Genetic and Environmental Factors in Dental Fluorosis

描述（由申请人提供）：近几十年来，氟斑牙的患病率显著增加，主要是由于使用氟化物预防龋齿。公认的原则是，氟斑牙是一个问题，完全是由于过量的氟化物摄入在牙齿发育期间。然而，越来越明显的是，氟中毒的易感性也存在相当大的个体差异。在我们与爱荷华州氟化物研究（R01-DE09551）的合作中，我们观察到氟中毒的严重程度在给定的氟化物摄入量类别中有很大差异。本应用的中心假设是，氟牙症涉及个体基因（设定氟牙症发展的阈值）与特定环境暴露（包括氟化物摄入和其他营养素的饮食模式）之间复杂的相互作用。作为爱荷华州氟化物研究的一部分，已经招募了一个大型队列，并维持了13年多的时间，包括详细的纵向氟化物摄入量、饮食摄入量和药物使用数据，以及初级和混合牙列的表面特异性氟中毒表型数据。作为爱荷华州骨骼发育研究（R01-DE12101）的一部分，该研究利用了爱荷华州氟化物研究队列，从600多名队列儿童和970名父母那里收集了遗传物质，并为大量可能与骨骼发育相关的候选基因提供了基因型。这些基因的子集也是牙齿形态发生和矿化作用的合理候选者。拟议的二级数据分析将根据氟牙症表型检查这些基因，以确定影响氟牙症的特定基因/途径，并了解这些基因如何与氟化物和其他因素（如钙摄入量、药物）相互作用，以改变个人患原发性和恒牙氟牙症的风险。遗传策略包括基于群体和家庭的单核苷酸多态性（SNPs）关联研究，以及特定的单倍型分析。这项拟议的工作将是第一个专门评估氟牙症发展中的遗传因素和基因-环境相互作用的人类研究。获得的新资料也将有助于规划今后的研究。所获得的知识可能导致有用的战略，以确定氟中毒风险增加的人，从而可以制定和应用更个性化的氟化物方案。

DESCRIPTION (provided by applicant): The prevalence of dental fluorosis has increased significantly in recent decades, due primarily to the caries-preventive use of fluoride. The accepted tenet has been that dental fluorosis is a problem that results solely from excessive fluoride intake during the time of tooth development. However, it is becoming increasingly apparent that there is also considerable individual variation in predisposition to fluorosis. In our work with the Iowa Fluoride Study (R01-DE09551), we have observed great variation in fluorosis severity within a given category of fluoride intake. The central hypothesis of this application is that dental fluorosis involves a complex interplay between individual genes (which set the threshold for development of fluorosis) and specific environmental exposures, including dietary patterns of fluoride intake and other nutrients. As part of the Iowa Fluoride Study, a large cohort has already been recruited and maintained for more than 13 years, with detailed longitudinal fluoride intake, dietary intake, and medication usage data, as well as surface-specific fluorosis phenotype data in the primary and mixed dentitions. As part of the Iowa Bone Development Study (R01-DE12101), which utilizes the Iowa Fluoride Study cohort, genetic material has been collected from over 600 cohort children and 970 parents, and genotypes are available for a substantial number of candidate genes potentially related to bone development. The subset of these genes is also reasonable candidates for roles in tooth morphogenesis and mineralization. The proposed secondary data analyses will examine these genes in light of dental fluorosis phenotypes, in order to identify specific genes/pathways that influence fluorosis, and to understand how these genes interact with fluoride and other factors (e.g., calcium intake, medications) to modify an individual's risk for dental fluorosis in both the primary and permanent dentitions. Genetic strategies include population- and family-based (child-parent trio) association studies with single nucleotide polymorphisms (SNPs), as well as specific haplotype analyses. The proposed work will be the first human study to specifically assess genetic factors and gene-environment interaction in dental fluorosis development. The novel information obtained will also assist in planning future studies. Knowledge gained may lead to useful strategies to identify those at increased risk for fluorosis so that more individualized fluoride regimens can be developed and applied.