RESUMO
Many of the factors affecting susceptibility to dental caries are likely influenced by genetics. In fact, genetics accounts for up to 65% of inter-individual variation in dental caries experience. Sex differences in dental caries experience have been widely reported, with females usually exhibiting a higher prevalence and severity of disease across all ages. The cause for this sex bias is currently uncertain, although it may be partly due to the differential effects of genetic factors between the sexes: gene-by-sex interactions. In this family based study (N = 2,663; 740 families; ages 1-93 years), we assessed dental caries via intra-oral examination and generated six indices of caries experience (DMFS, dfs, and indices of both pit-and-fissure surface caries and smooth surface caries in both primary and permanent dentitions). We used likelihood-based methods to model the variance in caries experience conditional on the expected genetic sharing among relatives in our sample. This modeling framework allowed us to test two lines of evidence for gene-by-sex interactions: (1) whether the magnitude of the cumulative effect of genes differs between the sexes, and (2) whether different genes are involved. We observed significant evidence of gene-by-sex interactions for caries experience in both the primary and permanent dentitions. In the primary dentition, the magnitude of the effect of genes was greater in males than females. In the permanent dentition, different genes may play important roles in each of the sexes. Overall, this study provides the first direct evidence that sex differences in dental caries experiences may be explained, in part, by gene-by-sex interactions.
Assuntos
Suscetibilidade à Cárie Dentária/genética , Cárie Dentária/genética , Predisposição Genética para Doença/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos de Coortes , Índice CPO , Fissuras Dentárias/genética , Restauração Dentária Permanente/classificação , Feminino , Interação Gene-Ambiente , Variação Genética/genética , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Fenótipo , Cromossomos Sexuais/genética , Fatores Sexuais , Perda de Dente/classificação , Dente Decíduo/patologia , Adulto JovemRESUMO
Dental caries continues to be the most common chronic disease in children today. Despite the substantial involvement of genetics in the process of caries development, the specific genes contributing to dental caries remain largely unknown. We performed separate genome-wide association studies of smooth and pit-and-fissure tooth surface caries experience in the primary dentitions of self-reported white children in two samples from Iowa and rural Appalachia. In total, 1,006 children (ages 3-12 years) were included for smooth surface analysis, and 979 children (ages 4-14 years) for pit-and-fissure surface analysis. Associations were tested for more than 1.2 million single nucleotide polymorphisms, either genotyped or imputed. We detected genome-wide significant signals in KPNA4 (p value = 2.0E-9), and suggestive signals in ITGAL (p value = 2.1E-7) and PLUNC family genes (p value = 2.0E-6), thus nominating these novel loci as putative caries susceptibility genes. We also replicated associations observed in previous studies for MPPED2 (p value = 6.9E-6), AJAP1 (p value = 1.6E-6) and RPS6KA2 (p value = 7.3E-6). Replication of these associations in additional samples, as well as experimental studies to determine the biological functions of associated genetic variants, are warranted. Ultimately, efforts such as this may lead to a better understanding of caries etiology, and could eventually facilitate the development of new interventions and preventive measures.
Assuntos
Cárie Dentária/genética , Fissuras Dentárias/genética , Dente Decíduo/patologia , Adolescente , Região dos Apalaches , Antígeno CD11a/genética , Moléculas de Adesão Celular/genética , Criança , Pré-Escolar , Mapeamento Cromossômico , Cromossomos Humanos Par 18/genética , Cromossomos Humanos Par 3/genética , Cromossomos Humanos X/genética , Índice CPO , Feminino , Predisposição Genética para Doença/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla , Genótipo , Glicoproteínas/genética , Humanos , Iowa , Zíper de Leucina/genética , Sistema de Sinalização das MAP Quinases/genética , Masculino , Fosfoproteínas/genética , Diester Fosfórico Hidrolases/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , alfa Carioferinas/genéticaRESUMO
BACKGROUND: Dental caries is the result of a complex interplay among environmental, behavioral, and genetic factors, with distinct patterns of decay likely due to specific etiologies. Therefore, global measures of decay, such as the DMFS index, may not be optimal for identifying risk factors that manifest as specific decay patterns, especially if the risk factors such as genetic susceptibility loci have small individual effects. We used two methods to extract patterns of decay from surface-level caries data in order to generate novel phenotypes with which to explore the genetic regulation of caries. METHODS: The 128 tooth surfaces of the permanent dentition were scored as carious or not by intra-oral examination for 1,068 participants aged 18 to 75 years from 664 biological families. Principal components analysis (PCA) and factor analysis (FA), two methods of identifying underlying patterns without a priori surface classifications, were applied to our data. RESULTS: The three strongest caries patterns identified by PCA recaptured variation represented by DMFS index (correlation, r = 0.97), pit and fissure surface caries (r = 0.95), and smooth surface caries (r = 0.89). However, together, these three patterns explained only 37% of the variability in the data, indicating that a priori caries measures are insufficient for fully quantifying caries variation. In comparison, the first pattern identified by FA was strongly correlated with pit and fissure surface caries (r = 0.81), but other identified patterns, including a second pattern representing caries of the maxillary incisors, were not representative of any previously defined caries indices. Some patterns identified by PCA and FA were heritable (h(2) = 30-65%, p = 0.043-0.006), whereas other patterns were not, indicating both genetic and non-genetic etiologies of individual decay patterns. CONCLUSIONS: This study demonstrates the use of decay patterns as novel phenotypes to assist in understanding the multifactorial nature of dental caries.
Assuntos
Suscetibilidade à Cárie Dentária/genética , Cárie Dentária/genética , Cárie Dentária/patologia , Estudo de Associação Genômica Ampla , Herança Multifatorial , Adolescente , Adulto , Idoso , Região dos Apalaches/epidemiologia , Índice CPO , Cárie Dentária/epidemiologia , Fissuras Dentárias/genética , Fissuras Dentárias/patologia , Dentição Permanente , Análise Fatorial , Variação Genética , Humanos , Pessoa de Meia-Idade , Fenótipo , Prevalência , Análise de Componente Principal , Adulto JovemRESUMO
Carious lesions are distributed nonuniformly across tooth surfaces of the complete dentition, suggesting that the effects of risk factors may be surface-specific. Whether genes differentially affect caries risk across tooth surfaces is unknown. We investigated the role of genetics on two classes of tooth surfaces, pit and fissure surfaces (PFS) and smooth surfaces (SMS), in more than 2,600 subjects from 740 families. Participants were examined for surface-level evidence of dental caries, and caries scores for permanent and/or primary teeth were generated separately for PFS and SMS. Heritability estimates (h(2), i.e. the proportion of trait variation due to genes) of PFS and SMS caries scores were obtained using likelihood methods. The genetic correlations between PFS and SMS caries scores were calculated to assess the degree to which traits covary due to common genetic effects. Overall, the heritability of caries scores was similar for PFS (h(2) = 19-53%; p < 0.001) and SMS (h(2) = 17-42%; p < 0.001). Heritability of caries scores for both PFS and SMS in the primary dentition was greater than in the permanent dentition and total dentition. With one exception, the genetic correlation between PFS and SMS caries scores was not significantly different from 100%, indicating that (mostly) common genes are involved in the risk of caries for both surface types. Genetic correlation for the primary dentition dfs (decay + filled surfaces) was significantly less than 100% (p < 0.001), indicating that genetic factors may exert differential effects on caries risk in PFS versus SMS in the primary dentition.
