James K. Hartsfield

Genetic predisposition to external apical root resorption

External apical root resorption (EARR) can be an undesirable sequela of orthodontic treatment. Previous studies have suggested that EARR has a substantial genetic component. Linkage and association were examined between polymorphisms of the interleukin IL-1 (IL-1A and IL-1B) genes and EARR in 35 white American families. Buccal swab cells were collected for DNA isolation and analysis. The EARR in the maxillary central incisors, the mandibular central incisors, and the mesial and distal roots of the mandibular first molar were analyzed separately and together by using both linkage and association methods of analysis. Highly significant (P =.0003) evidence of linkage disequilibrium of IL-1B polymorphism with the clinical manifestation of EARR was obtained. The analysis indicates that the IL-1B polymorphism accounts for 15% of the total variation of maxillary incisor EARR. Persons homozygous for the IL-1B allele 1 have a 5.6 fold (95% CI 1.9-21.2) increased risk of EARR greater than 2 mm as compared with those who are not homozygous for the IL-1β allele 1. Data indicate that allele 1 at the IL-1B gene, known to decrease the production of IL-1 cytokine in vivo, significantly increases the risk of EARR. These findings are consistent with an interpretation of EARR as a complex condition influenced by many factors, with the IL-1B gene contributing an important predisposition to this common problem. Defining genetic contributions to EARR is an important factor in understanding the contribution of environmental factors, such as habits and therapeutic biomechanics. (Am J Orthod Dentofacial Orthop 2003;123:242-52)

Genetic Factors in External Apical Root Resorption and Orthodontic Treatment

External apical root resorption (EARR) is a common sequela of orthodontic treatment, although it may also occur in the absence of orthodontic treatment. The degree and severity of EARR associated with orthodontic treatment are multifactorial, involving host and environmental factors. Genetic factors account for at least 50% of the variation in EARR. Variation in the Interleukin 1 beta gene in orthodontically treated individuals accounts for 15% of the variation in EARR. Historical and contemporary evidence implicates injury to the periodontal ligament and supporting structures at the site of root compression following the application of orthodontic force as the earliest event leading to EARR. Decreased IL-1beta production in the case of IL-1B (+3953) allele 1 may result in relatively less catabolic bone modeling (resorption) at the cortical bone interface with the PDL, which may result in prolonged stress concentrated in the root of the tooth, triggering a cascade of fatigue-related events leading to root resorption. One mechanism of action for EARR may be mediated through impairment of alveolar resorption, resulting in prolonged stress and strain of the adjacent tooth root due to dynamic functional loads. Future estimation of susceptibility to EARR will likely require the analysis of a suite of genes, root morphology, skeleto-dental values, and the treatment method to be used-or essentially the amount of tooth movement planned for treatment.

Original ArticleGenetic predisposition to external apical root resorption☆1☆2☆3☆4☆5☆6☆7☆8☆9☆10☆11

External apical root resorption (EARR) can be an undesirable sequela of orthodontic treatment. Previous studies have suggested that EARR has a substantial genetic component. Linkage and association were examined between polymorphisms of the interleukin IL-1 (IL-1A and IL-1B) genes and EARR in 35 white American families. Buccal swab cells were collected for DNA isolation and analysis. The EARR in the maxillary central incisors, the mandibular central incisors, and the mesial and distal roots of the mandibular first molar were analyzed separately and together by using both linkage and association methods of analysis. Highly significant (P =.0003) evidence of linkage disequilibrium of IL-1B polymorphism with the clinical manifestation of EARR was obtained. The analysis indicates that the IL-1B polymorphism accounts for 15% of the total variation of maxillary incisor EARR. Persons homozygous for the IL-1B allele 1 have a 5.6 fold (95% CI 1.9-21.2) increased risk of EARR greater than 2 mm as compared with those who are not homozygous for the IL-1β allele 1. Data indicate that allele 1 at the IL-1B gene, known to decrease the production of IL-1 cytokine in vivo, significantly increases the risk of EARR. These findings are consistent with an interpretation of EARR as a complex condition influenced by many factors, with the IL-1B gene contributing an important predisposition to this common problem. Defining genetic contributions to EARR is an important factor in understanding the contribution of environmental factors, such as habits and therapeutic biomechanics. (Am J Orthod Dentofacial Orthop 2003;123:242-52)

A comprehensive analysis of normal variation and disease-causing mutations in the human DSPP gene

Within nine dentin dysplasia (DD) (type II) and dentinogenesis imperfecta (type II and III) patient/families, seven have 1 of 4 net –1 deletions within the ∼2‐kb coding repeat domain of the DSPP gene while the remaining two patients have splice‐site mutations. All frameshift mutations are predicted to change the highly soluble DSPP protein into proteins with long hydrophobic amino acid repeats that could interfere with processing of normal DSPP and/or other secreted matrix proteins. We propose that all previously reported missense, nonsense, and splice‐site DSPP mutations (all associated with exons 2 and 3) result in dominant phenotypes due to disruption of signal peptide‐processing and/or related biochemical events that also result in interference with protein processing. This would bring the currently known dominant forms of the human disease phenotype in agreement with the normal phenotype of the heterozygous null Dspp (–/+) mice. A study of 188 normal human chromosomes revealed a hypervariable DSPP repeat domain with extraordinary rates of change including 20 slip‐replication indel events and 37 predominantly C‐to‐T transition SNPs. The most frequent transition in the primordial 9‐basepair (bp) DNA repeat was a sense‐strand CpG site while a CpNpG (CAG) transition was the second most frequent SNP. Bisulfite‐sequencing of genomic DNA showed that the DSPP repeat can be methylated at both motifs. This suggests that, like plants and some animals, humans methylate some CpNpG sequences. Analysis of 37 haplotypes of the highly variable DSPP gene from geographically diverse people suggests it may be a useful autosomal marker in human migration studies. Hum Mutat 0, 1–13, 2008. Published 2008, Wiley‐Liss, Inc.

Pathways in external apical root resorption associated with orthodontia

To review studies investigating if genetic factors play a role in external apical root resorption (EARR) during orthodontic treatment. Heritability estimation in human sib-pairs, comparison of multiple inbred mouse strains, human sib-pair linkage and parents-child trio association studies, and two gene (Il-1b, and P2rx7) knock out mouse models. Heritability for EARR of the maxillary central incisors concurrent with orthodontic treatment is 0.8. DBA/2J, BALB/cJ, and 129P3/J inbred mouse strains are highly susceptible (p < .05) to histological root resorption (RR) associated with orthodontic force (RRAOF), whereas A/J, C57BL/6J and SJL/J mice are resistant. Non-parametric sibling pair linkage analysis identified evidence of linkage (LOD = 2.5; p = 0.02) of EARR with microsatellite D18S64 (tightly linked to TNFRSF11A, also known as RANK). There is significant linkage disequilibrium of IL-1B (p = 0.0003), and OPG (p = 0.003) with EARR. RRAOF increases in Il1b KO (p < or = 0.013), and increases in P2rx7 KO (p < 0.02) mice compared to wild-type. Genetic factors play a marked role in EARR concurrent with orthodontic force, accounting for one-half to two-thirds of the variation. Two pathways for this may involve: 1) activation control of osteoclasts through the ATP/P2XR7/IL-1B inflammation modulation pathway; and 2) RANK/RANKL/OPG osteoclast activation control. Histological RR occurs and is typically healed. If resorption outpaces healing, then EARR develops. Normal and parafunctional forces, as well as orthodontic forces, may add to or interact with the individuals susceptibility to pass the threshold of developing EARR.

Major Gene and Multifactorial Inheritance of Mandibular Prognathism

Mandibular prognathism typically shows familial aggregation. Various genetic models have been described and it is assumed to be a multifactorial and polygenic trait, with a threshold for expression. Our goal was to examine specific genetic models of the familial transmission of this trait. The study sample comprised of 2,562 individuals from 55 families. Complete family histories for each proband were ascertained and the affection status of relatives were confirmed by lateral cephalograms, photographs, and dental models. Pedigrees were drawn using PELICAN and complex segregation analysis was performed using POINTER. Parts of some pedigrees were excluded to create one founder pedigrees, so the total N was 2,050. Analysis showed more affected females than males (P = 0.030). The majority of the pedigrees suggest autosomal dominant inheritance. Incomplete penetrance was demonstrated by the ratio of affected/unaffected parents and siblings. The heritability of mandibular prognathism was estimated to be 0.316. We conclude that there is a major gene that influences the expression of mandibular prognathism with clear signs of Mendelian inheritance and a multifactorial component.

Evaluation of retention protocols among members of the American Association of Orthodontists in the United States

INTRODUCTION Little research has been conducted to evaluate protocols and trends in orthodontic retention. The purpose of this study was to identify the general retention protocols used by orthodontists in the United States. Additionally, our goal was to identify trends in these orthodontic retention protocols by evaluating how they have changed over the past 5 years and how they might continue to change in the next 5 years. METHODS The study was conducted via a 36-question electronic survey (REDCap, Nashville, Tenn) with branching logic on certain questions. The survey was sent to all 9143 practicing members of the American Association of Orthodontists in the United States, and 1632 (18%) responded. RESULTS AND CONCLUSIONS Mean retention protocols of the surveyed population showed predominant use of Hawley or vacuum-formed retainers in the maxillary arch and fixed retention in the mandibular arch. For both arches, there is a current shift away from Hawley retainers and toward vacuum-formed retainers and fixed retention. Respondents who extract fewer teeth reported increased use of fixed retention in the maxillary (P = 0.041) and mandibular (P = 0.003) arches. Respondents who extract fewer teeth and use removable retainers were more likely to tell their patients to wear their retainers at night for the rest of their lives (P = 1.63 × 10(-6)).

Orthodontic mechanotransduction and the role of the P2X7 receptor

INTRODUCTION The P2X7 receptor plays a crucial role in bone biology and inflammation. Its main function is to promote necrotic tissue metabolism by ensuring a normal acute-phase inflammatory response. We used a mouse model to describe and compare orthodontic mechanotransduction in wild-type and P2X7 knock-out mice. METHODS By using finite element analysis, mouse orthodontic mechanics were scaled to produce typical human stress levels. External root resorption, bone modeling, and bone remodeling were analyzed with fluorescent bone labels, Masson trichrome stain, and microcomputed tomography. Relationships between the biologic responses and the calculated stresses were statistically tested and compared between mouse types. RESULTS There were direct relationships between certain stress magnitudes and root resorption and bone formation. Hyalinization and root and bone resorption were different in the 2 types of mice. CONCLUSIONS Orthodontic responses are related to the principal stress patterns in the periodontal ligament, and the P2X7 receptor plays a significant role in their mechanotransduction.

Effects of rapid maxillary expansion on the cranial and circummaxillary sutures.

INTRODUCTION The aim of this study was to determine whether the orthopedic forces of rapid maxillary expansion cause significant quantitative changes in the cranial and the circummaxillary sutures. METHODS Twenty patients (mean age, 12.3 ± 1.9 years) who required rapid maxillary expansion as a part of their comprehensive orthodontic treatment had preexpansion and postexpansion computed tomography scans. Ten cranial and circummaxillary sutures were located and measured on one of the axial, coronal, or sagittal sections of each patients preexpansion and postexpansion computed tomography scans. Quantitative variables between the 2 measurements were compared by using the Wilcoxon signed rank test. A P value less than 0.05 was considered statistically significant. RESULTS Rapid maxillary expansion produced significant width increases in the intermaxillary, internasal, maxillonasal, frontomaxillary, and frontonasal sutures, whereas the frontozygomatic, zygomaticomaxillary, zygomaticotemporal, and pterygomaxillary sutures showed nonsignificant changes. The greatest increase in width was recorded for the intermaxillary suture (1.7 ± 0.9 mm), followed by the internasal suture (0.6 ± 0.3 mm), and the maxillonasal suture (0.4 ± 0.2 mm). The midpalatal suture showed the greatest increase in width at the central incisor level (1.6 ± 0.8 mm) followed by the increases in width at the canine level (1.5 ± 0.8 mm) and the first molar level (1.2 ± 0.6 mm). CONCLUSIONS Forces elicited by rapid maxillary expansion affect primarily the anterior sutures (intermaxillary and maxillary frontal nasal interfaces) compared with the posterior (zygomatic interface) craniofacial structures.

The Nance-Horan syndrome: a rare X-linked ocular-dental trait with expression in heterozygous females

This report describes two families with the Nance‐Horan syndrome, an X‐linked trait featuring lenticular cataracts and anomalies of tooth shape and number. Previous reports have described blindness in affected males but posterior sutural cataracts with normal vision as the primary ocular expression in heterozygous females. In one of these two families, the affected female is not only blind in one eye but reportedly had supernumerary central incisors (mesiodens) removed. This constitutes the most severe ocular and dental expression of this gene in heterozygous females yet reported.