Effects of enamel matrix genes on dental caries are moderated by fluoride exposures

Abstract

Dental caries (tooth decay) is the most common chronic disease, worldwide, affecting most children and adults. Though dental caries is highly heritable, few caries-related genes have been discovered. We investigated whether 18 genetic variants in the group of non-amelogenin enamel matrix genes (AMBN, ENAM, TUFT1, and TFIP11) were associated with dental caries experience in 13 age- and race-stratified samples from six parent studies (N = 3,600). Linear regression was used to model genetic associations and test gene-by-fluoride interaction effects for two sources of fluoride: daily tooth brushing and home water fluoride concentration. Meta-analysis was used to combine results across five child and eight adult samples. We observed the statistically significant association of rs2337359 upstream of TUFT1 with dental caries experience via meta-analysis across adult samples (p < 0.002) and the suggestive association for multiple variants in TFIP11 across child samples (p < 0.05). Moreover, we discovered two genetic variants (rs2337359 upstream of TUFT1 and missense rs7439186 in AMBN) involved in gene-by-fluoride interactions. For each interaction, participants with the risk allele/genotype exhibited greater dental caries experience only if they were not exposed to the source of fluoride. Altogether, these results confirm that variation in enamel matrix genes contributes to individual differences in dental caries liability, and demonstrate that the effects of these genes may be moderated by protective fluoride exposures. In short, genes may exert greater influence on dental caries in unprotected environments, or equivalently, the protective effects of fluoride may obviate the effects of genetic risk alleles.

Fig 1

Genetic association in enamel matrix genes (columns from left to right): AMBN, ENAM, TFIP11, and TUFT1. Rows (top to bottom) represent (first row) main effects in child samples, (second row) main effects in adult samples, (third row) SNP-by-tooth brushing interaction effects for daily brushing, and (fourth row) SNP-by-fluoride concentration interaction effects for home water source. Negative log₁₀-transformed p-values are shown for association tests in all samples: COHRA1 children (cyan), IHS (blue), IFS (purple), COHRA1 adults (red), Dental SCORE (green), DRDR (orange), and CEDAR (yellow). Circles represent white samples and squares represents black samples. White diamonds represent meta-analysis across all white samples and gray diamonds represent meta-analysis across all black and white samples, combined. The dashed lines are displayed at p-value = 0.05. The blue arrows represent the physical location and direction of genes. Points labeled A to H correspond to the interactions shown in panels A to H, respectively, of Figure 3.

Fig 2

Interaction between tooth brushing and home water source fluoride concentration in COHRA1 white adults indicates that participants not exposed to either source of fluoride have more carious teeth than participants exposed to one or both sources of fluoride (p=0.02)

Fig 3

(A-B) Interactions between rs2337359 and home water source fluoride concentration in (A) IFS and (B) COHRA1 white children indicate that participants with CT and CC genotypes exhibit greater dental caries experience if not exposed to the fluoride source. (C-D) Interactions between rs7439186 and (C) tooth brushing and (D) home water source fluoride concentration in COHRA1 white adults indicates that participants with the A allele exhibit greater dental caries experience if not exposed to the fluoride source. (E-H) Interactions between SNPs (E) rs16833391, (F) rs6005060, and (G-H) rs12749 and tooth brushing in COHRA1 white (E-G) and black (H) adults show greater differences between genotype groups in participants not exposed to the fluoride source. Note, for all the interaction models the extreme strata (i.e., rarer genotype group in the unexposed environment) comprise at least 15 participants except for the extreme strata in (H) which comprises 3 participants.