Bone health index in the assessment of bone health: The Generation R Study.

Bone Health Index (BHI) has been proposed as a useful instrument for assessing bone health in children. However, its relationship with fracture risk remains unknown. We aimed to investigate whether BHI is associated with bone mineral density (BMD) and prevalent fracture odds in children from the Generation R Study. We also implemented genome-wide association study (GWAS) and polygenic score (PGS) approaches to improve our understanding of BHI and its potential. In total, 4150 children (49.4 % boys; aged 9.8 years) with genotyped data and bone assessments were included in this study. BMD was measured across the total body (less head following ISCD guidelines) using a GE-Lunar iDXA densitometer; and BHI was determined from the hand DXA scans using BoneXpert®. Fractures were self-reported collected with home questionnaires. The association of BHI with BMD and fractures was evaluated using linear models corrected for age, sex, ethnicity, height, and weight. We observed a positive correlation between BHI and BMD (ρ = 0.32, p-value<0.0001). Further, every SD decrease in BHI was associated with an 11 % increased risk of prevalent fractures (OR:1.11, 95 % CI 1.00-1.24, p-value = 0.05). Our BHI GWAS identified variants (lead SNP rs1404264-A, p-value = 2.61 × 10-14) mapping to the ING3/CPED1/WNT16 locus. Children in the extreme tails of the BMD PGS presented a difference in BHI values of -0.10 standard deviations (95% CI -0.14 to -0.07; p-value<0.0001). On top of the demonstrated epidemiological association of BHI with both BMD and fracture risk, our results reveal a partially shared biological background between BHI and BMD. These findings highlight the potential value of using BHI to screen children at risk of fracture.

Oral and craniofacial research in the Generation R study: an executive summary.

OBJECTIVES: Oral conditions are of high prevalence and chronic character within the general population. Identifying the risk factors and determinants of oral disease is important, not only to reduce the burden of oral diseases, but also to improve (equal access to) oral health care systems, and to develop effective oral health promotion programs. Longitudinal population-based (birth-)cohort studies are very suitable to study risk factors on common oral diseases and have the potential to emphasize the importance of a healthy start for oral health. In this paper, we provide an overview of the comprehensive oral and craniofacial dataset that has been collected in the Generation R study: a population-based prospective birth cohort in the Netherlands that was designed to identify causes of health from fetal life until adulthood. METHODS: Within the multidisciplinary context of the Generation R study, oral and craniofacial data has been collected from the age of 3 years onwards, and continued at the age of six, nine, and thirteen. Data collection is continuing in 17-year-old participants. RESEARCH OUTCOMES: In total, the cohort population comprised 9749 children at birth, and 7405 eligible participants at the age of seventeen. Based on questionnaires, the dataset contains information on oral hygiene, dental visits, oral habits, oral health-related quality of life, orthodontic treatment, and obstructive sleep apnea. Based on direct measurements, the dataset contains information on dental caries, developmental defects of enamel, objective orthodontic treatment need, dental development, craniofacial characteristics, mandibular cortical thickness, and 3D facial measurements. CONCLUSIONS: Several research lines have been set up using the oral and craniofacial data linked with the extensive data collection that exists within the Generation R study. CLINICAL RELEVANCE: Being embedded in a multidisciplinary and longitudinal birth cohort study allows researchers to study several determinants of oral and craniofacial health, and to provide answers and insight into unknown etiologies and oral health problems in the general population.

CYP11B1 variants influence skeletal maturation via alternative splicing.

We performed genome-wide association study meta-analysis to identify genetic determinants of skeletal age (SA) deviating in multiple growth disorders. The joint meta-analysis (N = 4557) in two multiethnic cohorts of school-aged children identified one locus, CYP11B1 (expression confined to the adrenal gland), robustly associated with SA (rs6471570-A; ß = 0.14; P = 6.2 × 10-12). rs6410 (a synonymous variant in the first exon of CYP11B1 in high LD with rs6471570), was prioritized for functional follow-up being second most significant and the one closest to the first intron-exon boundary. In 208 adrenal RNA-seq samples from GTEx, C-allele of rs6410 was associated with intron 3 retention (P = 8.11 × 10-40), exon 4 inclusion (P = 4.29 × 10-34), and decreased exon 3 and 5 splicing (P = 7.85 × 10-43), replicated using RT-PCR in 15 adrenal samples. As CYP11B1 encodes 11-ß-hydroxylase, involved in adrenal glucocorticoid and mineralocorticoid biosynthesis, our findings highlight the role of adrenal steroidogenesis in SA in healthy children, suggesting alternative splicing as a likely underlying mechanism.

Associations Between Prenatal, Perinatal, and Early Childhood Vitamin D Status and Risk of Dental Caries at 6 Years.

BACKGROUND: Previous studies have suggested that insufficient concentrations of vitamin D are associated with dental caries in primary teeth, but evidence remains inconclusive. OBJECTIVES: We assessed the longitudinal associations between prenatal, perinatal, and early childhood serum 25-hydroxyvitamin D concentrations [25(OH)D] and the risk of dental caries in 6-year-old children. METHODS: This research was conducted within the Generation R Study, a large, multi-ethnic, prospective cohort study located in Rotterdam, the Netherlands. Dental caries were assessed in children using the decayed-missing-filled-primary teeth index at a mean age of 6.1 years (90% range, 4.8-9.1). We measured serum total 25(OH)D concentrations at 3 time points: prenatally (at 18-24 weeks of gestation), perinatally (at birth), and during early childhood (at age 6 years). We performed logistic regression analyses to determine the longitudinal association of serum 25(OH)D concentrations with caries risks in 5257 children. Additionally, we constructed a Genetic Risk Score (GRS) for the genetic predispositions to serum total 25(OH)D concentrations based on 6 vitamin D-related single nucleotide polymorphisms in a subsample of 3385 children. RESULTS: Children with severe prenatal and early childhood serum 25(OH)D deficiencies (<25 nmol/L) were more likely to be diagnosed with caries [OR, 1.56 (95% CI, 1.18-2.06) and 1.58 (95% CI, 1.10-2.25), respectively] than children with optimal concentrations (≥75 nmol/L). After adjustment for residuals of serum 25(OH)D concentrations at other time points, only the early childhood serum 25(OH)D concentration was inversely associated with the caries risk at 6 years (OR, 0.97; 95% CI, 0.95-0.98). However, our GRS analysis showed that children who are genetically predisposed to have lower serum 25(OH)D concentrations do not have a higher risk of developing caries in primary teeth. CONCLUSIONS: Our study suggests a weak association between serum 25(OH)D concentrations and risks of caries in primary teeth. Based on our results, we do not recommend vitamin D supplementation for the prevention of dental caries in children.

Skeletal maturation in relation to ethnic background in children of school age: The Generation R Study.

Ethnicity is a well-established determinant of pediatric maturity, but the underlying genetic and environmental contributions to these ethnic differences are poorly comprehended. We aimed to evaluate the influence of ethnicity on skeletal age (SA), an assessment of pediatric maturation widely used in clinical settings. We included children from the Generation R Study, a multiethnic population-based pregnancy cohort, assessed at a mean age of 9.78 (±0.33) years. SA was evaluated by a trained observer on hand DXA scans using the Greulich and Pyle method. Ethnic background was defined as geographic ancestry (questionnaire-based assessment) (N = 5325) and genetic ancestry (based on admixture analysis) (N = 3413). Associations between the ethnic background and SA were investigated separately in boys and girls, using linear regression models adjusted for age, height and BMI. Based on geographic ancestry, 84% of the children were classified as European, 6% as Asian and 10% as African. Children of European background had on average younger SA than those of Asian or African descent. Asian boys had 0.46 (95% CI 0.26-0.66, p-value < 0.0001) and African boys 0.36 years (95% CI 0.20-0.53, p-value < 0.0001) older SA as compared to European boys. Similarly, Asian girls showed 0.64 (95% CI 0.51-0.77, p-value < 0.0001) and African girls 0.38 years (95% CI 0.27-0.48, p-value < 0.0001) older SA as compared to European girls. A similar pattern was observed in the analysis with genetically-defined ancestry. Furthermore, an increase in the proportion of Asian or African component was associated with older SA in both boys (log[Non-European/European]proportion = 0.10, 95% CI 0.06-0.13, p-value < 0.0001) and girls (log[Non-European/European]proportion = 0.06, 95% CI 0.04-0.08, p-value < 0.0001). In summary, children of Asian and African backgrounds have on average older SA as compared to children of European descent, partially explained by a genetic component.

Femoral stress is prominently associated with fracture risk in children: The Generation R Study.

Bone modeling is an important process in the growing skeleton. An inadequate bone modeling in response to mechanical loads would lead some children to develop weaker bones than others. The resulting higher stresses in the bones would render them more susceptible to fracture. We aimed to examine the association between femoral stress (FS) derived from structural parameters and BMD in relation to incident fractures in children. Bone stress was evaluated at the medial femoral neck, a skeletal site subject to large forces during normal locomotion. This study comprises 1840 children from the Generation R Study, with whole body and hip DXA scans at a mean age of 6.01 years. Hip structural analysis (HSA) was used to measure femur geometry for the FS calculation. Data on fractures occurring over the following 4 years after the DXA assessment were obtained by questionnaire. Incident fracture was observed in 7.6% of the participating children. Cox-multivariate regression analysis, described as hazard ratios (HR), showed that after adjustment for sex, ethnicity, age, weight and lean mass fraction, there was a significant increase in the risk of incident fracture for every standard deviation (SD) decrease in total body BMD (HR: 1.35, 95% CI 1.05-1.74, p-value = 0.021), femoral neck BMD (HR: 1.31, 95% CI 1.09-1.58, p-value = 0.005) and narrow neck BMD (HR: 1.39, 95% CI 1.14-1.68, p-value = 0.001). Whereas, every increment of one SD in femoral stress resulted in 1.33 increased risk of incident fractures (HR: 1.33, 95% CI 1.13-1.57, p-value = 0.001). This association remained (borderline) significant after the adjustment for DXA derived BMD measurements. Our results show that increased bone stress may underlie greater susceptibility to traumatic fractures in children (partially independent of BMD) and underscore the utility of hip DXA scans for the assessment of paediatric bone health and specifically fracture risk.

Fractures in school age children in relation to sex and ethnic background: The Generation R Study.

Fracture rate in childhood is increasing and its consequences may affect health and developmental processes and cause school absence and restricted activity days. There are scarce epidemiologic studies regarding fractures in children. The aim of this study was to evaluate if pediatric fractures show disparities across sexes and ethnic groups. This study was conducted based on data from 3632 participants of the Generation R Study. Prevalent fractures were assessed using a questionnaire at a mean age of 9.7 years. Child's ethnicity was determined based on country of birth of the parents using questionnaires (geographic ancestry) or admixture analysis (genetic ancestry). Associations between fracture occurrence and sex or ethnicity were evaluated using logistic regression models adjusted for age, weight, lean mass fraction, bone mineral density (BMD) and sex/ethnicity. Fracture was reported for 525 (14.5%) children. The great majority of these children were classified as European (N = 3164), followed by African (N = 283) and Asian (N = 185) based on geographic ancestry. Similarly, the highest proportion of Europeans was observed based on genetic ancestry. Prevalence of fractures was not different between boys and girls, even after adjustment for possible confounders (OR: 1.03, 95% CI 0.84-1.27, p-value = 0.8). However, odds of prevalent fractures were two times higher in European when compared to Asian children (OR: 2.01, 95% CI 1.17-3.45, p-value = 0.01), and 1.5 times higher when compared to African children (OR: 1.50, 95% CI 1.00-2.26, p-value = 0.05). Overall, in this study, European children showed a highest risk of prevalent fractures independently of factors such as body composition and BMD, while no difference in the prevalence of fractures between boys and girls was observed.

Consortium-based genome-wide meta-analysis for childhood dental caries traits.

Prior studies suggest dental caries traits in children and adolescents are partially heritable, but there has been no large-scale consortium genome-wide association study (GWAS) to date. We therefore performed GWAS for caries in participants aged 2.5-18.0 years from nine contributing centres. Phenotype definitions were created for the presence or absence of treated or untreated caries, stratified by primary and permanent dentition. All studies tested for association between caries and genotype dosage and the results were combined using fixed-effects meta-analysis. Analysis included up to 19 003 individuals (7530 affected) for primary teeth and 13 353 individuals (5875 affected) for permanent teeth. Evidence for association with caries status was observed at rs1594318-C for primary teeth [intronic within ALLC, odds ratio (OR) 0.85, effect allele frequency (EAF) 0.60, P 4.13e-8] and rs7738851-A (intronic within NEDD9, OR 1.28, EAF 0.85, P 1.63e-8) for permanent teeth. Consortium-wide estimated heritability of caries was low [h2 of 1% (95% CI: 0%: 7%) and 6% (95% CI 0%: 13%) for primary and permanent dentitions, respectively] compared with corresponding within-study estimates [h2 of 28% (95% CI: 9%: 48%) and 17% (95% CI: 2%: 31%)] or previously published estimates. This study was designed to identify common genetic variants with modest effects which are consistent across different populations. We found few single variants associated with caries status under these assumptions. Phenotypic heterogeneity between cohorts and limited statistical power will have contributed; these findings could also reflect complexity not captured by our study design, such as genetic effects which are conditional on environmental exposure.

Ancestry and dental development: A geographic and genetic perspective.

OBJECTIVE: In this study, we investigated the influence of ancestry on dental development in the Generation R Study. METHODS: Information on geographic ancestry was available in 3,600 children (1,810 boys and 1,790 girls, mean age 9.81 ± 0.35 years) and information about genetic ancestry was available in 2,786 children (1,387 boys and 1,399 girls, mean age 9.82 ± 0.34 years). Dental development was assessed in all children using the Demirjian method. The associations of geographic ancestry (Cape Verdean, Moroccan, Turkish, Dutch Antillean, Surinamese Creole and Surinamese Hindustani vs Dutch as the reference group) and genetic content of ancestry (European, African or Asian) with dental development was analyzed using linear regression models. RESULTS: In a geographic perspective of ancestry, Moroccan (ß = 0.18; 95% CI: 0.07, 0.28), Turkish (ß = 0.22; 95% CI: 0.12, 0.32), Dutch Antillean (ß = 0.27; 95% CI: 0.12, 0.41), and Surinamese Creole (ß = 0.16; 95% CI: 0.03, 0.30) preceded Dutch children in dental development. Moreover, in a genetic perspective of ancestry, a higher proportion of European ancestry was associated with decelerated dental development (ß = -0.32; 95% CI: -.44, -.20). In contrast, a higher proportion of African ancestry (ß = 0.29; 95% CI: 0.16, 0.43) and a higher proportion of Asian ancestry (ß = 0.28; 95% CI: 0.09, 0.48) were associated with accelerated dental development. When investigating only European children, these effect estimates increased to twice as large in absolute value. CONCLUSION: Based on a geographic and genetic perspective, differences in dental development exist in a population of heterogeneous ancestry and should be considered when describing the physiological growth in children.

The influence of bone mineral density and bisphosphonate therapy on the determinants of oral health and changes on dental panoramic radiographs in postmenopausal women.

OBJECTIVES: The aim of this study was to assess the determinants of oral health including the number of decayed, missing, and filled teeth (DMFT) and periodontal indices in postmenopausal women with osteoporosis, osteoporosis treated with bisphosphonate therapy, and control group and to examine the correlation between dental panoramic indices (Mental Index-MI, Mandibular Cortical Index-MCI) and bone mineral density in these three groups of patients. MATERIALS AND METHODS: The presented non-interventional study involved 120 postmenopausal women: women with osteoporosis (O) (n = 45), women with osteoporosis treated with bisphosphonates (OBP) (n = 45), and control group (C) (n = 30). DMFT, plaque, gingival and papilla bleeding index, pocket depth, clinical attachment loss, and the presence of periodontitis were evaluated for each patient. MI and MCI of all participants were measured on a dental panoramic radiograph. RESULTS: Group OBP showed significantly higher gingival, bleeding index and deeper pocket depth than C and/or O group. No significant differences were found in MI (p = .303) or MCI (p = .06) in all the examined groups. Also, there were no significant differences between the three groups in the presence of periodontitis as well as in the DMFT index. CONCLUSION: BP therapy could have a negative influence on periodontal health. Further, MI and MCI are not precise diagnostic tools for diagnosing low BMD in postmenopausal women. CLINICAL RELEVANCE: BP therapy could have a negative influence on the determinants of oral health in postmenopausal women with osteoporosis.

THE ROLE OF NUTRITION IN CARIES PREVENTION AND MAINTENANCE OF ORAL HEALTH DURING PREGNANCY.

INTRODUCTION: Pregnancy may pose an increased risk for the development of caries and other oral health problems. Continuous screening of oral health status, implementing appropriate preventive measures (particularly oral hygiene, healthy diet plans and education) is of paramount importance not only for oral health but also for the general health status of the future mother and her offspring. EFFECTS OF FOOD ON CARIES DEVELOPMENT: Caries prevention through healthy diet implicates the reduction in frequency and amount of intake of cariogenic food, above all ofrefined carbohydrates, i.e. sugars and sweets. Foods known to have caries-prophylactic effects should predominate in healthy diet plans. They mainly include solid foods, which have mechanical effects on teeth cleaning, as well as foods providing sufficient amounts of vitamins (A, C, D) and a variety of elements and compounds (calcium, phosphates, fluorides) favoring the preservation and remineralization of tooth structures. EDUCATION OF PREGNANT WOMEN ON HEALHY DEIT: In accomplishing these goals, education and direct positive communication between the educator and the pregnant woman play a crucial role. Educative approach is always individual and determined by the patient's specific cultural and socioeconomic features and status, as well as her habits, motivation and willingness to accept relevant recommendations. Accomplishing the aforementioned goals requires the appropriate organization and professional competence within the preventive dental service and its close cooperation with the relevant medical institutions and social support in the framework of public health protection. CONCLUSION: Preserving of oral health during pregnancy is predominantly influenced by the following factors: 1) healthy diet, 2) oral hygiene, 3) patients' education, 4) regular control of oral health, 5) appropriate organization of dental services and 6) community engagement.