Region 8q24 is a susceptibility locus for nonsyndromic oral clefting in Brazil

Abstract

BACKGROUND: Nonsyndromic cleft lip with or without cleft palate is a relatively common craniofacial defect with multifactorial inheritance. The association of the rs987525 single nucleotide variant, located in a gene desert at 8q24.21 region, has been consistently replicated in European populations. We performed a structured association approach combined with transcriptional analysis of the MYC gene to dissect the role of rs987525 in oral clefting susceptibility in the ethnically admixed Brazilian population. METHODS: We performed the association study conditioned on the individual ancestry proportions in a sample of 563 patients and 336 controls, and in an independent sample of 221 patients and 261 controls. The correlation between rs987525 genotypes and MYC transcriptional levels in orbicularis oris muscle mesenchymal stem cells was also investigated in 42 patients and 4 controls. RESULTS: We found a significant association in the larger sample (p 5 0.0016; OR 5 1.80 [95% confidence interval {CI}, 1.21-2.69], for heterozygous genotype, and 2.71 [95% CI, 1.47-4.96] for homozygous genotype). We did not find a significant correlation between rs987525 genotypes and MYC transcriptional levels (p 5 0.14; r 5 20.22, Spearman Correlation). CONCLU-SIONS: We present a positive association of rs987525 in the Brazilian population for the first time, and it is likely that the European contribution to our population is driving this association. We also cannot discard a role of rs987515 in MYC regulation, because this locus behaves as an expression quantitative locus of MYC in another tissue. Birth Defects Research (Part A) 94: 464-468, 2012. Ó

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

“…It is thus possible that CLO etiology might be genetically more homogenous than CLP, that is, only one or a few molecular pathways are deregulated among CLO patients. We previously reported on a positive association of rs987525 SNP (8q24.21) in Brazil, driven by a subpopulation of patients with the highest heritability estimates (from Barbalha; H 2 ¼ 85%) as compared to other four regions of Brazil (Santar em, Fortaleza, Macei o, and Rio de Janeiro presented H 2 ¼ 45-71%; [Brito et al, 2012]). A stratified analysis by region of origin in the present study did not reveal a strong association with any group (Supplementary eTable I-See Supporting Information online), however, we observed a trend of positive association only in the Barbalha subset (Barbalha, P ¼ 0.02; Santar em, P ¼ 0.59; Fortaleza, P ¼ 0.66; Macei o, P ¼ 0.44; Rio de Janeiro, P ¼ 0.69).…”

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

“…Similar results for rs987525 were obtained in a study on the Central European sample which showed a 1.7-fold increase in the risk of nsCL/P under the dominant inheritance model 19 . Although the association between rs987525 and the risk of nsCL/P has been replicated in numerous studies on various ethnicities [28][29][30][31] , the underlying functional mechanism remains unknown as rs987525 resides in a region of the genome containing no known genes 12 . It is possible that rs987525 or a linked causal SNP affects tissue-specific enhancers, altering the expression of one or more unspecified genes.…”

Variantes genéticas de risco às fissuras orofaciais

“…For this reason, we have used a structured association approach, which takes advantage of information on individual ancestry components of cases and controls before performing the association tests. Differently from our previous reports (Brito et al, 2012a;Brito et al, 2012c) we used here an AIM panel composed of biallelic SNPs and a larger sample set.…”

“…The association of the top-SNP rs987525 has been consistently replicated in populations from Europe (Cura et al, 2015), Central America (RojasMartinez et al, 2010), Brazil (Brito et al, 2012c) and Middle-East (Aldhorae et al, 2014).…”