GENE-ENVIRONMENT INTERACTION IN FACIAL CLEFTS

先天畸形占越来越大的比例 发达国家新生儿发病率和死亡率的原因分析 国家。虽然这些畸形的原因很多， 流行病学方法和再毒理学的进展表明 几种常见的疾病，如唇腭裂(CLP)， 神经管缺陷和先天性心脏缺陷有显著的 错综复杂的基因环境导致的病因比例 互动。伴随着病因学知识的不断发展， 分子遗传学技术和分析方法的进展 提供独特的机会来识别遗传和环境 对这些常见疾病的贡献。 20世纪30年代，丹麦的福格-安徒生首次发现了这种基因 中电的背景。在接下来的半个世纪里，在种族上 丹麦的同质人口一直是众多 慢性阻塞性肺病流行病学和遗传学综合研究。这个 然而，进行分子研究的巨大潜力并没有 到目前为止都被利用过。爱荷华大学的默里博士一直在 参与了几个单基因颅面的基因定位 疾病和他的团队是第一个确定基因关联的人 在人类分裂畸形和转化生长因子之间 阿尔法。该关联已在其他设置中确认，但尚未确认 所有的，并提出了对种族影响的担忧 在所研究种群中的分布。最近，新的 已确定与TGFB3的关联并产生交互效应 吸烟与TGFA暗示了基因研究的新窗口- 环境相互作用。 这项建议是基于丹麦的几个中电确定的消息来源。 年，丹麦开展了一项全国性的中电病例对照研究 1991年至1994年收集有关环境因素的资料。 在参与的322个CLP案例中，88%的生物样本和 606项控制已通过北大银行获得，该银行已在 自1981年开始运营。北大文库将成为基因的来源 有关另外1,000宗中电个案和4,000宗管制的资料。 最后，对大约200例CLP病例和800例CLP病例进行了病例对照研究 控制，包括遗传和环境暴露信息 可以嵌套在对100,000名孕妇的前瞻性研究中 1995-1997年期间在丹麦进行。基于丹麦语 数据资源、美国分子专业知识和联合分析 优势，丹麦和美国的合作将成为 环境、遗传和基因-环境相互作用 关联、连锁和Logistic回归。这呈现了一种独特的 有机会进行一项具有重大能力的研究，以发现新的 中电的病因和确认/驳斥当前的假说。这将是 特别令人感兴趣的是，这项研究是在相对 同质人口，这构成了一个重要的基础 国际中电研究的比例。

Congenital malformations make up an increasingly larger proportion of the causes of morbidity and mortality in newborns in developed countries. While there are many etiologies for these malformations, advances in epidemiologic approaches and reprotoxicology demonstrate that several common disorders such as cleft lip and/or palate (CLP), neural tube defects and congenital heart defects have a significant proportion of their causes due to complex gene-environment interactions. In parallel with this evolving knowledge of etiologies, advances in molecular genetics technologies and analytic approaches provide unique opportunities to identify both genetic and environmental contributions to these common disorders. In the 1930s Fogh-Andersen in Denmark first identified the genetic background of CLP. Through the following half century the ethnically homogeneous population of Denmark has been the platform for numerous comprehensive studies of the epidemiology and genetics of CLP. The large potential for doing molecular studies has, however, not been exploited to date. Dr. Murray at the University of Iowa has been involved in the gene mapping of several single gene craniofacial disorders and his group was the first to identify genetic associations in humans between clefting malformations and transforming growth factor alpha. This association has been confirmed in other settings but not all, and concern has been raised about the impact of ethnic distributions in the populations studied. More recently, new associations with TGFB3 have been identified and interactive effects of smoking with TGFA suggesting new windows into studies of gene- environment interaction. This proposal is based on several CLP ascertainment sources in Denmark. A nationwide case-control study of CLP was conducted in Denmark from 1991 to 1994 to collect information on environmental factors. Biological samples on 88 percent of the participating 322 CLP cases and 606 controls have been obtained through a PKU-bank which has been in operation since 1981. The PKU-bank will be the source of genetic information on an additional 1,000 CLP cases and 4,000 controls. Finally, a case-control study of approximately 200 CLP cases and 800 controls, including both genetic and environmental exposure information can be nested within a prospective study of 100,000 pregnancies to be conducted in Denmark in the period from 1995-1997. Based on Danish data-resources, American molecular expertise and joint analytic strengths, a Danish-American collaboration will characterize environmental, genetic and gene-environment interactions using association, linkage and logistic regression. This presents a unique opportunity to conduct a study with substantial power to detect new etiologies and confirm/refute current hypotheses of CLP. This will be of particular interest because the study is conducted in a relatively homogeneous population, which has constituted the basis of an important proportion of international CLP research.