Candidate Gene Associations with Fluorosis in the Early Permanent Dentition

Although there is clearly a strong association between fluoride exposure and fluorosis, the existence of a genetic component affecting susceptibility to dental fluorosis has been suggested by human and animal studies. Objectives: This study assessed associations between genotypes at candidate loci and the presence of fluorosis in the early-erupting permanent dentition. Methods: Fluorosis phenotypes of participants in the Iowa Fluoride Study were related to genetic information from the Iowa Bone Development Study. Genes important in bone mineralization or enamel formation were chosen as potential candidates with respect to fluorosis susceptibility; these included genes related to structural or matrix proteins, hormone receptors and growth factors. Cases were defined conservatively as having definitive fluorosis (Fluorosis Risk Index scores of two or higher) on both maxillary central incisors; to minimize misclassification, individuals with a single affected tooth were omitted. An alternative phenotypic definition was based on the presence of definitive fluorosis on at least two of twelve teeth in the early-erupting permanent dentition. Associations were assessed using standard case-control methodologies, including logistic regression, as well as haplotype profile analysis. Results: Analysis of genotype data from 472 white children suggested an association (p=0.002) between fluorosis phenotype and a SNP in intron 1 of the tuftelin gene (TUFT1). This association remained significant after adjustment for fluoride intake between birth and 24 months of age (p = 0.032). Further analyses suggested a dose response relationship after adjustment for fluoride intake (p=0.013); there was no evidence of interaction between this SNP and fluoride intake. Similar results were found for the alternative fluoride phenotype. Suggestive relationships were also identified between fluorosis phenotype and osteopontin (OPN) and kallikrein-related peptidase 4 (KLK4) genotypes. Conclusions: These results strengthen interest in the role of genetic predisposition to increased susceptibility/resistance to dental fluorosis. Supported by the NIH/NIDCR (R03-DE018013, R01-DE09551, R01-DE12101, and M01-RR00059).