCCAT-3', reverse primer, 5'-TCCTCCCTGCTCCGATTCCG-3', both at 2 µM, and MgCl2 (1.5 mM). PCR cycling and allele detection were carried out as described previously (Kornman et al., 1997).



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  		Figure 1. Transmission of D18S64 alleles in three families, each with two offspring who underwent orthodontic treatment. (Panel A) Pedigree. Circles denote females, squares denote males, and the 1, 2, 3, and 7 alleles within indicate the D18S64 genotype. Roman numeral (I) denotes parents and (II) denotes offspring. Arabic numbers below indicate the individual number. External apical root resorption (EARR) values, in millimeters, for the maxillary central incisors in treated offspring are shown. (Panel B) Polyacrylamide gel electrophoresis of PCR products derived from all individuals in the pedigrees. Each lane corresponds to the individual in the pedigree shown above in panel A. Band sizes in basepairs (bp) are indicated on the left (188 bp = allele 1, 190 bp = allele 2, 192pb = allele 3, and 206 bp = allele 7). (Panel C) Pre-treatment (Pre) and post-treatment (Post) lateral cephalograms for treated siblings (AII-3 and AII-4) in Family A. Apices of the roots of the central incisors and the incisal edges are indicated with upper and lower arrows, respectively.

 
Statistical Methods
We performed two types of genetic analyses to evaluate the role of the D18S64, AL215L, and TNF{alpha}-308 polymorphisms in EARR. First, we performed analyses to evaluate linkage of the EARR phenotype with the polymorphisms. We used the program MAPMAKER/SIBS (Kruglyak and Lander, 1995) to test if the markers in the candidate genes were linked to an EARR susceptibility gene, by testing if the magnitude of the squared phenotypic difference between two siblings is correlated with the number of alleles they share that are identical by descent (IBD). We formed and analyzed all possible n(n-1)/2 sibling pairs (n = number of siblings in a nuclear family), as well as utilizing the more conservative approach of weighting the contributions of sibships of more than two siblings to that of an equivalent number of independent sibling pairs (n-1). To evaluate the significance of the linkage results, we used a permutation method. In total, we generated 5000 replicates, re-assigning the phenotype on a family-wise basis while keeping the marker data constant. We then analyzed the replicates using the program MAPMAKER/SIBS, and used the distribution of the results from these replicates to derive the empirical threshold of significance for the linkage test statistic.

Second, we evaluated evidence of linkage disequilibrium for TNSALP and TNF{alpha} using the quantitative transmission disequilibrium test (Q-TDT) as implemented in the program Q-TDT (Abecasis et al., 2000). The method of Monks and Kaplan (2000) was used, which calculates the difference between the values of the quantitative trait of the offspring and the average quantitative trait of all offspring in all families studied, while simultaneously considering the allele transmission from parent to offspring. There was insufficient power to test the association of the marker D18S64 near the TNFRSF11A gene, due to the marker’s high heterozygosity and the limited sample available for study.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
We used 2 diallelic markers (AL215L and TNF{alpha}-308) and 1 microsatellite polymorphism marker (D18S64), flanking or lying within candidate loci, in a candidate gene approach to assess the evidence of linkage and association in 38 pedigrees. The 79 siblings produced 49 sibling pairs when all possible pairs of siblings were formed and 41 independent sibling pairs. In families A, B, and C, the numbers of D18S64 alleles shared by siblings and identical by descent (IBD) are 0, 1, and 2 (out of 2), respectively (Figs. 1AGo, 1BGo). The siblings with similar values of EARR in the maxillary central incisor in family C share more alleles IBD (2 out of 2), while the siblings with the widely differing EARR values in family A share zero (out of 2) alleles IBD (Figs. 1AGo, 1BGo). Four phenotypic variables were analyzed by pre- and post-treatment cephalograms: EARR on the maxillary central incisor (Fig. 1CGo), the mandibular central incisor, and the mesial and the distal roots of the mandibular first molar. Suggestive evidence for linkage between EARR in the maxillary central incisor and the polymorphic marker D18S64 was obtained (LOD score 2.51) (Table 2Go). Based on permutation studies performed on these data, the estimated significance of a LOD score of 2.5 when a single marker is tested is p = 0.02. No evidence for linkage was obtained with the markers for TNF{alpha} and TNSALP in our study population (Table 2Go).


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  		Table 2. Results of Single-point Linkage Analysis
 
The tests of linkage disequilibrium performed by the Q-TDT approach showed no evidence of linkage disequilibrium with any of the 4 EARR phenotypes and either of the polymorphisms tested in TNF{alpha} and TNSALP (p > 0.05, data not shown).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The linkage results for D18S64, which lies close to the candidate gene TNFRSF11A, provide suggestive evidence that this locus, or a closely linked one, contributes to the genetic component of EARR. The fact that the LOD score was highest for EARR in the maxillary central incisor is consistent with the results of previous studies (Harris et al., 1997), which found the highest heritability estimates (h2 = 79%) in this tooth as compared with other teeth.

The TNFRSF11A gene encodes the receptor activator of nuclear factor-kappa B (RANK), an essential signaling molecule in osteoclast formation and activation (Anderson et al., 1997; Nakagawa et al., 1998). FEO, familial PDB, and expansile skeletal hyperphosphatasia (ESH) have been associated with TNFRSF11A gene mutations (Hughes et al., 2000; Whyte and Hughes, 2002). FEO is a rare autosomal-dominant skeletal disorder characterized by early-onset hearing loss, root resorption of permanent teeth, and painful bony expansion with cortical bone thinning. The histopathologic findings of the active osteolytic lesion in FEO resemble the abnormalities in PDB. ESH features deafness in infancy, premature resorption of permanent teeth, progressive hyperostotic expansion of long bones, and episodic hypercalcemia (Whyte and Hughes, 2002). Three insertion mutations were identified in exon 1 of TNFRSF11A and were found to cause an increase in RANK-mediated nuclear factor-kappa B (NF-{kappa}B) signaling in vitro (gain of function activation mutation) (Hughes et al., 2000; Whyte and Hughes, 2002). All affected individuals in the eight families studied have one of the 3 mutations and have dental problems, with early loss of their permanent dentition due mainly to root resorption (Hughes et al., 2000; Whyte and Hughes, 2002). These reports and the strength of linkage of the D18S64 marker with EARR in this study make TNFRSF11A a candidate gene for further study.

Tnfrsf11a -/- mice lack osteoclasts and have a profound defect in bone resorption and remodeling processes (Li et al., 2000). While the administration of TNF{alpha} in Tnfrsf11a -/- mice led to occurrence of osteoclast formation near the site of injection, the administration of IL-1ß did not (Li et al., 2000). This and the association of IL-1B with EARR (Al-Qawasmi et al., 2003) imply that IL-1B and TNFRSF11A encoded proteins act on the same osteoclast formation pathway, which is involved in EARR associated with orthodontic treatment. This also suggests that TNF{alpha} functions in an alternative pathway leading to osteoclast formation, which might be unrelated to EARR (Fig. 2Go). This is consistent with the negative finding of association of EARR with the TNF{alpha} gene in the present study and the absence of any detectable TNF{alpha} mRNA level during orthodontic tooth movement (Alhashimi et al., 2001).



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  		Figure 2. Two proposed pathways for osteoclast formation in relation to EARR associated with orthodontic treatment. One pathway is RANK-dependent, while the other one might be mediated by TNFR1 and/or TNFR2 (tumor necrosis factor receptor). RANK is the intrinsic cell-surface determinant that mediates the effects of RANK ligand (RANKL) and osteoprotegerin (OPG) on bone resorption as well as the effects of cytokines like IL-1ß. RANKL (also known as ODF and OPGL), expressed on the surfaces of pre-osteoblastic cells, binds to RANK on the osteoclastic precursor cells and is critical for differentiation, fusion, activation, and survival of osteoclastic cells. OPG (also known as OCIF) puts a brake on the entire system by blocking the effects of RANKL. The pro-resorptive cytokine lL-1ß modulates this system by directly increasing the RANKL expression. Two main components of this pathway (IL-1ß and a marker closely linked to RANK) were found to be in linkage disequilibrium and/or genetically linked to EARR associated with orthodontic treatment. This suggests that osteoclasts stimulated through this pathway are related to root resorption during orthodontic tooth movement. In contrast, TNF{alpha} in the second pathway is able to induce osteoclast formation in the RANK-independent pathway, presumably by activation of either TNFR1 and/or TNFR2. The absence of association of TNF{alpha} with EARR in the current study and in previous studies suggests that osteoclastic cells induced through this pathway are not related to root resorption during orthodontic treatment.

 
Currently, there are no reliable markers to predict either which patients will develop EARR or the severity of EARR following orthodontic tooth movement (Vlaskalic et al., 1998). The association of a specific IL-1B allele and EARR, which accounts for approximately 15% of the total EARR variation seen in orthodontic patients, has emerged as a potential genetic marker (Al-Qawasmi et al., 2003). One or more genes flanking the D18S64 polymorphism, perhaps TNFRSF11A, appear also to influence EARR, although to what extent is not yet known. Implicating another genetic factor supports the multigenic nature of EARR susceptibility. Future estimation of an individual’s susceptibility to EARR will likely require the analysis of a suite of genes.

In conclusion, suggestive linkage of the D18S64 marker with EARR is presented. Further studies are needed to confirm these initial findings and better define the genetic polymorphisms responsible for the observed linkage. The strength of linkage of the D18S64 marker with EARR and the report of severe root resorption as a part of FEO, ESH, and familial PDB with TNFRSFR11A mutations (Hughes et al., 2000; Whyte and Hughes, 2002) indicate that this gene is an important candidate for further study.


   ACKNOWLEDGMENTS
 
We sincerely thank the patients and their families for making this study possible. We also thank the staff of the Indiana University School of Dentistry orthodontic clinic as well as the staff of Dr. James V. Macri’s private practice of orthodontics in South Bend, IN. An American Association of Orthodontists Foundation Biomedical Research Award to JKH supported this work. This paper is based upon a thesis submitted to the Graduate Faculty, Indiana University, in partial fulfillment of the requirements for the PhD degree.

Received July 22, 2002; Last revision January 21, 2003; Accepted January 31, 2003


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