title: Haplotype-based gene-gene interaction of bone morphogenetic protein 4 and interferon regulatory factor 6 in the etiology of non-syndromic cleft lip with or without cleft palate in a Chilean population.
abstract: Non-syndromic cleft lip with or without cleft palate (NSCL/P) is the most common craniofacial birth defect in humans, the etiology of which can be dependent on the interactions of multiple genes. We previously reported haplotype associations for polymorphic variants of interferon regulatory factor 6 (IRF6), msh homeobox 1 (MSX1), bone morphogenetic protein 4 (BMP4), and transforming growth factor beta 3 (TGFB3) in Chile. Here, we analyzed the haplotype-based gene-gene interaction for markers of these genes and NSCL/P risk in the Chilean population. We genotyped 15 single nucleoptide polymorphisms (SNPs) in 152 Chilean patients and 164 controls. Linkage disequilibrium (LD) blocks were determined using the Haploview software, and phase reconstruction was performed by the Phase program. Haplotype-based interactions were evaluated using the multifactor dimensionality reduction (MDR) method. We detected two LD blocks composed of two SNPs from BMP4 (Block 1) and three SNPs from IRF6 (Block 2). Although MDR showed no statistical significance for the global interaction model involving these blocks, we found four combinations conferring a statistically significantly increased NSCL/P risk (Block 1-Block 2): T-T/T-G C-G-T/G-A-T; T-T/T-G C-G-C/C-G-C; T-T/T-G G-A-T/G-A-T; and T-T/C-G G-A-T/G-A-T. These findings may reflect the presence of a genomic region containing potential causal variants interacting in the etiology of NSCL/P and may contribute to disentangling the complex etiology of this birth defect.
authors.affiliation: Programa de Genética Humana, Instituto de Ciencias Biomédica, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Rafael
authors.initials: R
authors.lastname: Blanco
authors.affiliation: Programa de Anatomía y Biología del Desarrollo, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.|Servicio de Anatomía Patológica, Hospital Clínico Universidad de Chile, Santiago, Chile.
authors.forename: Alicia
authors.initials: A
authors.lastname: Colombo
authors.affiliation: Sección de Genética, Hospital Clínico Universidad de Chile, Santiago, Chile.|Unidad de Neonatología, Hospital Clínico Universidad de Chile, Santiago, Chile.|Unidad de Genética, Hospital Dr. Sótero del Río, Santiago, Chile.
authors.forename: Rosa
authors.initials: R
authors.lastname: Pardo
authors.affiliation: Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología, Universidad de Chile, Santiago, Chile.
authors.forename: José
authors.initials: J
authors.lastname: Suazo
mesh_terms: D000483:Alleles; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics*; D002677:Chile; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide
chemical_list: D055415:Bone Morphogenetic Protein 4; C109803:IRF6 protein, human; D050835:Interferon Regulatory Factors
keywords: haplotype association; multifactor dimensionality reduction; orofacial clefts