Yoko Tomoyasu

Effects of an Asian-specific nonsynonymous EDAR variant on multiple dental traits.

Dental morphology is highly diverse among individuals and between human populations. Although it is thought that genetic factors mainly determine common dental variations, only a few such genetic factors have been identified. One study demonstrated that a nonsynonymous single-nucleotide polymorphism (370V/A, rs3827760) in the ectodysplasin A receptor gene (EDAR) is associated with shoveling and double-shoveling grades of upper first incisors and tooth crown size. Here, we examined the association of EDAR 370V/A with several dental characters in Korean and Japanese subjects. A meta-analysis that combined analyses of Korean and Japanese subjects revealed that the Asian-specific 370A allele is associated with an increase in the grades of shoveling and double shoveling, as previously found. We also showed a highly significant association between EDAR 370V/A genotype and crown size, especially mesiodistal diameters of anterior teeth. Moreover, we found that the 370A allele was associated with the presence of hypoconulids of lower second molars. These results indicated that the EDAR polymorphism is responsible, in part, for the Sinodonty and Sundadonty dichotomy in Asian populations, and clearly demonstrated that the EDAR polymorphism has pleiotropic effects on tooth morphology. As the 370A allele is known to be a most likely target of positive selection in Asian populations, some phenotypes associated with the variant may be ‘hitchhiking phenotypes’, while others may be actual targets of selection.

Exome resequencing combined with linkage analysis identifies novel PTH1R variants in primary failure of tooth eruption in Japanese

Massively parallel sequencing of target regions, exomes, and complete genomes has begun to increase the opportunities for identifying genetic variants underlying rare and common diseases dramatically. Here we applied exome resequencing to primary failure of tooth eruption (PFE) to identify the genetic causality of the disease. Two Japanese families having PFE were recruited and examined by genome‐wide linkage study and subsequently exome analyses. Linkage analyses of these two families comprising eight affected individuals and two unaffected individuals revealed linkage signals at 10 loci with a maximum LOD score of 1.5. Four affected individuals in one family were pooled and further processed for exome analysis, followed by massive parallel sequencing. After three‐step filtering including annotation and functional expectation, three variants were found to be candidates for PFE. Among the three variants, only a novel variant of parathyroid hormone 1 receptor gene (PTH1R), R383Q, was cosegregated in the first PFE family. Accordingly, we screened the gene for variants at all coding exons and the respective intron‐exon boundaries in the second family and two sporadic individuals with PFE. We also identified a novel missense variant, P119L, cosegregating in the second family and missense variants P132L and R147C in the sporadic cases. These variants all were in the highly conserved region across zebrafish to chimpanzee and not observed in 192 unrelated controls, supporting the pathogenicity of the variants. The combination of linkage and exome analyses employed in this study provides a powerful strategy for identifying genes responsible for Mendelian disorders.

Further evidence for an association between mandibular height and the growth hormone receptor gene in a Japanese population

INTRODUCTION Craniofacial morphology has a significant genetic component. It has recently been reported that single nucleotide polymorphisms (SNPs) in the growth hormone receptor gene (GHR) are associated with mandibular height. To confirm these findings, we genotyped SNPs in healthy Japanese subjects, about 1.7 times the number analyzed in previous reports. METHODS By using 5 SNPs in exon 10 of the GHR, we studied the relationships between genotypes and craniofacial linear measurements. The allelic frequencies in a multi-ethnic population (Han Chinese, African American, European American, and Hispanic) were also observed. RESULTS There was a significant association between SNPs and mandibular ramus height (P = 0.029), confirming our previous report of an association between polymorphism P561T and mandibular ramus height. Moreover, the SNP, C422F, was in linkage disequilibrium with P561T. Subjects with genotype CC of polymorphism P561T and genotype GG of polymorphism C422F had significantly greater mandibular ramus height than those with genotypes CA and GT. Four of the 5 SNPs were found almost exclusively in Asians, with the frequencies in other populations extremely small. CONCLUSIONS Our results indicate that the GHR polymorphisms P561T and C422F are associated with mandibular ramus height in Japanese population and suggest that the SNPs of the GHR associated with the Japanese are likely to be different in other ethnic groups. This might partly explain the differing craniofacial morphology among different ethnicities.

Association of the growth hormone receptor gene polymorphisms with mandibular height in a Korean population

Growth hormone receptor gene (GHR) is one of the likely candidates for determining morphological traits, because GH is a key regulator of bone growth. The genetic association of GHR in exon 10 with mandibular ramus height has been found in different populations, Japanese and Chinese. On the other hand, two common isoforms of GHR, one full-length (fl-GHR) and the other lacking the extracellular domain encoded by exon 3 (d3-GHR), are associated with differences in responsiveness to GH. The purpose of this study involving 159 Korean subjects was to study the associations between a GHR polymorphism (d3/fl-GHR) that results in genomic deletion of exon 3 and craniofacial morphology, and to study the associations between GHR genotypes in exon 10 and craniofacial morphology. Moreover, the allelic frequencies in a multi-ethnic population (24 Han Chinese, 24 African-Americans, 24 European-Americans, and 24 Hispanics) in a GHR polymorphism (d3/fl-GHR) were compared in this study. The five craniofacial linear measurements (cranial base length, maxillary length, overall mandibular length, mandibular corpus length, and mandibular ramus height) obtained from lateral cephalograms were examined as craniofacial morphology. We found that the d3/fl-GHR polymorphism had no association for any measurements, and a statistically significant association (P=0.024) between the GHR polymorphisms P561T and C422F in exon 10 and mandibular ramus height. Neither SNPs besides P561T and C422F polymorphisms in exon 10 nor the measurements besides mandibular ramus height have statistically significances. Both derived alleles at P561T and C422F SNPs were highly associated with only one haplotype, haplotype-4 in Korean population. As quantitative haplotype association, the results showed a significant difference in mandibular ramus height between individuals having one haplotype-4 and others without haplotype-4 (P=0.028). Moreover, we found that the d3/fl-GHR polymorphism showed diverse frequency in different population. Regarding GHR genotypes in exon 10, the present study mostly reflected the results obtained for a Japanese population, although our current study does not replicate the correlation between the I526L polymorphism of GHR and mandibular ramus height as was reported in a previous study of Han Chinese. The results of the present study suggest that the GHR exon 10 SNPs, not d3/fl-GHR, contribute to changes in the mandibular ramus height of Koreans.

Association of common PAX9 variants with permanent tooth size variation in non-syndromic East Asian populations

Studies on the heredity of dental characteristics in humans have indicated that the variance in many dental traits results from genetic variation. However, the genetic factors that influence commonly occurring dental variants are poorly understood. Paired domain box 9 (PAX9) codes a transcription factor that is important in tooth development. We investigated whether PAX9 polymorphisms are associated with normal variations in tooth agenesis and morphology. The study subjects were 273 Japanese and 223 Korean adults. Single-nucleotide polymorphisms (SNPs) in PAX9 (rs2295222, rs4904155, rs2073244, rs12881240 and rs4904210) were genotyped, and third molar agenesis and mesiodistal and buccolingual diameters were measured. We found that four of the five SNPs were significantly associated with the crown size. However, no SNP was associated with third molar agenesis. In additional analyses on non-metric dental traits, we found significant associations of PAX9 SNPs with shoveling of upper first incisors. In summary, common variants in PAX9 contributed to morphological variation in permanent teeth in humans.

External apical root resorption and the interleukin-1B gene polymorphism in the Japanese population

Abstract External apical root resorption (EARR) is a common consequence of orthodontic treatment. Recently, several studies have reported an association between EARR and an underlying genetic cause. This study investigated whether a single interleukin (IL)-1B gene polymorphism (rs1143634) was associated with EARR in the Japanese population. Genomic DNA, lateral cephalograms, and panoramic radiographs were obtained from 54 Japanese. We measured the EARR in the maxillary central incisors, the mandibular central incisors, and the mesial and distal roots of the mandibular first molar, and analyzed statistically the association between IL-1B polymorphism and EARR. We also examined differences in allelic frequency of this IL-1B polymorphism in a multi-ethnic study population consisting of Japanese, Han Chinese, African American, European Caucasian, and Hispanic individuals. We found no significant difference in the frequency of the IL-1B polymorphism between EARR cases and controls in the Japanese population. We also report marked diversities in the allelic frequencies of the IL-1B polymorphism within the multi-ethnic study population. The European Caucasian population carried the T allele at a frequency of 29.2%, whereas the Japanese population carried the T allele at a frequency of 5.6%. The low frequency of the T allele in Japanese population made it difficult to compare population allelic frequencies among different populations. Further studies are required to confirm our findings and to investigate the effect of other single nucleotide polymorphisms in IL-1B or other genetic risk factors underlying susceptibility to EARR.

Allergy as a possible predisposing factor for hypodontia.

The aim of this retrospective study was to identify general health problems as potential predisposing factors for hypodontia in a population of Japanese orthodontic patients. The study included 3683 individuals (1312 males and 2371 females, 13-42 years of age; mean, 23 years 7 months). Dental pantomograms (DPTs) were used to diagnose hypodontia. Health histories were obtained through a questionnaire administered by the dentist in charge. The Mantel-Haenszel test was used to determine the significance of the differences in the prevalence of health problems. The overall frequency of hypodontia was 5.8 per cent. The average number of missing teeth per patient was 1.7. There was a high prevalence of systemic complications, which included allergy, asthma, atopy, and enlarged adenoids associated with hypodontia. Only allergy showed a significant relationship with hypodontia (P < 0.01). The environmental aetiology of hypodontia is not yet fully understood. However, based on the results of this retrospective study, predisposing general health problems, especially allergy, seem to be involved.

Recent Advances in the Genetics of Orthodontics

Consideration of genetic factors is an essential element of diagnosis that underlies orofacial traits. In particular, orthodontic clinicians may have an interest in craniofacial growth and tooth movement. These parts of the diagnostic process are important to understand the cause of the problem before attempting treatment. In this chapter, we present our studies on the genetic causes of external apical root resorption and mandibular morphology, and review related studies.

Craniofacial Morphology in Human Genetics

Hereditary studies of dental characteristics (size and shape) in humans have demonstrated that strong genetic factors affect the variance of many dental traits. In addition, the characteristics of the dental morphology have acted as an indicator of biological distance between human populations. Recent advances in molecular biology have revealed major molecules involved in the development of teeth. However, genetic determinants of common dental characteristics have been less understood. It was previously reported that a variant of EDAR is associated with shovel-shaped incisors; this is an example of where a genetic determinant of common dental characteristics has been identified. PAX9 is an important transcription factor for developing teeth. Dysfunctional mutations in PAX9 cause selective tooth agenesis in humans. The purpose of this study was to examine whether common variants of PAX9 participate in common dental characteristics in East Asian populations. The study subjects were Japanese and Korean adults. The single nucleotide polymorphisms (SNP) in PAX9 were genotyped with the TaqMan method. The mesiodistal and buccolingual diameters were measured as metric dental traits. As non-metric traits, the shovel grade, double shovel grade, tuberculum dentale in upper incisors and canines, Carabelli trait in upper molars, cusp numbers of the upper and lower molars, and groove pattern of the lower molars were examined. This facilitated the association between genotypes and dental characteristics to be determined. The SNP was significantly associated with several tooth crown diameters and the tuberculum dentale in the upper incisors. It is concluded that a common variant of PAX9 contributes to crown size and shape variation in human permanent teeth.

Interdisciplinary Treatment of Aggressive Periodontitis: Three-Dimensional Cone-Beam X-Ray Computed Tomography Evaluation

Periodontitis is characterized by an inflammatory reaction that affects tooth attachment tissues and can be classified as chronic periodontitis or aggressive periodontitis (AgP) according to clinical characteristics and rate of progression. The current classification of periodontal disease describes two clinically distinct forms of periodontitis. AgP is characterized by rapid progression and severe periodontal destruction, mainly seen in younger individuals (Meng et al., 2007). Chronic periodontitis is characterized by a lower rate of progression (Schatzle et al., 2009). AgP constitutes a group of rare and rapidly progressing forms of periodontitis that are frequently characterized by an early age of clinical onset (Genco et al., 1986). AgP is defined as a destructive periodontal disease affecting more than 14 teeth in young individuals. Its etiology has been linked to the presence of Aggregatibacter actinomycetemcomitans (Fine et al., 2007; Haraszthy et al., 2000; Di Rienzo et al., 1994), host response defects (Page et al., 1984, 1985; Lavine et al., 1979), and possibly to genetic inheritance (Hart & Kornman, 1997; Kinane et al., 2000; Boleghman et al., 1992; Beaty et al., 1987; Hart et al., 1992; Melnick et al., 1976; Page et al., 1985). In contrast, chronic periodontitis is characterized by a lower rate of progression (Schatzle et al., 2009), although like AgP it can reach a severe stage, leading to tooth loss and edentualism. Many clinicians report difficulty in establishing a differential diagnosis for AgP and chronic periodontitis due to an overlapping “gray area” that often negates a clear-cut diagnosis. Such issues raise the question of whether these are actually two distinct clinical entities.