International Genetic Epidemiology of Oral Clefts

描述(由申请人提供)：唇裂伴/不伴腭裂(CLP)是一种复杂和不同种类的出生缺陷，由于其高患病率和对受影响婴儿及其家庭造成的医疗负担，构成了主要的公共卫生负担。尽管有强有力的证据表明，遗传和环境因素都必须参与，无论是单独的还是通过相互作用，口腔裂的病因仍然是个谜。我们提出了一项国际多中心的CL/P病例家系研究，它将使用单倍型和多点检验来测试一些候选基因和候选染色体区域，以确定连锁和连锁引起的不平衡。孤立的非综合征CL/P病例及其家属将从5个地点招募：马里兰州(约翰霍普金斯大学)、新加坡、台湾、北京和山东省潍坊市。具体目标是：1)使用人口统计、家族和病史信息对从这5个地点确定的病例家系进行描述性分析；2)结合新加坡国立大学的高通量SNP分型方法和更稳健的基于序列的SNP基因分型方法，在大量候选基因中分型多个单核苷酸多态(SNP)标记。对病例父母的等位基因和单倍型频率的分析将提供群体间遗传距离的估计；3)在存在不平衡的情况下，使用基于家庭的关联检验，并建立可同时考虑单个标记和多点数据的统计模型；4)使用基于单倍型的分析和条件Logistic回归模型来检验基因-环境和基因-基因交互作用。这项国际多中心研究将能够及时积累大量的病例-家系，并提供足够的统计能力来识别控制CL/P风险的基因，即使它们可能相互作用或与环境因素相互作用。

DESCRIPTION (provided by applicant): Cleft lip with/without cleft palate (CLP) is a complex and heterogeneous birth defect that represent a major public health burden because of the high prevalence and the medical burden they create for both affected infants and their families. The etiology of oral clefts remains enigmatic despite strong evidence that both genetic and environmental factors must be involved, both individually and through interaction. We propose an international multi-center, case-family study of CL/P that will test a number of candidate genes and candidate chromosomal regions using haplotype and multipoint tests for linkage and disequilibrium due to linkage. Isolated, nonsyndromic CL/P cases and their families will be recruited from 5 sites: Maryland (Johns Hopkins Univ.), Singapore, Taiwan, Beijing and Weifang City in Shandong Province. The specific aims are: 1) To conduct a descriptive analysis of case families ascertained from these 5 sites using demographic, family and medical history information; 2) To type multiple single nucleotide polymorphisms (SNP) markers in a large number of candidate genes using a combination of high throughput SNP typing methods along with more robust sequence based methods for SNP genotyping at the National University of Singapore. Analysis of allele and haplotype frequencies among parents of cases will provide estimates of genetic distance among populations; 3) To use family-based association tests for linkage in the presence of disequilibrium with statistical models that can consider both individual markers and multipoint data; 4) To test for gene-environment and gene-gene interaction using haplotype-based analyses and conditional logistic regression models. This international multicenter study will be able to accumulate large numbers of case-families in a timely fashion, and providing adequate statistical power to identify genes controlling risk to CL/P even when they may interaction with one another or with environment factors.