Genetic Epidemiology and Pharmacogenetics of Dental Fluorosis

氟牙症的遗传流行病学和药物遗传学

• 批准号: 7931948
• 负责人: SCOTT R DIEHL
• 金额: $ 69.41万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ DENTAL SCHOOL
• 依托单位国家: 美国
• 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/7931948
• 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

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）：众所周知，儿童早期接触高浓度氟化物会增加氟斑牙的风险。小鼠身上的证据强烈表明遗传变异也很重要。动物模型和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) 的高通量检测极大地增强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，因此需要大样本量才能提供足够的统计能力。这项研究将对爱尔兰一个地区 3,458 名 11-15 岁的学童进行评估，该地区大多数（但不是全部）饮用水都含有氟化物。总共将招募 520 名氟中毒病例和 605 名对照者。唾液中的 DNA 将用于全基因组 SNP 关联研究以及具有最高统计显着性的区域和基于生物功能（例如牙釉质蛋白）的高优先级候选基因的精细定位。还将获得龋齿和氟化物暴露数据。我们的团队在 10 年前获得了其中 125 名受试者的氟化物暴露情况，后续行动将评估回顾性家长报告的准确性。将招募 100 名病例和 100 名对照的嵌套组中的父母和一名兄弟姐妹，并进行临床和遗传评估，并对其中 100 名父母（50 名受影响的氟中毒和 50 名未受影响的）进行氟化物挑战研究，方法是测量口服 3 毫克氟化物剂量后 24 小时的尿液排泄量。药物遗传学的主要目的是确定影响氟斑牙风险个体差异的特定基因和变异。次要目标是在考虑氟化物暴露的变化后，评估氟斑牙病例家庭与对照家庭中氟斑牙聚集的程度；评估氟中毒病例和对照之间 24 小时尿液氟化物排泄率是否存在差异，以及氟中毒易感基因是否对排泄率有影响；评估个人和家庭氟斑牙与龋齿之间的关系；并鉴定龋齿的易感基因。