Raija Lähdesmäki

Genome-wide association study reveals multiple loci associated with primary tooth development during infancy.

Tooth development is a highly heritable process which relates to other growth and developmental processes, and which interacts with the development of the entire craniofacial complex. Abnormalities of tooth development are common, with tooth agenesis being the most common developmental anomaly in humans. We performed a genome-wide association study of time to first tooth eruption and number of teeth at one year in 4,564 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966) and 1,518 individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC). We identified 5 loci at P<5×10−8, and 5 with suggestive association (P<5×10−6). The loci included several genes with links to tooth and other organ development (KCNJ2, EDA, HOXB2, RAD51L1, IGF2BP1, HMGA2, MSRB3). Genes at four of the identified loci are implicated in the development of cancer. A variant within the HOXB gene cluster associated with occlusion defects requiring orthodontic treatment by age 31 years.

Genome-wide association study of primary tooth eruption identifies pleiotropic loci associated with height and craniofacial distances

Twin and family studies indicate that the timing of primary tooth eruption is highly heritable, with estimates typically exceeding 80%. To identify variants involved in primary tooth eruption, we performed a population-based genome-wide association study of ‘age at first tooth’ and ‘number of teeth’ using 5998 and 6609 individuals, respectively, from the Avon Longitudinal Study of Parents and Children (ALSPAC) and 5403 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966). We tested 2 446 724 SNPs imputed in both studies. Analyses were controlled for the effect of gestational age, sex and age of measurement. Results from the two studies were combined using fixed effects inverse variance meta-analysis. We identified a total of 15 independent loci, with 10 loci reaching genome-wide significance (P < 5 × 10−8) for ‘age at first tooth’ and 11 loci for ‘number of teeth’. Together, these associations explain 6.06% of the variation in ‘age of first tooth’ and 4.76% of the variation in ‘number of teeth’. The identified loci included eight previously unidentified loci, some containing genes known to play a role in tooth and other developmental pathways, including an SNP in the protein-coding region of BMP4 (rs17563, P = 9.080 × 10−17). Three of these loci, containing the genes HMGA2, AJUBA and ADK, also showed evidence of association with craniofacial distances, particularly those indexing facial width. Our results suggest that the genome-wide association approach is a powerful strategy for detecting variants involved in tooth eruption, and potentially craniofacial growth and more generally organ development.

Root Lengths in 47,XYY Males’ Permanent Teeth

Studies on individuals with sex chromosome anomalies have demonstrated the promoting effect of the Y chromosome on tooth crown enamel and dentin growth. The present research investigated permanent tooth root lengths in 47,XYY males. The measurements were made from panoramic radiographs. The results indicate longer tooth roots in 47,XYY males compared with those in control males and females. The promoting effect of the Y chromosome on dental growth thus continues in the form of root dentin after the completion of crown growth. The results, together with those on tooth crown sizes in 47,XYY males, suggest that growth excesses are evident and final, beginning a few months after birth and continuing up to the age of 14 years, at least. The excess root dentin growth in 47,XYY males, as well as sexual dimorphism in the growth of crown and root dentin, might be caused by the same factor on the Y chromosome.

Early Headgear Effects on the Eruption Pattern of the Maxillary Canines

OBJECTIVE To test the null hypothesis that early headgear (HG) treatment has no effect on the eruption pattern of the maxillary canines in the early mixed dentition. MATERIALS AND METHODS Sixty-eight children (40 boys and 28 girls) with a Class II tendency in occlusion and moderate crowding of the dental arches were randomized into two groups. HG treatment was initiated immediately in the first group. In the second group only minor interceptive procedures were performed during the first follow-up period of 2 years. Orthopantomograms were taken at the baseline, three times at 1-year intervals, and after growth at the age of 16. Eruption geometry was performed. The space from the maxillary first molar to the lateral incisor was measured on the dental casts. RESULTS The inclination of the maxillary canine in relation to the midline appeared to be significantly more vertically oriented on the right side in the HG group 1 and 2 years after starting the HG therapy (P = .0098 and P = .0003, respectively). The inclination in relation to the lateral incisors was smaller in the HG group bilaterally after 1 year and 2 years of HG treatment, and on the right side after 3 years of treatment. CONCLUSION The hypothesis is rejected. Early HG treatment significantly affects the inclination of the maxillary canine during eruption. The strongest influence was seen after 2 years of HG use, more prominently in the right-side canine.

Prevalence of malocclusion traits and orthodontic treatment in a Finnish adult population.

Abstract Objective The aim of the study was to examine the prevalence of malocclusion traits and the extent of orthodontic treatment in a Finnish adult population. Materials and methods The study population comprised subjects (n = 1964) from the Northern Finland Birth Cohort 1966 living in the city of Oulu and within 100 km of it. A clinical oral and dental examination with registration of occlusion was carried out in 2012 in connection with a 46-year follow-up survey. Data on previous orthodontic treatment were collected based on a questionnaire. Results In the clinical examination, 39.5% of the subjects had at least one malocclusion trait. The most common malocclusion traits were lateral crossbite (17.9%), overbite ≥ 6 mm (11.7%) and overjet ≥ 6 mm (9.7%). Crossbite on the left premolars, negative overjet and increased overbite were found more frequently in men. The prevalence of malocclusion traits was at the same level in treated and untreated groups. Overall, 18.6% of the subjects had undergone orthodontic treatment. Women showed a significantly higher prevalence of orthodontic treatment. Conclusions The most common malocclusion trait in the present study was lateral crossbite. Significant male dominance in the prevalence of malocclusion was observed, which has not been reported earlier in Finland. Orthodontic treatment of malocclusion traits was more common among females in Northern Finland. This study indicates that orthodontic treatment provided in childhood was, on average, adequate in reducing malocclusion traits to the level observed in the general population.

Root resorptions related to ectopic and normal eruption of maxillary canine teeth – A 3D study

Abstract Objective. To assess the incidence and severity of root resorption of maxillary incisors caused by ectopically and normally erupting maxillary canines and to analyse factors influencing root resorption of incisors using cone beam computed tomography. Subjects and methods. The study sample comprised 59 patients with a total of 80 canines. Forty-six of the canines, in 37 patients, were defined as ectopic and 34 canines, in 22 patients, were defined as normal. The severity of root resorptions were analysed according to studies by Ericson and Kurol. Multiple logistics regression was used to evaluate the association between various factors and root resorptions. Results. The prevalence of root resorptions was significantly higher in the ectopic canine group, 11.0% of the central incisors and 67.6% of the lateral incisors in comparison to 0% and 36.2% in the normal erupting group. Most resorptions were defined as ‘slight’ and were located in the middle third of the root. There was a statistically significant relationship between canines located mesial to the midline of the lateral incisor and root resorption on the maxillary incisors. Conclusion. The present results show that root resorption of maxillary lateral incisors was common in patients referred to CBCT imaging due to maxillary canine eruption disturbances. Although significantly more frequent in patients with ectopically erupting canines, lateral incisor resorption was also found in association with approximately every third of the normally erupting canines. The best predictor for root resorption seemed to be location of the canine mesial in relation to the midline of the lateral incisor root.

Root length in the permanent teeth of women with an additional X chromosome (47,XXX females)

Abstract Objective. Previous studies have demonstrated differential effects of the X and Y chromosomes on dental development. The expression of sexual dimorphism in terms of tooth size, shape, number and developmental timing has been explained especially by Y chromosome influence. The Y chromosome promotes enamel, crown and root dentin development. The X chromosome has an effect on enamel deposition. The aim of this research is to study the influence of the extra X chromosome on the development of permanent tooth root length. Material and methods. The study subjects (all of whom were from the Kvantti Dental Research Project) were seven 47,XXX females, five female relatives and 51 and 52 population control men and women, respectively. Measurements were made from panoramic radiographs on available permanent teeth by a digital calliper according to established procedures. Results. The results showed that the maxillary root lengths of the 47,XXX females were of the same magnitude as those in normal women, but the mandibular root lengths were longer in 47,XXX females than in normal men or women. Conclusions. Increased enamel thickness in the teeth of 47,XXX females is apparently caused by the active enamel gene in all X chromosomes having no increased influence on crown dentin formation. These results in 47,XXX females indicate an increase in root dentin development, at least in the mandible, which together with the data on crown formation reflects a continuous long-lasting effect of the X chromosome on dental development.

Root lengths in the permanent teeth of 45,X females

Abstract Objective. Studies in permanent and deciduous tooth crowns and permanent tooth roots in individuals with sex chromosome anomalies and in their relatives have given proof that the X chromosome affects enamel formation, root length and crown and root morphology. The present research studies the effects of sex chromosome deficiency on the development of permanent tooth root. Materials and methods. This research investigated tooth root lengths in a group of 97 45,X females. As controls there were 32 sisters and 28 mothers of the 45,X females, 45 female and 42 male population controls and 15 45,X/46,XX females from the KVANTTI research project. Tooth root lengths on both sides of the jaws were measured from panoramic radiographs in each acceptable instance. Results. The results showed significantly shorter tooth root lengths in the 45,X females than in the female and male controls in all teeth measured, whereas in the female relatives tooth root lengths were shifted towards the aneuploids in relation to that in the general population. The tooth root lengths in the 45,X females differed more from those found in their sisters than in their mothers. Conclusions. These results with the large pure sample size of the whole dentitions in patients with monosomy X confirm the earlier findings of short tooth roots in 45,X females. The fact that in most instances there were no significant differences in tooth root lengths between 45,X and 45,X/46,XX females comes close to the earlier findings regarding mesio-distal tooth crown sizes.

GWAS Identifies New Loci for Painful Temporomandibular Disorder: Hispanic Community Health Study/Study of Latinos:

Temporomandibular disorder (TMD) is a musculoskeletal condition characterized by pain and reduced function in the temporomandibular joint and/or associated masticatory musculature. Prevalence in the United States is 5% and twice as high among women as men. We conducted a discovery genome-wide association study (GWAS) of TMD in 10,153 participants (769 cases, 9,384 controls) of the US Hispanic Community Health Study/Study of Latinos (HCHS/SOL). The most promising single-nucleotide polymorphisms (SNPs) were tested in meta-analysis of 4 independent cohorts. One replication cohort was from the United States, and the others were from Germany, Finland, and Brazil, totaling 1,911 TMD cases and 6,903 controls. A locus near the sarcoglycan alpha (SGCA), rs4794106, was suggestive in the discovery analysis (P = 2.6 × 106) and replicated (i.e., 1-tailed P = 0.016) in the Brazilian cohort. In the discovery cohort, sex-stratified analysis identified 2 additional genome-wide significant loci in females. One lying upstream of the relaxin/insulin-like family peptide receptor 2 (RXP2) (chromosome 13, rs60249166, odds ratio [OR] = 0.65, P = 3.6 × 10−8) was replicated among females in the meta-analysis (1-tailed P = 0.052). The other (chromosome 17, rs1531554, OR = 0.68, P = 2.9 × 10−8) was replicated among females (1-tailed P = 0.002), as well as replicated in meta-analysis of both sexes (1-tailed P = 0.021). A novel locus at genome-wide level of significance (rs73460075, OR = 0.56, P = 3.8 × 10−8) in the intron of the dystrophin gene DMD (X chromosome), and a suggestive locus on chromosome 7 (rs73271865, P = 2.9 × 10−7) upstream of the Sp4 Transcription Factor (SP4) gene were identified in the discovery cohort, but neither of these was replicated. The SGCA gene encodes SGCA, which is involved in the cellular structure of muscle fibers and, along with DMD, forms part of the dystrophin-glycoprotein complex. Functional annotation suggested that several of these variants reside in loci that regulate processes relevant to TMD pathobiologic processes.

Crown heights in the permanent teeth of 45,X and 45,X/46,XX females

Abstract Objective. Previous results regarding human sex chromosome aneuploidies have shown that the X and Y chromosomes affect tooth size and morphology. This study looked for the effect of sex chromosome deficiency on permanent tooth crown heights. Materials and methods. The material, from the Finnish KVANTTI Research Project, consisted of 97 45,X females and 15 45,X/46,XX females. The controls were 32 sisters and 28 mothers of the 45,X females, eight sisters and two mothers of the 45,X/46,XX females and 35 female population controls. Crown heights of all the available teeth except third molars on both sides of the jaws were measured from panoramic radiographs with a digital calliper according to the defined procedure. Results. The tooth crown heights were significantly smaller in the 45,X females than in the female population controls, except for the incisors and one canine in the maxilla, whereas the tooth crown heights of the 45,X/46,XX females were close to those of the normal control females. The differences between the 45,X and 45,X/46,XX females were statistically significant, excluding the upper incisor area and a few teeth in the mandible. Conclusions. The effect of the sex chromosome deficiency on permanent tooth crown height is due to the magnitude of lacking sex chromosome material. The present results regarding the 45,X females are parallel to previous findings in Turner patients regarding reduced mesiodistal and labiolingual dimensions and tooth crown heights in the permanent dentition.