GENE-ENVIRONMENT INTERACTION IN FACIAL CLEFTS

先天性畸形在儿童中所占比例越来越大， 发达国家新生儿发病和死亡的原因 国家 虽然这些畸形有许多病因， 流行病学方法和生殖毒理学的进展表明， 几种常见的疾病，如唇裂和/或腭裂（CLP）， 神经管缺陷和先天性心脏病有显着的 复杂的基因-环境因素 交互. 在病因学知识不断发展的同时， 分子遗传学技术和分析方法的进展 提供了独特的机会，以确定遗传和环境 对这些常见疾病的贡献。 20世纪30年代，丹麦的福格-安德森首次发现了 CLP的背景 在随后的半个世纪里， 丹麦的同质人口一直是众多 对CLP的流行病学和遗传学进行全面研究。 的 然而，进行分子研究的巨大潜力还没有被 迄今为止被剥削。 爱荷华州大学的默里博士 参与了几个单基因颅面的基因定位 他的研究小组是第一个确定遗传关联的人 在人类中，裂畸形和转化生长因子 α的 此关联已在其他设置中得到确认，但 所有人，并对种族冲突的影响表示关切。 在研究人群中的分布。 最近，新 与TGFB 3的关联已经被确定， 吸烟与TGFA的关系为基因研究提供了新的窗口， 环境交互作用 该建议基于丹麦的几个CLP确认来源。 在丹麦进行了一项全国性的CLP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例CLP病例中， 606个对照品已通过一个北大库获得，该库已在 自1981年以来的业务。 PKU库将成为基因的来源， 关于另外1，000例CLP病例和4，000例对照病例的信息。 最后，对大约200例CLP病例和800例 控制，包括遗传和环境暴露信息 可以嵌套在一项对10万例妊娠的前瞻性研究中， 1995-1997年期间在丹麦进行的一项研究。 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-美国的合作将体现 环境、遗传和基因-环境相互作用， 关联、连锁和Logistic回归。 这是一个独特的 有机会进行研究，有很大的力量来发现新的 病因和确认/驳斥目前的假设CLP。 这将是 特别令人感兴趣的是，这项研究是在相对 同质的人口，这构成了一个重要的基础， 国际CLP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.