Gene-enviornment interactions in facial clefts

描述（由申请人提供）：唇腭裂是最常见和最容易诊断的出生缺陷之一，可以为复杂的性状分析提供模型。家庭和双胞胎研究清楚地表明，遗传因素在唇腭裂的病因中起着重要作用，但环境因素也起着重要作用。确定的环境危险因素（如药物、酒精、吸烟、营养缺乏）较弱（O.R. < 1.5）。同样，遗传分析还没有发现任何强大的单一基因在裂裂中起主要作用。在该提案的前一个资助周期中，我们能够分析大样本，用于环境数据和分子分析，包括病例母三联体和病例对照。最初的提交利用了自20世纪30年代以来一直在丹麦研究的裂隙人口，该人口提供了一个种族同质的人口，以及一个广泛的历史数据库来进行研究。在这次重新提交中，我们现在将与挪威正在进行的平行努力合作，并利用挪威、丹麦和美国之间建立良好的合作关系。此外，我们还在国家环境与健康科学研究所增加了一个最先进的流行病学分析小组，他们正在开发新的分析工具，以利用现有的样本量。最后，分子技术的进步——特别是单核苷酸多态性（snp）的鉴定——为一组具有高先验概率直接参与裂裂的基因提供了以前所未有的水平进行基因分型的机会。这些独特资源的结合为详细研究唇腭裂提供了机会。在本项目中，我们将在600例分离性腭裂和伴或不伴腭裂的唇裂亲本三联体中对50个候选基因和150个SNP标记进行表征。这一初步分析的阳性结果随后将在使用800多例病例和2800名对照的病例控制分析中得到证实。在这一阶段确认的发现将进行统计分析，重点是基因-基因相互作用，并最终进行基因-环境相互作用的研究。该项目还将为我们利用在丹麦和挪威进行的两项大型队列研究奠定基础，其中将确定20万次连续怀孕，并为研究唇裂提供详细的流行病学、环境和生物学数据。这项研究将为复杂的出生缺陷特征提供一个新的认识水平。

DESCRIPTION (provided by applicant): Clefts of the lip and/or palate are among the most common and easily diagnosed birth defects, and can provide a model for complex trait analysis. Family and twin studies have clearly indicated a genetic role in the etiology of cleft lip and palate, but environmental components play a major role, as well. The environmental risk factors identified (e.g., medications, alcohol, smoking, nutritional deficiencies) are weak (O.R. < 1.5). Similarly, genetic analysis has not as yet identified any strong single gene as playing a major role in clefting. In the previous funding cycle of this proposal, we were able to analyze a large sample for both case parent triads and case controls for environmental data and molecular analysis. The initial submission took advantage of the cleft population that has been studied in Denmark since the 1930s and which provided an ethnically homogenous population, as well as an extensive historic database to carry out the studies. In this resubmission, we will now partner with parallel efforts underway in Norway, and take advantage of a well-established collaboration between Norway, Denmark and the United States. In addition, we have added a state-of-the-art epidemiologic analytic team based at the National Institutes of Environmental and Health Sciences who are developing new analytic tools to take advantage of the sample sizes available. Finally, advances in molecular technologies--particularly the identification of single nucleotide polymorphisms (SNPs)--have afforded the opportunity to carry out genotyping at an unprecedented level for a group of genes which have a high prior probability of being directly involved in clefting. The combination of these unique resources affords the opportunity to study cleft lip and palate in detail. In this project, we will characterize 50 candidate genes and 150 SNP markers within those genes in a total of 600 case parent triads for both isolated cleft palate and cleft lip with or without cleft palate. Positive findings from this initial analysis will then be confirmed in a case control analysis using over 800 cases and 2800 controls. Confirmed findings at this stage will then undergo statistical analysis with an emphasis on gene-gene interaction and, eventually, studies of gene-environment interaction. This project will also set the stage for our use of two large cohort studies taking place in Denmark and Norway in which 200,000 consecutive pregnancies will be ascertained, and detailed epidemiologic, environmental, and biological data made available for studies of clefting. This study will provide a new level of understanding for a complex birth defect trait.