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Interaction between IRF6 and TGFA Genes Contribute to the Risk of Nonsyndromic Cleft Lip/Palate

Letra, A and Fakhouri, W and Fonseca, RF and Menezes, R and Kempa, I and Prasad, JL and McHenry, TG and Lidral, AC and Moreno, L and Murray, JC and Daack-Hirsch, S and Marazita, ML and Castilla, EE and Lace, B and Orioli, IM and Granjeiro, JM and Schutte, BC and Vieira, AR (2012) Interaction between IRF6 and TGFA Genes Contribute to the Risk of Nonsyndromic Cleft Lip/Palate. PLoS ONE, 7 (9).

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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. © 2012 Letra et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Letra, A
Fakhouri, W
Fonseca, RF
Menezes, R
Kempa, I
Prasad, JLjlp92@pitt.eduJLP92
McHenry, TG
Lidral, AC
Moreno, L
Murray, JC
Daack-Hirsch, S
Marazita, MLmarazita@pitt.eduMARAZITA
Castilla, EE
Lace, B
Orioli, IM
Granjeiro, JM
Schutte, BC
Vieira, ARalexandre_vieira@pitt.eduARV11
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorHedges, Dale J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 20 September 2012
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 7
Number: 9
DOI or Unique Handle: 10.1371/journal.pone.0045441
Schools and Programs: Graduate School of Public Health > Human Genetics
School of Dental Medicine > Dental Science
Refereed: Yes
Other ID: NLM PMC3447924
PubMed Central ID: PMC3447924
PubMed ID: 23029012
Date Deposited: 30 Oct 2012 17:02
Last Modified: 02 Feb 2019 14:55
URI: http://d-scholarship.pitt.edu/id/eprint/15906

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