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. ? ?
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