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，可以为复杂的特征分析提供一个模型。家庭和双胞胎研究清楚地表明，遗传在唇腭裂的病因中起到了作用，但环境因素也起到了重要作用。已确定的环境风险因素(例如，药物、酒精、吸烟、营养不足)较弱(手术室和1.5)。同样，到目前为止，遗传分析还没有发现任何强大的单基因在裂隙形成中发挥重要作用。在这项提案的前一个资金周期中，我们能够分析病例亲本三合会和病例对照的大样本，用于环境数据和分子分析。最初提交的材料利用了丹麦自20世纪30年代以来一直在研究的裂隙人口，这些人口提供了种族同质的人口，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、丹麦和美国之间业已建立的合作。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(SNPs)的鉴定--提供了在前所未有的水平上对一组基因进行基因分型的机会，这些基因具有很高的先前直接参与分裂的概率。这些独特资源的结合为详细研究唇腭裂提供了机会。在这个项目中，我们将在总共600个病例中鉴定50个候选基因和这些基因中的150个SNP标记，这些基因包括孤立的腭裂和伴有或不伴有腭裂的唇裂的亲本三联体。这项初步分析的阳性结果将在使用800多个病例和2800个对照的病例对照分析中得到确认。在这一阶段得到确认的发现随后将接受统计分析，重点是基因与基因的相互作用，并最终研究基因与环境的相互作用。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，在这两项研究中，将确定20万例连续怀孕，并为裂隙研究提供详细的流行病学、环境和生物学数据。这项研究将为理解复杂的出生缺陷特征提供一个新的水平。

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.