Genome-wide association study of primary dentition pit-and-fissure and smooth surface caries.

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.

Effects of life-long fluoride intake on bone measures of adolescents: a prospective cohort study.

Controversy persists concerning the impact of community water fluoridation on bone health in adults, and few studies have assessed relationships with bone at younger ages. Ecological studies of fluoride's effects showed some increase in bone mineral density of adolescents and young adults in areas with fluoridated water compared with non-fluoridated areas. However, none had individual fluoride exposure measures. To avoid ecological fallacy and reduce bias, we assessed associations of average daily fluoride intake from birth to age 15 yr for Iowa Bone Development Study cohort members with age 15 yr dual-energy x-ray absorptiometry (DXA) bone outcomes (whole body, lumbar spine, and hip), controlling for known determinants (including daily calcium intake, average daily time spent in moderate-to-vigorous intensity physical activity, and physical maturity). Mean (SD) daily fluoride intake was 0.66 mg (0.24) for females and 0.78 mg (0.30) for males. We found no significant relationships between daily fluoride intake and adolescents' bone measures in adjusted models (for 183 females, all p values ≥ .10 and all partial R(2) ≤ 0.02; for 175 males, all p values ≥ .34 and all partial R(2) ≤ 0.01). The findings suggest that fluoride exposures at the typical levels for most US adolescents in fluoridated areas do not have significant effects on bone mineral measures.

Genetic and environmental factors associated with dental caries in children: the Iowa Fluoride Study.

Dental caries remains the most common chronic childhood disease. Despite strong evidence of genetic components, there have been few studies of candidate genes and caries. In this analysis we tried to assess genetic and environmental factors contributing to childhood caries in the Iowa Fluoride Study. Environmental factors (age, sex, race, tooth-brushing frequencies and water fluoride level) and three dental caries scores (d(2)fs-total, d(2)fs-pit/fissure, and d(2)fs-smooth surface) were assessed in 575 unrelated children (mean age 5.2 years). Regression analyses were applied to assess environmental correlates. The Family-Based Association Test was used to test genetic associations for 23 single nucleotide polymorphism (SNP) markers in 7 caries candidate genes on 333 Caucasian parent-child trios. We evaluated the associations between caries status and the level of both single and multiple SNPs (haplotype) respectively. Permutation procedure was performed for correction of inflated type I errors due to multiple testing. Age, tooth-brushing frequency and water fluoride level were significantly correlated to at least one carious score. Caries on pit and fissure surfaces was substantially higher than on smooth surfaces (61 vs. 39%). SNPs in three genes (DSPP, KLK4 and AQP5) showed consistent associations with protection against caries. Of note, KLK4 and AQP5 were also highlighted by subsequent haplotype analysis. Our results support the concept that genes can modify the susceptibility of caries in children. Replication analysis in independent cohorts is highly needed in order to verify the validity of our findings.

Genome-wide association scan for childhood caries implicates novel genes.

Dental caries is the most common chronic disease in children and a major public health concern due to its increasing incidence, serious health and social co-morbidities, and socio-demographic disparities in disease burden. We performed the first genome-wide association scan for dental caries to identify associated genetic loci and nominate candidate genes affecting tooth decay in 1305 US children ages 3-12 yrs. Affection status was defined as 1 or more primary teeth with evidence of decay based on intra-oral examination. No associations met strict criteria for genome-wide significance (p < 10E-7); however, several loci (ACTN2, MTR, and EDARADD, MPPED2, and LPO) with plausible biological roles in dental caries exhibited suggestive evidence for association. Analyses stratified by home fluoride level yielded additional suggestive loci, including TFIP11 in the low-fluoride group, and EPHA7 and ZMPSTE24 in the sufficient-fluoride group. Suggestive loci were tested but not significantly replicated in an independent sample (N = 1695, ages 2-7 yrs) after adjustment for multiple comparisons. This study reinforces the complexity of dental caries, suggesting that numerous loci, mostly having small effects, are involved in cariogenesis. Verification/replication of suggestive loci may highlight biological mechanisms and/or pathways leading to a fuller understanding of the genetic risks for dental caries.

Streptococcus mutans strains recovered from caries-active or caries-free individuals differ in sensitivity to host antimicrobial peptides.

Antimicrobial peptides (AMPs) are among the repertoire of host innate immune defenses. In the oral cavity, several AMPs are present in saliva and have antimicrobial activities against oral bacteria, including Streptococcus mutans, a primary etiological agent of dental caries. In this study, we hypothesized that unique S. mutans strains, as determined by DNA fingerprinting from sixty 13-year-old subjects with or without experience of caries, would have different susceptibilities to α-defensins-1-3 (HNP-1-3), ß-defensins-2-3 (HBD-2-3) and LL-37. The salivary levels of these peptides in subjects were also measured by enzyme-linked immunosorbent assays. We found that S. mutans strains from children with active caries showed greater resistance to salivary HNP-1-2, HBD-2-3 and LL-37 at varying concentrations than those from caries-free subjects. In addition, combinations of these peptides increased their antimicrobial activity against S. mutans either additively or synergistically. The salivary levels of these peptides were highly variable among subjects with no correlation to host caries experience. However, the levels of a number of these peptides in saliva appeared to be positively correlated within an individual. Our findings suggest that the relative ability of S. mutans to resist host salivary AMPs may be considered a potential virulence factor for this species such that S. mutans strains that are more resistant to these peptides may have an ecological advantage to preferentially colonize within dental plaque and increase the risk of dental caries.

Association between enamel hypoplasia and dental caries in primary second molars: a cohort study.

The purpose of this study was to assess the longitudinal relationships between enamel hypoplasia and caries experience of primary second molars. The study sample was 491 subjects who received dental examinations at both age 5 and 9 by the calibrated examiners. Four primary second molars (n = 1,892) were scored for the presence of enamel hypoplasia for each participant. Caries presence and number of decayed and filled surfaces (dfs) were determined at age 5 and 9. The relationships between enamel hypoplasia and caries experience were assessed. Among primary second molars, 3.9% of children and 1.7% of primary second molars had enamel hypoplasia. At age 5, 36.8% of children with hypoplasia had caries, while 16.9% of children without enamel hypoplasia had caries. At age 9, the corresponding numbers were 52.6% for children with hypoplasia and 34.5% for children without hypoplasia, respectively. At the tooth level, for age 5, 28.1% of teeth with hypoplasia had caries (mean dfs = 0.40), and 7.6% of teeth without hypoplasia had caries (mean dfs = 0.11). At age 9, the corresponding numbers were 41.9% (mean dfs = 0.76) for teeth with hypoplasia and 18.3% (mean dfs = 0.34) for teeth without hypoplasia. In multivariable logistic regression analyses, teeth of subjects with enamel hypoplasia had a significantly higher risk for caries at age 5 and 9 after controlling for other risk factors. Enamel hypoplasia appears to be a significant risk factor for caries and should be considered in caries risk assessment.

Fluoride, beverages and dental caries in the primary dentition.

Knowledge concerning risk factors for primary dentition caries in young children is incomplete. Models are presented for caries development using longitudinally gathered fluoride exposure and dietary intake data in the Iowa Fluoride Study. Primary tooth caries examinations were conducted at age 5. Dietary (beverage) and fluoride exposure data were gathered longitudinally from age 6 weeks through 4 years (n = 291); 23% had decayed or filled surfaces. Logistic regression revealed that beverage components and toothbrushing made unique contributions to caries experience. Water consumption (36-48 months), milk consumption (24-36 months), and fluoridated toothpaste brushings (36-48 months) were negatively associated with caries; sugared beverages and milk (6 weeks to 12 months) were positively associated. Although fluoride exposure is important, sugared beverages contribute substantially to caries risk, while water and milk consumption and frequent toothbrushing early can have protective effects.

A psychometric analysis of the sexual arousability index.

The Sexual Arousability Index (SAI) assesses self-reported sexual arousal in women and was administered on four occasions to a group of normal sexually active women (n = 57) and to another group undergoing surgical gynecologic treatment (n = 66) that resulted in a predictable and clinical level of sexual dysfunction. These data were used for a psychometric analysis of the SAI. In terms of reliability, internal consistency estimates were in the .92-.96 range, and 4-month test-retest reliabilities ranged from .74 to .90. An evaluation of validity revealed both strengths and limitations of the SAI. The content analysis indicated that at least six domains are sampled, including seduction activities, body caressing, oral-genital and genital stimulation, intercourse, masturbation, and erotic media. To examine construct validity, we conducted a factor analysis that revealed a five-factor solution accounting for 85% of the variance. Furthermore, the factor solution was stable across groups and time, and the factors were sensitive to the occurrence of important behavior changes. The SAI, like other psychological measures, was poor in predicting a criterion (i.e., the occurrence of inhibited sexual excitement) concurrently or at the time of follow-up.

Is there a reliable and valid self-report measure of sexual behavior?

A psychometric analysis of the Sexual Experience Scale (SES) from the Derogatis Sexual Functioning Inventory was conducted. This sexual behavior measure was administered on four occasions to a large sample of normal, heterosexual, sexually active women and a comparable sample which underwent gynecologic treatment that resulted in a predictable and clinical level of sexual dysfunction. In terms of reliability, internal consistency estimates for the SES were in the .85 to .90 range, but the stability of the SES was lower and ranged from .55 to .85. An evaluation of the validity revealed both strengths and limitations of the SES. The content analysis reveals that a wider range of sexual behaviors is sampled by the SES than comparable measures. To examine construct validity, a factor analysis provided a five-factor solution which would account for 82% of the variance, but the solution was not stable across groups or time and the factors were not sensitive to detecting important behavior changes. As many other psychological measures, the SES was poor in predicting a criterion (i.e., the occurrence of sexual dysfunction) concurrently or at the time of follow-up. The outcome of this analysis is discussed in the context of selecting reliable and valid self-report measures of sexual behavior.