International Genetic Epidemiology of Oral Clefts

描述（由申请人提供）：唇裂伴/不伴腭裂（CLP）是一种复杂且异质性的出生缺陷，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，因此是一种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，但口裂的病因仍然是个谜。我们提出了一个国际性的多中心，病例家庭研究CL/P，将测试一些候选基因和候选染色体区域使用单倍型和多点测试的连锁和不平衡，由于连锁。将从5个研究中心招募孤立的非综合征性CL/P病例及其家族：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）使用人口统计学、家族和病史信息对从这5个位点确定的病例家族进行描述性分析; 2）在新加坡国立大学使用高通量SNP分型方法沿着更稳健的基于序列的SNP基因分型方法对大量候选基因中的多个单核苷酸多态性（SNP）标记进行分型。分析病例父母间的等位基因和单体型频率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，使用可以考虑个体标记和多点数据的统计模型进行连锁; 4）使用基于单体型的分析和条件Logistic回归模型来检验基因-环境和基因-基因相互作用。这项国际多中心研究将能够及时积累大量的病例家族，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.