Letter abstract
Nature Genetics 40, 1341 - 1347 (2008)
Published online: 5 October 2008 | doi:10.1038/ng.242
Disruption of an AP-2
binding site in an IRF6 enhancer is associated with cleft lip
Fedik Rahimov1, Mary L Marazita2, Axel Visel3, Margaret E Cooper2, Michael J Hitchler4, Michele Rubini5, Frederick E Domann4, Manika Govil2, Kaare Christensen6, Camille Bille6, Mads Melbye7, Astanand Jugessur8, Rolv T Lie8, Allen J Wilcox9, David R Fitzpatrick10, Eric D Green11, NISC Comparative Sequencing Program11, Peter A Mossey12, Julian Little13, Regine P Steegers-Theunissen14, Len A Pennacchio3, Brian C Schutte1 & Jeffrey C Murray1
Previously we have shown that nonsyndromic cleft lip with or without cleft palate (NSCL/P)1 is strongly associated with SNPs in IRF6 (interferon regulatory factor 6)2. Here, we use multispecies sequence comparisons to identify a common SNP (rs642961, G>A) in a newly identified IRF6 enhancer. The A allele is significantly overtransmitted (P = 1 
10-11) in families with NSCL/P, in particular those with cleft lip but not cleft palate. Further, there is a dosage effect of the A allele, with a relative risk for cleft lip of 1.68 for the AG genotype and 2.40 for the AA genotype. EMSA and ChIP assays demonstrate that the risk allele disrupts the binding site of transcription factor AP-2
and expression analysis in the mouse localizes the enhancer activity to craniofacial and limb structures. Our findings place IRF6 and AP-2 in the same developmental pathway and identify a high-frequency variant in a regulatory element contributing substantially to a common, complex disorder.
- Department of Pediatrics, University of Iowa, 2182 ML, S Grand Ave, Iowa City, Iowa 52242, USA.
- Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Suite 500, Bridgeside Point Building, Pittsburgh, Pennsylvania 15219, USA.
- Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.
- Department of Radiation Oncology, University of Iowa, 4202 MERF, Iowa City, Iowa 52242, USA.
- Department of Experimental Diagnostic Medicine, Medical Genetics Unit, University of Ferrara, Ferrara 44100, Italy.
- Center for the Prevention of Congenital Malformations, Institute of Public Health, University of Southern Denmark, J.B. Winsløws Vej 9B, DK-5000 Odense C, Denmark.
- Department of Epidemiology Research, Danish Epidemiology Science Center, Statens Serum Institute, Copenhagen DK-2300, Denmark.
- Section for Epidemiology and Medical Statistics, Department of Public Health and Primary Health Care, University of Bergen, Kalfarveien 31, N-5018, Bergen, Norway.
- Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T.W. Alexander Drive, Durham, North Carolina 27709, USA.
- Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, UK.
- Genome Technology Branch and US National Institutes of Health Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
- Dental Hospital & School, University of Dundee, Dundee, Scotland DD1 4HR, UK.
- Department of Epidemiology and Community Medicine, University of Ottawa, 451 Smyth Road, Room 3227, Ottawa, Ontario K1H 8M5, Canada.
- University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands.
Correspondence to: Jeffrey C Murray1 e-mail: jeff-murray@uiowa.edu
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