An over-dominant effect associated with an SNP in a TP63 regulatory region is implicated in susceptibility to non-syndromic orofacial clefts.

Background: Non-syndromic orofacial clefts (NSOC) are complex phenotypes, involving multiple low penetrance genetic and environmental factors. Using a candidate gene approach, we aimed to analyze the role of four single nucleotide polymorphisms (SNPs) in the susceptibility to NSOC.

Methods: A total of 254 individuals, 120 patients with NSOC, and 134 controls, all of Portuguese origin and non-consanguineous, were recruited. About 92% of patients had cleft lip with or without cleft palate (NSCL/P) and 8% had cleft palate (NSCP).  Four SNPs in the MTHFR, IRF6, PAX7, and TP63 genes were studied, using a real-time approach with TaqMan probes. Statistical analysis was performed with IBM SPSS Statistics and included chi-squared, Cochran test for trend and binomial logistic regression. Bonferroni correction was applied. Statistical significance was set to 0.05.

Results: All SNPs were in Hardy-Weinberg equilibrium. A significant statistical association was found for TP63 rs9332461 in an over-dominant model (p = 0.016; OR 1.897 (1.144 - 3.147)).

Discussion and conclusion: Few SNPs have been so far identified in TP63 in population association studies. In our sample, a significant association was only highlighted for rs9332461, localized in upstream regulatory region. Mechanisms involved in heterozygous advantage may underlie the association.