Association Between IRF6 Variants and Nonsyndromic Cleft Lip With or Without Cleft Palate in Chile

The aim of this study was to assess the association between IRF6 single nucleotide polymorphisms and nonsyndromic cleft lip, with or without cleft palate (NSCL/P), in a Chilean population, based on a case-control sample and confirmed in a case-parent trio population. In a sample of 150 Chilean case-parent trios and 164 controls (cohort 1), we evaluated the association between three common IRF6 variants (rs764093, rs2236909, rs2235375) and NSCL/P using odds ratio (OR) for case-control and case-parent trios and in a combined OR of both designs. To confirm associations from the cohort 1, we increased the sample size to 215 triads and 320 controls (cohort 1 + cohort 2). The combined OR for the cohort 1 reveals that the rs2235375 C allele is associated with NSCL/P in Chile (OR 1.34; p = 0.013), which was supported by the results for the two cohorts (OR 1.29; p = 0.006). Bioinformatic prediction showed that this variant, located 27 bp downstream from IRF6 exon 6, potentially alters the splicing process and based on functional annotations is associated with a decrease of gene expression. We propose that the C allele of rs2235375 from IRF6 gene seems to be a risk factor for NSCL/P in a Chilean population. However, we cannot discard a population stratification bias in our findings. On the other hand, further studies are necessary to confirm the biological role of rs2235375 in IRF6 function at craniofacial development level.