Ethnic heterogeneity of IRF6 AP-2a binding site promoter SNP association with nonsyndromic cleft lip and palate

Objective: The goal of this study was to confirm the reported association between a noncoding SNP (rs642961) in IRF6 and nonsyndromic cleft lip and palate. Design, Setting, and Participants: Two SNPs in IRF6 (rs2235371 and rs64296) were genotyped in Hispanic and non-Hispanic white multiplex (122) and simplex (308) nonsyndromic cleft lip and palate families. Linkage and family-based association analyses were performed on the individual SNPs as well as the 2-SNP haplotype. Results: Only modest evidence was found for an association with rs642961 and the 2-SNP haplotype. In contrast, strong evidence was found for the association with rs2235371; this was most evident in the non-Hispanic white simplex families. Conclusions: Although it is confirmed that variation in IRF6 is associated with nonsyndromic cleft lip and palate, the results do not support the reported association with SNP rs64296. Importantly, the association varies between ethnic groups. This finding underscores the need for evaluating additional variations in IRF6 across multiple populations to better determine its role in nonsyndromic cleft lip and palate.