Interaction between IRF6 and TGFA genes contribute to the risk of nonsyndromic cleft lip/palate

Ariadne Letra; Walid Fakhouri; Renata F Fonseca; Renato Menezes; Inga Kempa; Joanne L Prasad; Toby G McHenry; Andrew C Lidral; Lina Moreno; Jeffrey C Murray; Sandra Daack-Hirsch; Mary L Marazita; Eduardo E Castilla; Baiba Lace; Ieda M Orioli; Jose M Granjeiro; Brian C Schutte; Alexandre R Vieira

doi:10.1371/journal.pone.0045441

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Interaction between IRF6 and TGFA genes contribute to the risk of nonsyndromic cleft lip/palate

Journal article

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Interaction between IRF6 and TGFA genes contribute to the risk of nonsyndromic cleft lip/palate

Ariadne Letra, Walid Fakhouri, Renata F Fonseca, Renato Menezes, Inga Kempa, Joanne L Prasad, Toby G McHenry, Andrew C Lidral, Lina Moreno, Jeffrey C Murray, …

PloS one, Vol.7(9), pp.e45441-e45441

2012

DOI: 10.1371/journal.pone.0045441

PMCID: PMC3447924

PMID: 23029012

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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.

Genetic Predisposition to Disease - genetics

Humans

Interferon Regulatory Factors - metabolism

Interferon Regulatory Factors - genetics

Linkage Disequilibrium - genetics

European Continental Ancestry Group

Genotype

Cleft Palate - genetics

Cleft Lip - metabolism

Transforming Growth Factor alpha - genetics

Cleft Lip - genetics

Animals

Brazil

Polymorphism, Single Nucleotide - genetics

Protein Binding

Cleft Palate - metabolism

Mice

Transforming Growth Factor alpha - metabolism

Details

Title: Subtitle: Interaction between IRF6 and TGFA genes contribute to the risk of nonsyndromic cleft lip/palate
Creators: Ariadne Letra - Department of Oral Biology, University of Pittsburgh, School of Dental Medicine, Pittsburgh, PA, USA
Walid Fakhouri
Renata F Fonseca
Renato Menezes
Inga Kempa
Joanne L Prasad
Toby G McHenry
Andrew C Lidral
Lina Moreno
Jeffrey C Murray
Sandra Daack-Hirsch
Mary L Marazita
Eduardo E Castilla
Baiba Lace
Ieda M Orioli
Jose M Granjeiro
Brian C Schutte
Alexandre R Vieira
Resource Type: Journal article
Publication Details: PloS one, Vol.7(9), pp.e45441-e45441
DOI: 10.1371/journal.pone.0045441
PMID: 23029012
PMCID: PMC3447924
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: Public Library of Science; United States
Grant note: R01 DE014899 / NIDCR NIH HHS R01-DE14899 / NIDCR NIH HHS R01 DE016148 / NIDCR NIH HHS R01 DE008559 / NIDCR NIH HHS K99 018954-01 / PHS HHS R37 DE008559 / NIDCR NIH HHS R01-DE16148 / NIDCR NIH HHS K99 018913-02 / PHS HHS R21-DE016718 / NIDCR NIH HHS R21 DE016718 / NIDCR NIH HHS R01 DE013513 / NIDCR NIH HHS
Language: English
Date published: 2012
Academic Unit: Orthodontics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Pediatric Dentistry; Craniofacial Anomalies Research Center; Nursing; Fraternal Order of Eagles Diabetes Research Center; Public Policy Center (Archive); Dental Research
Record Identifier: 9984025424002771

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