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，它代表了一个主要的公共卫生负担。尽管有强有力的证据表明，遗传和环境因素必须单独或相互作用，但口腔唇裂的病因仍然是一个谜。我们建议开展一项国际多中心病例家族研究，使用单倍型和多点检测来检测连锁和连锁不平衡，从而检测一些候选基因和候选染色体区域。从马里兰州（约翰霍普金斯大学）、新加坡、台湾、北京和山东省潍坊市5个地点招募孤立的、无综合征的CL/P病例及其家属。具体目的是：1)利用人口统计学、家族史和病史信息，对这5个地点确定的病例家庭进行描述性分析；2)在新加坡国立大学，利用高通量SNP分型方法和更强大的基于序列的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。对病例父母间等位基因和单倍型频率的分析将提供种群间遗传距离的估计；3)在存在不平衡的情况下，使用基于家庭的关联检验，使用既能考虑个体标记又能考虑多点数据的统计模型；4)利用基于单倍型的分析和条件逻辑回归模型检验基因-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.