IRF6 is a risk factor for nonsyndromic cleft lip in the Brazilian population

Abstract

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a complex disorder with a worldwide incidence estimated at 1:700. Among the putative susceptibility loci, the IRF6 gene and a region at 8q24.21 have been corroborated in different populations. To test the role of IRF6 in NSCL/P predisposition in the Brazilian population, we conducted a structured association study with the SNPs rs642961 and rs590223, respectively, located at 5' and 3' of the IRF6 gene and not in strong linkage disequilibrium (LD), in patients from five different Brazilian locations. We also evaluated the effect of these SNPs in IRF6 expression in mesenchymal stem cells (MSC). We observed association between rs642961 and cleft lip only (CLO) (P=0.009; odds ratio (OR) for AA genotype=1.83 [95% Confidence interval (CI), 0.64-5.31]; OR for AG genotype=1.72 [95% CI, 1.03-2.84]). This association seems to be driven by the affected patients from Barbalha, a location which presents the highest heritability estimate (H2=0.85), and the A allele at rs642961 is acting through a dominant model. No association was detected for the SNP rs590223. We did not find any correlation between expression levels and genotypes of the two loci, and it is possible that these SNPs have a functional role in some specific period of embryogenesis.

Polymorphisms at 1q32, 8q24, and 17q22 loci are associated with nonsyndromic cleft lip with or without cleft palate risk in the Slovak population

“…The most significant results, persisting after Bonferroni correction, were observed when the additive model was used, confirming dosage risk effect of minor allele A. Positive association between the IRF6 rs642961 variant and nsCL/P has been confirmed by multiple studies involving various ethnicities [21][22][23][24] . Also, our results are in accordance with the findings from two case-control studies on Central European populations which showed similar magnitudes of odds ratios 10,19 .…”

Genetics and genomics in Brazil: a promising future

“…Accordingly, AIMs have proven to be useful for inferring the putative biogeographic ancestry of individuals, estimating the ancestry proportions of admixed individuals and populations (Shriver et al 1997; Halder et al 2008; Pena et al 2011; Pereira et al 2012; Suarez-Kurtz et al 2012; Manta et al 2013), correcting case–control studies for stratification bias (Brito et al 2012a,b; Bagordakis et al 2013), and performing admixture mapping approaches. Many of such studies have benefited from AIM panels built by Brazilian research groups, focused specifically on discriminating Brazilian parental populations (Bastos-Rodrigues et al 2006; Santos et al 2010; Brito et al 2012a; Manta et al 2013). In addition, in an ethnically admixed population, it is possible to evaluate the impact of certain at-risk alleles on the occurrence of some disorders or to drug response among different ethnicities simultaneously, under similar environmental and socio-economical conditions (Suarez-Kurtz et al 2014).…”

TGFA and IRF6 Contribute to the Risk of Nonsyndromic Cleft Lip with or without Cleft Palate in Northeast China

“…Research has shown common alleles in IRF6 that are associated with NSCL/P, which has been independently replicated in genome-wide association (GWA) [11], [40] and candidate gene studies [41], [42]. Animal models have also supported the role of IRF6 in NSCL/P [43], [44].…”