title: Interaction between IRF6 and TGFA genes contribute to the risk of nonsyndromic cleft lip/palate.
abstract: Previous evidence from tooth agenesis studies suggested IRF6 and TGFA interact. Since tooth agenesis is commonly found in individuals with cleft lip/palate (CL/P), we used four large cohorts to evaluate if IRF6 and TGFA interaction contributes to CL/P. Markers within and flanking IRF6 and TGFA genes were tested using Taqman or SYBR green chemistries for case-control analyses in 1,000 Brazilian individuals. We looked for evidence of gene-gene interaction between IRF6 and TGFA by testing if markers associated with CL/P were overtransmitted together in the case-control Brazilian dataset and in the additional family datasets. Genotypes for an additional 142 case-parent trios from South America drawn from the Latin American Collaborative Study of Congenital Malformations (ECLAMC), 154 cases from Latvia, and 8,717 individuals from several cohorts were available for replication of tests for interaction. Tgfa and Irf6 expression at critical stages during palatogenesis was analyzed in wild type and Irf6 knockout mice. Markers in and near IRF6 and TGFA were associated with CL/P in the Brazilian cohort (p<10(-6)). IRF6 was also associated with cleft palate (CP) with impaction of permanent teeth (p<10(-6)). Statistical evidence of interaction between IRF6 and TGFA was found in all data sets (p = 0.013 for Brazilians; p = 0.046 for ECLAMC; p = 10(-6) for Latvians, and p = 0.003 for the 8,717 individuals). Tgfa was not expressed in the palatal tissues of Irf6 knockout mice. IRF6 and TGFA contribute to subsets of CL/P with specific dental anomalies. Moreover, this potential IRF6-TGFA interaction may account for as much as 1% to 10% of CL/P cases. The Irf6-knockout model further supports the evidence of IRF6-TGFA interaction found in humans.
authors.affiliation: Department of Oral Biology, University of Pittsburgh, School of Dental Medicine, Pittsburgh, PA, USA.
authors.forename: Ariadne
authors.initials: A
authors.lastname: Letra
authors.forename: Walid
authors.initials: W
authors.lastname: Fakhouri
authors.forename: Renata F
authors.initials: RF
authors.lastname: Fonseca
authors.forename: Renato
authors.initials: R
authors.lastname: Menezes
authors.forename: Inga
authors.initials: I
authors.lastname: Kempa
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Prasad
authors.forename: Toby G
authors.initials: TG
authors.lastname: McHenry
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Lidral
authors.forename: Lina
authors.initials: L
authors.lastname: Moreno
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Murray
authors.forename: Sandra
authors.initials: S
authors.lastname: Daack-Hirsch
authors.forename: Mary L
authors.initials: ML
authors.lastname: Marazita
authors.forename: Eduardo E
authors.initials: EE
authors.lastname: Castilla
authors.forename: Baiba
authors.initials: B
authors.lastname: Lace
authors.forename: Ieda M
authors.initials: IM
authors.lastname: Orioli
authors.forename: Jose M
authors.initials: JM
authors.lastname: Granjeiro
authors.forename: Brian C
authors.initials: BC
authors.lastname: Schutte
authors.forename: Alexandre R
authors.initials: AR
authors.lastname: Vieira
mesh_terms: D000818:Animals; D001938:Brazil; D002971:Cleft Lip / Q000235:genetics / Q000378:metabolism*; D002972:Cleft Palate / Q000235:genetics / Q000378:metabolism*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D015810:Linkage Disequilibrium / Q000235:genetics; D051379:Mice; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011485:Protein Binding; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D044465:White People
chemical_list: C109803:IRF6 protein, human; D050835:Interferon Regulatory Factors; D016211:Transforming Growth Factor alpha