High incidence and geographic distribution of cleft palate in Finland are associated with the IRF6 gene.

Autor: Rahimov F; Department of Human Genetics, Genomics Research Center, AbbVie Inc, North Chicago, IL, 60064, USA., Nieminen P; Orthodontics, Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, 00014, Finland., Kumari P; Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA, 52242, USA.; Department of Oral Health Sciences, University of Washington, Seattle, WA, 98195, USA., Juuri E; Orthodontics, Department of Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, Helsinki, 00014, Finland.; Cleft Palate and Craniofacial Center, Department of Plastic Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, 00029 HUS, Finland., Nikopensius T; Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, 51010, Estonia., Paraiso K; Environmental Genomics and Systems Biology Division, Lawrence Berkeley Laboratories, Berkeley, CA, 94720, USA.; U.S. Department of Energy Joint Genome Institute, Lawrence Berkeley Laboratories, Berkeley, CA, 94720, USA., German J; Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, 00014, Finland.; Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA., Karvanen A; Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, 00014, Finland., Kals M; Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, 51010, Estonia.; Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, 00014, Finland., Elnahas AG; Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, 51010, Estonia., Karjalainen J; Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, 00014, Finland.; Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, 02114, USA., Kurki M; Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, 00014, Finland.; Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, 02114, USA., Palotie A; Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, 00014, Finland.; Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, 02114, USA., Heliövaara A; Cleft Palate and Craniofacial Center, Department of Plastic Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, 00029 HUS, Finland., Esko T; Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, 51010, Estonia., Jukarainen S; Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, 00014, Finland., Palta P; Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, 51010, Estonia.; Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, 00014, Finland., Ganna A; Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, 00014, Finland., Patni AP; Department of Oral Health Sciences, University of Washington, Seattle, WA, 98195, USA.; Department of Biochemistry, University of Washington School of Medicine, Seattle, WA, 98195, USA.; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, 98109, USA.; Cancer Biology and Stem Cell Biology Laboratory, Department of Genetic Engineering, School of Bioengineering, College of Engineering and Technology, SRM Institute of Science and Technology, Chennai, 603203, India., Mar D; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, 98109, USA.; UW Medicine South Lake Union, University of Washington, Seattle, WA, 98109, USA., Bomsztyk K; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, 98109, USA.; UW Medicine South Lake Union, University of Washington, Seattle, WA, 98109, USA.; Matchstick Technologies, Inc, Kirkland, WA, 98033, USA., Mathieu J; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, 98109, USA.; Department of Comparative Medicine, University of Washington School of Medicine, Seattle, WA, 98195, USA., Ruohola-Baker H; Department of Oral Health Sciences, University of Washington, Seattle, WA, 98195, USA.; Department of Biochemistry, University of Washington School of Medicine, Seattle, WA, 98195, USA.; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, 98109, USA.; Brotman Baty Institute for Precision Medicine, Seattle, WA, 98195, USA.; Department of Bioengineering, University of Washington, Seattle, WA, 98195, USA., Visel A; Environmental Genomics and Systems Biology Division, Lawrence Berkeley Laboratories, Berkeley, CA, 94720, USA.; U.S. Department of Energy Joint Genome Institute, Lawrence Berkeley Laboratories, Berkeley, CA, 94720, USA.; School of Natural Sciences, University of California, Merced, CA, 95343, USA., Fakhouri WD; Department of Diagnostic and Biomedical Sciences, School of Dentistry, University of Texas Health Science Center at Houston, Houston, TX, 77054, USA.; Department of Pediatrics, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA., Schutte BC; Department of Microbiology, Genetics and Immunology, College of Osteopathic Medicine, Michigan State University, East Lansing, MI, 48824, USA. schutteb@msu.edu., Cornell RA; Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA, 52242, USA. cornellr@uw.edu.; Department of Oral Health Sciences, University of Washington, Seattle, WA, 98195, USA. cornellr@uw.edu.; Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, WA, 98109, USA. cornellr@uw.edu., Rice DP; Orthodontics, Department of Oral and Maxillofacial Diseases, University of Helsinki and Helsinki University Hospital, Helsinki, 00014, Finland. david.rice@helsinki.fi.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Nov 06; Vol. 15 (1), pp. 9568. Date of Electronic Publication: 2024 Nov 06.
DOI: 10.1038/s41467-024-53634-2
Abstrakt: In Finland, the frequency of isolated cleft palate (CP) is higher than that of isolated cleft lip with or without cleft palate (CL/P). This trend contrasts to that in other European countries but its genetic underpinnings are unknown. We conducted a genome-wide association study in the Finnish population and identified rs570516915, a single nucleotide polymorphism highly enriched in Finns, as strongly associated with CP (P = 5.25 × 10 -34 , OR = 8.65, 95% CI 6.11-12.25), but not with CL/P (P = 7.2 × 10 -5 ), with genome-wide significance. The risk allele frequency of rs570516915 parallels the regional variation of CP prevalence in Finland, and the association was replicated in independent cohorts of CP cases from Finland (P = 8.82 × 10 -28 ) and Estonia (P = 1.25 × 10 -5 ). The risk allele of rs570516915 alters a conserved binding site for the transcription factor IRF6 within an enhancer (MCS-9.7) upstream of the IRF6 gene and diminishes the enhancer activity. Oral epithelial cells derived from CRISPR-Cas9 edited induced pluripotent stem cells demonstrate that the CP-associated allele of rs570516915 concomitantly decreases the binding of IRF6 and the expression level of IRF6, suggesting impaired IRF6 autoregulation as a molecular mechanism underlying the risk for CP.
(© 2024. The Author(s).)
Databáze: MEDLINE