Human Molecular Genetics Advance Access published online on June 22, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm150
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The coding polymorphism T263I in TGF-ß1 is associated with otosclerosis in two independent populations
1 Department of Medical Genetics, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium 2 Molecular Otolaryngology Research Laboratories, Department of Otolaryngology, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA 3 Laboratoire de Genetique Moleculaire et chromosomique CHU, IURC Montpellier, 641 avenue du Doyen Gaston Giraud, 34093 Montpellier Cedex 5, France 4 Department of Otorhinolaryngology, University Medical Centre St Radboud, Philips van Leydenlaan 15, 6500 HB Nijmegen, The Netherlands 5 Department of Otorhinolaryngology, University Hospital of Ghent, De Pintelaan 185, 9000 Ghent, Belgium 6 Department of ORL, University Hospital of Antwerp, Wilrijkstraat 10, 2650 Edegem, Belgium 7 Jean Causse Ear Clinic, Traverse de Béziers, 34440 Colombiers, France 8 University Department of Otolaryngology, St-Augustinus Hospital Antwerp, Oosterveldlaan 24, 2610 Antwerp, Belgium 9 Present address: European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany 10 Present address: Stem Cell Institute Leuven (SCIL), Catholic University Leuven, Herestraat 49, 3000 Leuven, Belgium
* Corresponding author: Guy Van Camp Department of Medical Genetics, University of Antwerp Universiteitsplein 1, 2610 Wilrijk, Belgium, Tel: +323 820 2491, Fax: +323 820 2566, Email: Guy.VanCamp{at}ua.ac.be
Received May 8, 2007; Revised June 8, 2007; Accepted June 8, 2007
Otosclerosis is a progressive hearing loss characterized by an abnormal bone homeostasis of the otic capsule that leads to stapes fixation. Although its etiology remains unknown, otosclerosis can be considered a complex disease. Transforming growth factor beta 1 (TGF-ß1) was chosen for a case-control association study, because of several non-genetic indications of involvement in otosclerosis. SNP analysis in a large Belgian-Dutch sample set gave significant results (p = 0.0044) for an amino acid changing SNP, T263I. Analysis of an independent French population replicated this association with SNP T263I (p = 0.00019). The results remained significant after multiple testing correction in both populations. Haplotype analysis and the results of an independent effect test using WHAP in both populations were both compatible with SNP T263I being the only causal variant. The variant I263 is underrepresented in otosclerosis patients and hence protective against the disease. Combining the data of both case-control groups for SNP T263I with a Mantel-Haenszel estimate of common odds ratios gave a very significant result (p = 9.2 x 10). Functional analysis of SNP T263I with a luciferase reporter assay showed that the protective variant I263 of TGF-ß1 is more active than the WT variant T263 (p = 1.6 x 10–6). On the basis of very low p-values, replication in an independent population and a functional effect of the protective variant, we conclude that TGFB1 influences the susceptibility for otosclerosis, and that the I263 variant is protective against the disease.
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