Nonsyndromic cleft lip with or without cleft palate (NSCL ± P) is strongly associated with both environmental and genetic risk factors, but its genetic underpinnings remain partially known. While variants in interferon regulatory factor 6 (IRF6) are linked to NSCL ± P risk in populations from Asia and Europe, studies on the highly admixed Brazilian population are scarce and have produced ambiguous results. This study aimed to investigate the contribution of IRF6 variants to the risk of NSCL ± P. Five tag-single nucleotide polymorphisms (rs599021, rs2073485, rs2235375, rs7552506, and rs642961) were analyzed in a large multicenter cohort composed of 1006 patients with NSCL ± P and 942 healthy controls. Statistical analyses involved multiple logistic regression tests consideration the tri-hybrid genetic origin of the Brazilian population, under a Bonferroni p value correcting for multiple comparisons. The A allele (OR: 1.43, 95% CI: 1.22-1.67, p < 0.0001) and AA genotype (OR: 2.04, 95% CI: 1.46-2.86, p < 0.0001) frequencies of rs642961 were significantly associated with NSCL ± P risk. Stratified analyses indicated that the variant is associated with susceptibility to both nonsyndromic cleft lip only (NSCLO) and nonsyndromic cleft lip and palate (NSCLP). However, the association with NSCLO was primarily observed in patients with high African ancestry, whereas the association with NSCLP was predominantly seen in patients with high European ancestry. No significant associations were found for the other investigated variants. Our results support the notion that the IRF6 rs642961 variant represents a marker of susceptibility to NSCL ± P in the Brazilian population, and that genetic ancestry composition plays a central role in the association with the cleft type.
Keywords: IRF6; case-control study; nonsyndromic orofacial clefts; risk factor; single-nucleotide polymorphism.