Genome-Wide Association Study of Early Childhood Caries

儿童早期龋齿的全基因组关联研究

• 批准号: 9143077
• 负责人: Kimon Divaris
• 金额: $ 239.59万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-10 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9143077
• 关键词: 12 year old; 4 year old; Address; Adult; Affect; African; African American; Age; American; Area; Behavior; Behavioral; Caring; Characteristics; Child; Childhood; Chronic; Chronic Disease; Clinical; Clinical Data; Collaborations; Communities; Community Health Systems; Complex; Coronary heart disease; DNA; Data; Dental; Dental Care; Dental Enamel Hypoplasia; Dental Plaque; Dental caries; Detection; Diagnosis; Diagnostic; Disease; Economically Deprived Population; Economics; Enrollment; Epidemiologic Studies; Epidemiology; Ethnic group; Etiology; European; Family; Funding; Future; General Anesthesia; Genes; Genetic; Genetic Determinism; Genetic Structures; Genetic study; Genome; Genomics; Genotype; Head Start Program; Health; Healthcare; Heritability; Hispanics; Human; International; Investigation; Knowledge; Latino; Lesion; Life Cycle Stages; Low Income Population; Measures; Meta-Analysis; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; North Carolina; Nursery Schools; Parents; Pathway interactions; Pattern; Personal Satisfaction; Phenotype; Population; Preschool Child; Prevalence; Preventive; Preventive care; Primary Dentition; Procedures; Protocols documentation; Public Health; Regulatory Element; Reporting; Research; Research Infrastructure; Risk; Risk Factors; Saliva; Sample Size; Sampling; Sedation procedure; Severities; Social Impacts; Stratification; Surveys; System; Techniques; Testing; Time; Tooth Diseases; Tooth structure; Underrepresented Minority; Visual system structure; Vulnerable Populations; age group; aged; base; burden of illness; cohort; deciduous tooth; density; early childhood; early onset; economic cost; economic impact; experience; falls; follow-up; genetic information; genetic variant; genome wide association study; high risk; improved; insight; knowledge base; microbiome; novel; permanent tooth; population based; prevent; racial and ethnic; racial disparity; response; restorative treatment; risk variant; sample collection; secondary outcome; social; tooth surface; trait

 DESCRIPTION (provided by applicant): Early childhood caries (ECC) is the most common chronic disease of childhood, and one that is characterized by marked social, economic, and racial disparities. The prevalence of ECC in the US increased by 15% during the last 2 decades, and according to the most recent national data 28% of children ages 2-5 are affected. Importantly, management of ECC among young children often requires complex and costly restorative procedures with the use of advanced behavior management techniques including sedation and general anesthesia. ECC can have severe sequelae for children's general health and well-being, and confers important social and economic impacts on their families, communities, and the health system. Caries is a multifactorial disease with a substantial genetic component, which is estimated between 40-60%, but little is known regarding specific contributing genetic factors. A large-scale genome-wide association study (GWAS) involving a multi-cohort meta-analysis recently nominated 29 loci as associated with dental caries among adult, predominantly European-American (EA), populations. So far, the only GWAS examining caries in the primary dentition employed a sample of 1,300 3-12 year-old EA children and nominated 7 genes, 2 of which showed additional evidence of association in follow-up studies among children and adults. Here, we propose to conduct a large-scale GWAS of ECC involving a multi-ethnic community-based sample of 6,000 children ages 3 and 4. For Aim 1, we will undertake a comprehensive clinical dental characterization of a state-representative sample of approximately 6,000 children enrolled in Early Head Start and Head Start programs in North Carolina. We will use a tested clinical examination protocol including saliva sample collection for DNA extraction, and will use the latest International Caries Diagnosis System (ICDAS) visual diagnostic criteria to determine disease prevalence and severity. We will collect and store dental plaque samples for future microbiome analyses that will be funded separately. To identify genetic variants that are associated with ECC, in Aim 2, we will conduct a trans-ethnic GWAS of ECC and related traits, utilizing high-density genotyping, imputation to 1000 Genomes Project reference panels and advanced statistical approaches to leverage differences in genetic structure between racial/ethnic groups. In Aim 3, we will utilize publicly available GWAS data of early childhood and adult caries, to determine the racial/ethnic and age-group generalization/transferability of loci, genes, and gene sets/pathways identified in our study. Our group's experience in conducting dental epidemiologic studies among young children including an ongoing collaboration with EHS/HS and expertise in large-scale, multi-ethnic GWAS, create a unique opportunity to carry out this important investigation and advance the knowledge base of genomics of dental caries. The study will improve our understanding of ECC's epidemiology and genomic etiology, key knowledge to reduce the burden of disease in populations of young children, including those underrepresented in research.

 描述（由申请人提供）：幼儿龋齿 (ECC) 是儿童期最常见的慢性疾病，其特点是存在显着的社会、经济和种族差异。过去 20 年来，美国 ECC 的患病率增加了 15%，根据最新的全国数据，28% 的 2-5 岁儿童受到影响。重要的是，幼儿 ECC 的管理通常需要复杂且昂贵的恢复程序，并使用先进的行为管理技术，包括镇静和全身麻醉。 ECC 可能会对儿童的总体健康和福祉产生严重的后遗症，并对他们的家庭、社区和卫生系统产生重要的社会和经济影响。龋齿是一种多因素疾病，具有很大的遗传成分，估计在 40-60% 之间，但对于具体的遗传因素知之甚少。一项涉及多队列荟萃分析的大规模全基因组关联研究 (GWAS) 最近提名了 29 个与成人（主要是欧洲裔美国人 (EA)）人群中的龋齿相关的位点。迄今为止，唯一检查乳牙列龋齿的 GWAS 采用了 1,300 名 3-12 岁 EA 儿童的样本，并指定了 7 个基因，其中 2 个在儿童和成人的后续研究中显示了额外的相关证据。在这里，我们建议开展一项大规模的 ECC GWAS，涉及 6,000 名 3 岁和 4 岁儿童的多种族社区样本。对于目标 1，我们将对北卡罗来纳州参加早期启蒙和启蒙计划的约 6,000 名具有州代表性的儿童样本进行全面的临床牙科特征分析。我们将使用经过测试的临床检查方案，包括唾液样本采集 DNA提取，并将使用最新的国际龋齿诊断系统（ICDAS）视觉诊断标准来确定疾病的患病率和严重程度。我们将收集和存储牙菌斑样本，用于未来的微生物组分析，该分析将单独资助。为了识别与 ECC 相关的遗传变异，在目标 2 中，我们将利用高密度基因分型、对 1000 个基因组计划参考组的估算以及先进的统计方法来利用 ECC 和相关性状的跨种族 GWAS，以利用种族/族裔群体之间遗传结构的差异。在目标 3 中，我们将利用公开的幼儿期和成人龋齿 GWAS 数据来确定我们研究中确定的基因座、基因和基因集/通路的种族/族裔和年龄组概括/可转移性。我们小组在幼儿中进行牙科流行病学研究的经验，包括与 EHS/HS 的持续合作以及大规模、多种族 GWAS 的专业知识，为开展这项重要调查并推进龋齿基因组学知识库创造了独特的机会。这项研究将提高我们对 ECC 流行病学和基因组病因学的理解，这些知识是减轻幼儿群体（包括研究中代表性不足的儿童）疾病负担的关键知识。