Genetic Epidemiology and Pharmacogenetics of Dental Fluorosis

描述(由申请人提供)：众所周知，在儿童早期暴露于高氟水平会增加患氟牙症的风险。老鼠身上的证据有力地表明，遗传遗传变异也很重要。动物模型和对人类双胞胎的分析都提供了强有力的证据，表明患龋齿的风险也是高度可遗传的。然而，到目前为止，还没有人类研究评估个体基因变异对氟化物生物学或氟中毒风险的影响。高通量的单核苷酸多态(SNPs)分析极大地提高了识别氟斑牙等复杂性状基因的能力。研究人员可以以合理的成本快速分析分布在整个基因组中的50多万个SNPs。由于这些表型涉及多个基因和与环境变量的交互作用，大样本大小是必要的，以提供足够的统计能力。这项研究将评估爱尔兰一个地区的3458名11-15岁的学童，那里的饮用水大部分(但不是全部)是含氟的。将招募520名氟中毒患者和605名对照。唾液中的DNA将用于全基因组SNP关联研究，并在具有最高统计意义的区域和基于生物功能的高优先级候选基因(如釉质蛋白)中进行精细定位。还将获得龋齿和氟化物暴露数据。我们的研究小组在10年前已经获得了其中125名受试者的氟化物暴露情况，后续的研究将使我们能够评估父母回顾报告的准确性。将招募100名患者和100名对照的父母和一名兄弟姐妹进行临床和遗传学评估，并对其中100名父母(50名氟骨症患者和50名未受影响的父母)进行氟化物挑战研究，测量口服3毫克氟化物剂量后24小时的尿量。主要的药物遗传学目标是确定影响个体患氟斑牙风险差异的特定基因和变异。第二个目标是在考虑氟暴露的差异后，评估氟中毒患者和对照组的氟斑牙聚集程度；评估24小时尿氟排泄率在氟中毒患者和对照组之间的差异以及氟中毒易感基因是否对排泄率有影响；评估个人和家庭中氟斑牙与龋病的关系；以及确定龋病的易感基因。

DESCRIPTION (provided by applicant): It is well-established that exposure to high fluoride levels during early childhood increases risk of Dental fluorosis. Evidence in mice strongly suggests that inherited genetic variation is also important. Both animal models and analyses of human twins provide strong evidence that risk of Dental caries is also highly heritable. To date, however, no human studies have evaluated the effect of individual genetic variation on fluoride biology or fluorosis risk. High-throughput assays for Single Nucleotide Polymorphisms (SNPs) have greatly enhanced the ability to identify genes for complex traits such as Dental fluorosis. Investigators can analyze over 500,000 SNPs distributed throughout the genome quickly and at reasonable cost. Since these phenotypes involve multiple genes and interactions with environmental variables, large sample sizes are necessary to provide adequate statistical power. This study will evaluate 3,458 school children age 11-15 in a region of Ireland where most (but not all) drinking water is fluoridated. A total of 520 fluorosis cases and 605 controls will be recruited. DNA from saliva will be used for whole genome SNP association studies and fine mapping in regions with highest statistical significance and in high-priority candidate genes based on biological function (e.g., enamel proteins). Caries and fluoride exposure data will also be obtained. Fluoride exposure was previously obtained by our team 10 years ago for 125 of these subjects and the follow-up will allow assessment of the accuracy of retrospective parental reports. Both parents and one sibling for a nested set of 100 cases and 100 controls will be recruited and clinically and genetically evaluated, and a fluoride challenge study will be conducted on 100 of these parents (50 fluorosis affected and 50 unaffected) by measuring 24 hour urine excretion following a 3 mg oral fluoride dose. The primary pharmacogenetic Aim is to identify specific genes and variants that affect individual differences in risk of Dental fluorosis. Secondary Aims are to evaluate the extent that Dental fluorosis aggregates in families of fluorosis cases versus controls after accounting for variation in fluoride exposure; to assess whether 24 hour urine excretion rates of fluoride differ between fluorosis cases and controls and whether fluorosis susceptibility genes have an effect on excretion rates; to evaluate relationships between Dental fluorosis and caries in individuals and families; and to identify susceptibility genes for Dental caries.