Genetic Epidemiology and Pharmacogenetics of Dental Fluorosis

描述（由申请人提供）：儿童早期接触高浓度氟化物会增加氟斑牙的风险，这是公认的事实。在老鼠身上的证据强烈表明，遗传基因变异也很重要。动物模型和对人类双胞胎的分析都提供了强有力的证据，证明龋齿的风险也是高度遗传的。然而，迄今为止，还没有人类研究评估了个体遗传变异对氟生物学或氟中毒风险的影响。单核苷酸多态性（SNPs）的高通量测定大大提高了识别复杂性状（如氟斑牙）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snp。由于这些表型涉及多个基因和与环境变量的相互作用，因此需要大样本量来提供足够的统计能力。这项研究将评估爱尔兰一个地区的3,458名11-15岁的学童，该地区大部分（但不是全部）饮用水都经过氟化处理。总共将招募520例氟中毒病例和605例对照。唾液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（例如，牙釉质蛋白）中进行精细定位。龋齿和氟化物暴露数据也将获得。我们的研究小组在10年前获得了其中125名受试者的氟化物暴露情况，后续研究将评估父母回顾性报告的准确性。将招募父母双方和一个兄弟姐妹，对100例病例和100例对照进行临床和遗传评估，并对其中100名父母（50名患有氟中毒，50名未受影响）进行氟化物挑战研究，测量口服3毫克氟化物剂量后24小时的尿液排泄情况。主要的药理学目的是确定影响氟斑牙风险个体差异的特定基因和变异。次要目的是在考虑氟化物暴露的差异后，评估氟牙症在氟病例家庭中与对照家庭中聚集的程度；评估氟中毒病例与对照组24小时尿氟排泄率是否存在差异，氟中毒易感基因是否对排泄率有影响；评估个人和家庭氟斑牙与龋齿之间的关系；以及确定龋齿的易感基因。

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.