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。家庭和双胞胎的研究已经清楚地表明遗传因素在唇腭裂的病因学中起着重要作用，但环境因素也起着重要作用。确定的环境风险因素（例如，药物，酒精，吸烟，营养缺乏）是薄弱的（O.R. < 1.5）。同样，遗传分析也没有发现任何单一的基因在裂缝中起主要作用。在本提案的上一个资助周期中，我们能够分析大样本的病例母体三联体和病例对照的环境数据和分子分析。最初提交的资料利用了自1930年代以来在丹麦研究的唇裂人口，这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、丹麦和美国之间的良好合作。此外，我们还在美国国立环境与健康科学研究院（National Institutes of Environmental and Health Sciences）增加了一个最先进的流行病学分析团队，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（SNPs）的鉴定-为在一个前所未有的水平上对一组基因进行基因分型提供了机会，这些基因具有直接参与分裂的高先验概率。这些独特的资源的组合提供了详细研究唇腭裂的机会。在这个项目中，我们将在总共600例孤立性腭裂和唇裂伴或不伴腭裂的父母三联体中描述50个候选基因和这些基因中的150个SNP标记。然后，将在使用800多例病例和2800例对照的病例对照分析中确认该初步分析的阳性结果。在这一阶段确认的结果将进行统计分析，重点是基因-基因相互作用，并最终研究基因-环境相互作用。该项目还将为我们使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200，000例连续妊娠，并为裂缝研究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性状提供新的理解水平。

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.