Genome-Wide Association Study of Early Childhood Caries

 描述(申请人提供)：幼儿龋病(ECC)是儿童最常见的慢性疾病，具有明显的社会、经济和种族差异。在美国，ECC的患病率在过去20年里增加了15%，根据最新的国家数据，2-5岁的儿童中有28%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性程序，并使用包括镇静和全身麻醉在内的先进行为管理技术。幼儿保育可对儿童的总体健康和福祉产生严重的后遗症，并对其家庭、社区和卫生系统产生重要的社会和经济影响。龋病是一种多因素疾病，有很大的遗传成分，估计在40%-60%之间，但关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最近在以欧洲裔美国人(EA)为主的成年人群中提名了29个与龋齿相关的基因座。到目前为止，唯一在乳牙期检查龋齿的GWAS使用了1300名3-12岁EA儿童的样本，并提名了7个基因，其中2个在儿童和成人的后续研究中显示出额外的证据。在这里，我们建议进行一次大规模的幼儿保育和健康教育，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登记参加早期Head Start和Head Start计划的大约6,000名儿童进行具有州代表性的样本的全面临床牙科特征分析。我们将使用经过测试的临床检查方案，包括采集唾液样本 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，这些分析将单独获得资金。为了确定与ECC相关的遗传变异，在目标2中，我们将对ECC和相关特征进行跨种族GWA，利用高密度基因分型、1000基因组计划参考小组和先进的统计方法来利用种族/民族群体之间的遗传结构差异。在目标3中，我们将利用可公开获得的儿童早期和成人龋齿的Gwas数据，来确定我们研究中确定的基因座、基因和基因集/途径的种族/民族和年龄组泛化/可转移性。我们小组在幼儿中进行牙齿流行病学研究方面的经验，包括与EHS/HS的持续合作，以及在大规模、多种族GWA方面的专业知识，为开展这项重要的调查创造了独特的机会，并推进了龋齿基因组学的知识库。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，这是减少幼儿人群中疾病负担的关键知识，包括那些在研究中代表性不足的人群。

 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.