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Olga A. Korczeniewska
Interdisciplinary Biomedical Sciences Program
B.A. 2004, Rutgers University, Newark, NJ

Thesis Advisor: Scott R. Diehl, Ph.D.
Department of Oral Biology

Monday, April 30, 2012
4:00 P.M., NJDS B-723


Introduction: Non-syndromic orofacial clefting is the second most common birth defect and occurs alone or in combination with cleft palate (CL/P) in approximately one to two cases per 1,000 live births whereas isolated cleft palate (CPO) occurs in approximately 1 in 2,500 live births worldwide. Prevalence of cleft lip with or without cleft palate (CL/P) varies widely depending on geographic region and ethnic background with the highest rates of occurrence in Native Americans (3.6 per 1,000 live births), followed by Asians (2.0 per 1,000 live births), people of European ancestry (1.0 per 1,000 live births), and lowest in Africans (0.3 per 1,000 live births). Orofacial clefting has a complex etiology with a heritability of 70% and environmental factors also implicated. The goal of this study was to evaluate previously reported genetic risk factors for non-syndromic orofacial clefting based on Genome Wide Association Studies (GWAS) in Caucasians. Eleven Single Nucleotide Polymorphisms (SNPs) in six candidate genes (IRF6, FOXE1, ABCA4, COL2A1, CLEC4GP1, and NAT2) and a candidate gene region (8q24) were genotyped.
Materials and Methods: A total of 307 Caucasian families with one or more cleft affected members were studied with 947 subjects with DNA available (383 cases and 564 controls). The sample included 220 Caucasian families with >=1 family member affected by non-syndromic CLP or cleft lip only (CLO) and 74 families with cleft palate only (CPO). Genotypes were assayed using the Taqman method and statistical analysis was performed using JMP and Golden Helix Software for dominant, additive and recessive genetic models.
Results: SNP rs987525 located in 8q24 region showed statistically significant evidence of association with CLP+CLO in a combined gender association analysis (P=0.015, additive model). As reported previously, SNP rs642961 located in the enhancer region of the IRF6 gene showed significant association with isolated CLO (P=0.01) but was not associated with CLP. After stratification by gender, two SNPs in the 8q24 region and one SNP in IRF6 were significantly associated with CL/P but only in males. For CPO, a SNP in NAT2 showed statistically significant evidence of association in males while in females only a SNP in IRF6 was significantly associated with disease risk.
Conclusions: This study confirms some but not all of the previously reported associations of genetic polymorphisms and risk of non-syndromic orofacial clefting. Evidence of gender specific effects was discovered for the first time. The findings emphasize the heterogeneity of this disorder in that different subtypes of clefting appear to be associated with different genes. The majority of the large heritable component of orofacial clefting risk is not explained by these or other findings reported in the literature and requires further investigation using next generation sequencing and complex models of gene by gene and gene by environment interaction.

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