Genetic Epidemiology and Pharmacogenetics of Dental Fluorosis

氟牙症的遗传流行病学和药物遗传学

基本信息

批准号：
7672370
负责人：
SCOTT R DIEHL
金额：
$ 64.69万
依托单位：
UNIV OF MED/DENT OF NJ-NJ DENTAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7672370
关键词：
Accounting Acquired Dental Fluorosis Adult Affect Age Animal Model Beverages Biological Biological Assay Biological Process Biology Candidate Disease Gene Case-Control Studies Child Clinical Collection Complex Consumption DNA Data Dental Enamel Dental caries Development Diet Disease Dose Etiology Excretory function Exposure to Family Family Study Family member Female Fluorides Food Frequencies Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genetic Variation Genome Genomics Genotype Goals Haplotypes Hour Human Human Gene Mapping Human Genetics Individual Individual Differences Information Systems Ingestion Inherited Ireland Knowledge Laboratories Light Literature Maps Measures Mouse Strains Mouthwash Mus Nuclear Family Oral Parents Pharmacogenetics Phenotype Placebos Population Predisposition Proteins Protocols documentation Questionnaires Recruitment Activity Relative (related person)Reporting Research Research Design Research Personnel Risk Saliva Sample Size Sampling Schools Siblings Single Nucleotide Polymorphism Statistical Methods Study Subject Surveys Susceptibility Gene Testing Time Tooth Diseases Toothpaste Twin Multiple Birth Urine Variant base case control cost density disorder risk drinking water early childhood fluorosis follow-up gene interaction genetic analysis genetic association genetic epidemiology genome wide association study high throughput screening male nutrition programs research study systems research tool trait

项目摘要

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.

描述（由申请人提供）：良好的，在幼儿期间暴露于氟化物高度的水平会增加牙齿氟中毒的风险。小鼠的证据强烈表明遗传遗传变异也很重要。动物模型和人双胞胎的分析都提供了有力的证据，表明龋齿的风险也很高。然而，迄今为止，尚无人类研究评估个体遗传变异对氟化物生物学或氟中毒风险的影响。单核苷酸多态性（SNP）的高通量测定极大地增强了鉴定牙齿氟中毒等复杂性状的基因的能力。研究人员可以以合理的成本来分析超过500,000个SNP。由于这些表型涉及多个基因以及与环境变量的相互作用，因此需要大型样本量以提供足够的统计能力。这项研究将在爱尔兰的一个地区（但不是全部）饮用水氟化的地区评估3,458名儿童11-15岁的儿童。总共将招募520例氟中毒病例和605例对照。唾液中的DNA将用于整个基因组SNP关联研究，并根据生物学功能（例如，搪瓷蛋白）在具有最高统计学意义和高优势候选基因的区域进行精细映射。还将获得龋齿和氟化物暴露数据。氟化物暴露于10年前的125名受试者之前已获得氟化物的暴露，随访将允许评估回顾性父母报告的准确性。父母和一个兄弟姐妹都将汇集100例嵌套，并通过临床和遗传评估100例，并通过测量3 mg口服液化剂量后的100个父母（50个受影响的氟中毒和50个未影响）对氟化物挑战研究进行。主要的药物遗传学目的是确定影响牙齿氟中毒风险个体差异的特定基因和变体。次要目的是评估氟中毒病例家族中牙齿氟中毒聚集体的程度，而氟化物暴露的变化后对照组的对照；评估氟中毒病例和对照之间的氟化物的24小时排泄率是否有所不同，以及氟中毒易感基因是否对排泄率有影响；评估个人和家庭中牙齿氟中毒与龋齿之间的关系；并确定龋齿的易感基因。