title: Risk variants in BMP4 promoters for nonsyndromic cleft lip/palate in a Chilean population.
abstract: BACKGROUND
  Bone morphogenetic protein 4 gene (BMP4) plays a key role during maxillofacial development, since orofacial clefts are observed in animals when this gene is conditionally inactivated. We recently reported the existence of association between nonsyndromic cleft lip/palate (NSCLP) and BMP4 polymorphisms by detecting transmission deviations for haplotypes that include a region containing a BMP4 promoter in case-parent trios. The aim of the present study was to search for possible causal mutations within BMP4 promoters (BMP4.1 and BMP4.2).
  
  
  METHODS
  We analyzed the sequence of BMP4.1 and BMP4.2 in 167 Chilean NSCLP cases and 336 controls.
  
  
  RESULTS
  We detected three novel variants in BMP4.1 (c.-5514G > A, c.-5365C > T and c.-5049C > T) which could be considered as cleft risk factors due to their absence in controls. Additionally, rs2855530 G allele (BMP4.2) carriers showed an increased risk for NSCLP restricted to males (OR = 1.52; 95% C.I. = 1.07-2.15; p = 0.019). For this same SNP the dominant genotype model showed a higher frequency of G/G+G/C and a lower frequency of C/C in cases than controls in the total sample (p = 0.03) and in the male sample (p = 0.003). Bioinformatic prediction analysis showed that all the risk variants detected in this study could create new transcription factor binding motifs.
  
  
  CONCLUSIONS
  The sex-dependent association between rs2855530 and NSCLP could indirectly be related to the differential gene expression observed between sexes in animal models. We concluded that risk variants detected herein could potentially alter BMP4 promoter activity in NSCLP. Further functional and developmental studies are necessary to support this hypothesis.
authors.affiliation: Department of Nutrition, Diabetes and Metabolism, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile. jsuazo@med.puc.cl
authors.forename: José
authors.initials: J
authors.lastname: Suazo
authors.forename: Julio C
authors.initials: JC
authors.lastname: Tapia
authors.forename: José Luis
authors.initials: JL
authors.lastname: Santos
authors.forename: Víctor G
authors.initials: VG
authors.lastname: Castro
authors.forename: Alicia
authors.initials: A
authors.lastname: Colombo
authors.forename: Rafael
authors.initials: R
authors.lastname: Blanco
mesh_terms: D055415:Bone Morphogenetic Protein 4 / Q000235:genetics*; D002677:Chile; D002971:Cleft Lip / Q000453:epidemiology / Q000235:genetics*; D002972:Cleft Palate / Q000453:epidemiology / Q000235:genetics; D019295:Computational Biology; D005260:Female; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D012737:Sex Factors
chemical_list: C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4